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Ependymoma classification

2019-06-27T17:33:04Z

Kamal Akbar: /* Overview */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]]<ref name="pmid26251794">{{cite journal| author=Sarıkafa Ş, Çelik SE, Yarikkaya E, Sayılgan A| title=Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. | journal=J Neurol Surg Rep | year= 2015 | volume= 76 | issue= 1 | pages= e151-5 | pmid=26251794 | doi=10.1055/s-0035-1549311 | pmc=4520988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26251794 }} </ref>.
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas<ref name="pmid26425155">{{cite journal| author=Mangalore S, Aryan S, Prasad C, Santosh V| title=Imaging characteristics of supratentorial ependymomas: Study on a large single institutional cohort with histopathological correlation. | journal=Asian J Neurosurg | year= 2015 | volume= 10 | issue= 4 | pages= 276-81 | pmid=26425155 | doi=10.4103/1793-5482.162702 | pmc=4558802 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26425155 }} </ref>
:*[[Infratentorial]] ependymomas<ref name="pmid25822933">{{cite journal| author=Mandera M, Makarska J, Sobol G, Musioł K| title=Infratentorial ependymomas--a study of the centre in Katowice. | journal=Childs Nerv Syst | year= 2015 | volume= 31 | issue= 7 | pages= 1089-96 | pmid=25822933 | doi=10.1007/s00381-015-2683-9 | pmc=4493855 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25822933 }} </ref>
:*[[Spinal cord]] ependymomas<ref name="pmid20511182">{{cite journal| author=Armstrong TS, Vera-Bolanos E, Bekele BN, Aldape K, Gilbert MR| title=Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 8 | pages= 862-70 | pmid=20511182 | doi=10.1093/neuonc/noq009 | pmc=2940672 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20511182 }} </ref>

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:32:20Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]]<ref name="pmid26251794">{{cite journal| author=Sarıkafa Ş, Çelik SE, Yarikkaya E, Sayılgan A| title=Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. | journal=J Neurol Surg Rep | year= 2015 | volume= 76 | issue= 1 | pages= e151-5 | pmid=26251794 | doi=10.1055/s-0035-1549311 | pmc=4520988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26251794 }} </ref>.
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas<ref name="pmid26425155">{{cite journal| author=Mangalore S, Aryan S, Prasad C, Santosh V| title=Imaging characteristics of supratentorial ependymomas: Study on a large single institutional cohort with histopathological correlation. | journal=Asian J Neurosurg | year= 2015 | volume= 10 | issue= 4 | pages= 276-81 | pmid=26425155 | doi=10.4103/1793-5482.162702 | pmc=4558802 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26425155 }} </ref>
:*[[Infratentorial]] ependymomas<ref name="pmid25822933">{{cite journal| author=Mandera M, Makarska J, Sobol G, Musioł K| title=Infratentorial ependymomas--a study of the centre in Katowice. | journal=Childs Nerv Syst | year= 2015 | volume= 31 | issue= 7 | pages= 1089-96 | pmid=25822933 | doi=10.1007/s00381-015-2683-9 | pmc=4493855 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25822933 }} </ref>
:*[[Spinal cord]] ependymomas<ref name="pmid20511182">{{cite journal| author=Armstrong TS, Vera-Bolanos E, Bekele BN, Aldape K, Gilbert MR| title=Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 8 | pages= 862-70 | pmid=20511182 | doi=10.1093/neuonc/noq009 | pmc=2940672 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20511182 }} </ref>

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:29:47Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]]<ref name="pmid26251794">{{cite journal| author=Sarıkafa Ş, Çelik SE, Yarikkaya E, Sayılgan A| title=Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. | journal=J Neurol Surg Rep | year= 2015 | volume= 76 | issue= 1 | pages= e151-5 | pmid=26251794 | doi=10.1055/s-0035-1549311 | pmc=4520988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26251794 }} </ref>.
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas<ref name="pmid26425155">{{cite journal| author=Mangalore S, Aryan S, Prasad C, Santosh V| title=Imaging characteristics of supratentorial ependymomas: Study on a large single institutional cohort with histopathological correlation. | journal=Asian J Neurosurg | year= 2015 | volume= 10 | issue= 4 | pages= 276-81 | pmid=26425155 | doi=10.4103/1793-5482.162702 | pmc=4558802 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26425155 }} </ref>
:*[[Infratentorial]] ependymomas<ref name="pmid25822933">{{cite journal| author=Mandera M, Makarska J, Sobol G, Musioł K| title=Infratentorial ependymomas--a study of the centre in Katowice. | journal=Childs Nerv Syst | year= 2015 | volume= 31 | issue= 7 | pages= 1089-96 | pmid=25822933 | doi=10.1007/s00381-015-2683-9 | pmc=4493855 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25822933 }} </ref>
:*[[Spinal cord]] ependymomas

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:28:25Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]]<ref name="pmid26251794">{{cite journal| author=Sarıkafa Ş, Çelik SE, Yarikkaya E, Sayılgan A| title=Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. | journal=J Neurol Surg Rep | year= 2015 | volume= 76 | issue= 1 | pages= e151-5 | pmid=26251794 | doi=10.1055/s-0035-1549311 | pmc=4520988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26251794 }} </ref>.
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas<ref name="pmid26425155">{{cite journal| author=Mangalore S, Aryan S, Prasad C, Santosh V| title=Imaging characteristics of supratentorial ependymomas: Study on a large single institutional cohort with histopathological correlation. | journal=Asian J Neurosurg | year= 2015 | volume= 10 | issue= 4 | pages= 276-81 | pmid=26425155 | doi=10.4103/1793-5482.162702 | pmc=4558802 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26425155 }} </ref>
:*[[Infratentorial]] ependymomas
:*[[Spinal cord]] ependymomas

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:26:04Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]]<ref name="pmid26251794">{{cite journal| author=Sarıkafa Ş, Çelik SE, Yarikkaya E, Sayılgan A| title=Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. | journal=J Neurol Surg Rep | year= 2015 | volume= 76 | issue= 1 | pages= e151-5 | pmid=26251794 | doi=10.1055/s-0035-1549311 | pmc=4520988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26251794 }} </ref>.
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas
:*[[Infratentorial]] ependymomas
:*[[Spinal cord]] ependymomas

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:24:21Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid26755489">{{cite journal| author=Tomek M, Jayajothi A, Brandner S, Jaunmuktane Z, Lee CH, Davagnanam I| title=Imaging features of spinal tanycytic ependymoma. | journal=Neuroradiol J | year= 2016 | volume= 29 | issue= 1 | pages= 61-5 | pmid=26755489 | doi=10.1177/1971400915621322 | pmc=4978340 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755489 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]].
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas
:*[[Infratentorial]] ependymomas
:*[[Spinal cord]] ependymomas

==References==
{{reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Neurology]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Neurology]]
[[Category:Neurosurgery]]

Ependymoma classification

2019-06-27T17:22:47Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]].
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas
:*[[Infratentorial]] ependymomas
:*[[Spinal cord]] ependymomas

==References==
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Ependymoma classification

2019-06-27T17:20:05Z

Kamal Akbar: /* Classification */

__NOTOC__
{{Ependymoma}}
{{CMG}}{{AE}} {{AAM}}
==Overview==
Ependymoma may be classified into several subtypes based on [[WHO]] classification (grade I, II, III) and the site of origin.<ref name=radio>.Ependymomas Dr Bruno Di Muzio and Dr Frank Gaillard Gold Supporter since June 24, 2015">. Radiopaedia.org 2015.http://radiopaedia.org/articles/ependymoma</ref>

==Classification==

*In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into the following four main subtypes:<ref name=Luois>Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.</ref><ref name=Cancergove> Eoendymoma. http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_35 URL Accessed on 10 6 2015.</ref>

:*Subependymoma (WHO grade I): a subependymoma is a slow-growing neoplasm, usually attached to the ventricle wall and is composed of [[Glial cell|glial tumor cell clusters]] ingrained in a [[matrix|fibrillary matrix]].<ref name="pmid25973126">{{cite journal| author=Huang Y| title=Subependymoma with extensive microcystic transformation: a case report. | journal=Int J Clin Exp Pathol | year= 2015 | volume= 8 | issue= 2 | pages= 2191-4 | pmid=25973126 | doi= | pmc=4396238 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25973126 }} </ref>

:*Myxopapillary ependymoma (WHO grade I): a myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.<ref name="pmid25301811">{{cite journal| author=Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A et al.| title=Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. | journal=Neuro Oncol | year= 2015 | volume= 17 | issue= 4 | pages= 588-95 | pmid=25301811 | doi=10.1093/neuonc/nou293 | pmc=4483075 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25301811 }} </ref>

:*Ependymoma (WHO grade II): the ependymoma, which is considered a grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on [[histological]] findings, into the following four subtypes<ref name="pmid16794247">{{cite journal| author=Grier JT, Batchelor T| title=Low-grade gliomas in adults. | journal=Oncologist | year= 2006 | volume= 11 | issue= 6 | pages= 681-93 | pmid=16794247 | doi=10.1634/theoncologist.11-6-681 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16794247 }} </ref>:

::*[[Cellular]] ependymoma: the most common subtype, this subtype usually demonstrates significant cellularity without an increase in mitotic activity<ref name="pmid27022130">{{cite journal| author=Wu J, Armstrong TS, Gilbert MR| title=Biology and management of ependymomas. | journal=Neuro Oncol | year= 2016 | volume= 18 | issue= 7 | pages= 902-13 | pmid=27022130 | doi=10.1093/neuonc/now016 | pmc=4896548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27022130 }} </ref>.
::*[[Papillary]] ependymoma: forms linear, [[epithelial|epithelial-like]] surfaces along [[cerebrospinal fluid]].
::*[[Clear cell]] ependymoma: displays an [[oligodendroglia|oligodendroglial-like]] appearance with perinuclear halos, this variant is preferentially located in the [[supratentorial]] compartment of the [[brain]]<ref name="pmid22102956">{{cite journal| author=Lee BH, Kwon JT, Park YS| title=Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 3 | pages= 240-3 | pmid=22102956 | doi=10.3340/jkns.2011.50.3.240 | pmc=3218185 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102956 }} </ref>.
::*Tanycytic ependymoma: the rarest form of grade II ependymoma, this subtype is most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and are poorly intertwined.
:*[[Anaplastic]] ependymoma (WHO grade III): also known as malignant ependymoma. An anaplastic ependymoma is considered a malignant [[glioma]] of ependymal differentiation and, compared with the grade II ependymomas, shows increased cellularity and increased mitotic activity. It is often associated with [[microvascular]] proliferation and [[necrosis]].
*Ependymal tumors are also classified based on their sites of origin into:<ref name=Cancergove> Eoendymoma.http://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq#section/_40 URL Accessed on 10 6 2015.</ref><ref name="pmid20615923">{{cite journal| author=Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C et al.| title=Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. | journal=Neuro Oncol | year= 2010 | volume= 12 | issue= 11 | pages= 1126-34 | pmid=20615923 | doi=10.1093/neuonc/noq074 | pmc=PMC3098029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20615923 }} </ref>
:*[[Supratentorial]] ependymomas
:*[[Infratentorial]] ependymomas
:*[[Spinal cord]] ependymomas

==References==
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Ependymoma classification

2019-06-27T16:40:37Z

Kamal Akbar: /* Classification */

Ependymoma classification

2019-06-27T16:37:51Z

Kamal Akbar: /* Classification */

Ependymoma classification

2019-06-26T20:38:38Z

Kamal Akbar: /* Classification */

Ependymoma classification

2019-06-26T20:36:11Z

Kamal Akbar: /* Classification */

Ependymoma classification

2019-06-26T19:35:34Z

Kamal Akbar:

Ependymoma historical perspective

2019-06-26T18:06:26Z

Kamal Akbar:

__NOTOC__
{{Ependymoma}}
{{CMG}}; {{AE}}

==Overview==
==Historical Perspective==

===Discovery===
* There is limited information about the historical perspective of [disease name].
OR
*[Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event].

*The association between [important risk factor/cause] and [disease name] was made in/during [year/event].
*In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].
*In [year], [gene] mutations were first implicated in the pathogenesis of [disease name].

===Landmark Events in the Development of Treatment Strategies===

===Impact on Cultural History===

===Famous Cases===
The following are a few famous cases of [disease name]:

==References==
{{reflist|2}}

[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Rare diseases]]
[[Category:Needs content]]
[[Category:Neurology]]

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Acute lymphoblastic leukemia pathophysiology

2019-04-02T17:59:36Z

Kamal Akbar: /* Pathogenesis */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors<ref name="LucAnderson2008">{{cite journal|last1=Luc|first1=S.|last2=Anderson|first2=K.|last3=Kharazi|first3=S.|last4=Buza-Vidas|first4=N.|last5=Boiers|first5=C.|last6=Jensen|first6=C. T.|last7=Ma|first7=Z.|last8=Wittmann|first8=L.|last9=Jacobsen|first9=S. E. W.|title=Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential|journal=Blood|volume=111|issue=7|year=2008|pages=3424–3434|issn=0006-4971|doi=10.1182/blood-2007-08-108324}}</ref>
**Common lymphoid progenitors<ref name="ManssonZandi2009">{{cite journal|last1=Mansson|first1=R.|last2=Zandi|first2=S.|last3=Welinder|first3=E.|last4=Tsapogas|first4=P.|last5=Sakaguchi|first5=N.|last6=Bryder|first6=D.|last7=Sigvardsson|first7=M.|title=Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity|journal=Blood|volume=115|issue=13|year=2009|pages=2601–2609|issn=0006-4971|doi=10.1182/blood-2009-08-236398}}</ref>
**Pro–B cells<ref name="Bertrand2001">{{cite journal|last1=Bertrand|first1=F. E.|title=Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein|journal=Blood|volume=98|issue=12|year=2001|pages=3398–3405|issn=00064971|doi=10.1182/blood.V98.12.3398}}</ref>
**Pre–B cells<ref name="PattonPlumb2014">{{cite journal|last1=Patton|first1=Daniel T.|last2=Plumb|first2=Adam W.|last3=Abraham|first3=Ninan|title=The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449|journal=The Journal of Immunology|volume=193|issue=7|year=2014|pages=3446–3455|issn=0022-1767|doi=10.4049/jimmunol.1302925}}</ref>
**Mature B cells<ref name="BurgerGhia2009">{{cite journal|last1=Burger|first1=J. A.|last2=Ghia|first2=P.|last3=Rosenwald|first3=A.|last4=Caligaris-Cappio|first4=F.|title=The microenvironment in mature B-cell malignancies: a target for new treatment strategies|journal=Blood|volume=114|issue=16|year=2009|pages=3367–3375|issn=0006-4971|doi=10.1182/blood-2009-06-225326}}</ref>
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis<ref name="SaitakisDogniaux2017">{{cite journal|last1=Saitakis|first1=Michael|last2=Dogniaux|first2=Stéphanie|last3=Goudot|first3=Christel|last4=Bufi|first4=Nathalie|last5=Asnacios|first5=Sophie|last6=Maurin|first6=Mathieu|last7=Randriamampita|first7=Clotilde|last8=Asnacios|first8=Atef|last9=Hivroz|first9=Claire|title=Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity|journal=eLife|volume=6|year=2017|issn=2050-084X|doi=10.7554/eLife.23190}}</ref>
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity<ref name="pmid360370">{{cite journal| author=Haneberg B, Wesenberg F, Aarskog D| title=Lymphocyte multiplication in vitro induced by mitogens and antigens. | journal=Scand J Immunol | year= 1978 | volume= 8 | issue= 1 | pages= 9-13 | pmid=360370 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=360370 }} </ref>
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells<ref name="pmid24292902">{{cite journal| author=Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM| title=T cell responses: naive to memory and everything in between. | journal=Adv Physiol Educ | year= 2013 | volume= 37 | issue= 4 | pages= 273-83 | pmid=24292902 | doi=10.1152/advan.00066.2013 | pmc=4089090 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24292902 }} </ref>

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known<ref name="pmid22326931">{{cite journal| author=Wiemels J| title=Perspectives on the causes of childhood leukemia. | journal=Chem Biol Interact | year= 2012 | volume= 196 | issue= 3 | pages= 59-67 | pmid=22326931 | doi=10.1016/j.cbi.2012.01.007 | pmc=3839796 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22326931 }} </ref>
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T17:57:10Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors<ref name="LucAnderson2008">{{cite journal|last1=Luc|first1=S.|last2=Anderson|first2=K.|last3=Kharazi|first3=S.|last4=Buza-Vidas|first4=N.|last5=Boiers|first5=C.|last6=Jensen|first6=C. T.|last7=Ma|first7=Z.|last8=Wittmann|first8=L.|last9=Jacobsen|first9=S. E. W.|title=Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential|journal=Blood|volume=111|issue=7|year=2008|pages=3424–3434|issn=0006-4971|doi=10.1182/blood-2007-08-108324}}</ref>
**Common lymphoid progenitors<ref name="ManssonZandi2009">{{cite journal|last1=Mansson|first1=R.|last2=Zandi|first2=S.|last3=Welinder|first3=E.|last4=Tsapogas|first4=P.|last5=Sakaguchi|first5=N.|last6=Bryder|first6=D.|last7=Sigvardsson|first7=M.|title=Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity|journal=Blood|volume=115|issue=13|year=2009|pages=2601–2609|issn=0006-4971|doi=10.1182/blood-2009-08-236398}}</ref>
**Pro–B cells<ref name="Bertrand2001">{{cite journal|last1=Bertrand|first1=F. E.|title=Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein|journal=Blood|volume=98|issue=12|year=2001|pages=3398–3405|issn=00064971|doi=10.1182/blood.V98.12.3398}}</ref>
**Pre–B cells<ref name="PattonPlumb2014">{{cite journal|last1=Patton|first1=Daniel T.|last2=Plumb|first2=Adam W.|last3=Abraham|first3=Ninan|title=The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449|journal=The Journal of Immunology|volume=193|issue=7|year=2014|pages=3446–3455|issn=0022-1767|doi=10.4049/jimmunol.1302925}}</ref>
**Mature B cells<ref name="BurgerGhia2009">{{cite journal|last1=Burger|first1=J. A.|last2=Ghia|first2=P.|last3=Rosenwald|first3=A.|last4=Caligaris-Cappio|first4=F.|title=The microenvironment in mature B-cell malignancies: a target for new treatment strategies|journal=Blood|volume=114|issue=16|year=2009|pages=3367–3375|issn=0006-4971|doi=10.1182/blood-2009-06-225326}}</ref>
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis<ref name="SaitakisDogniaux2017">{{cite journal|last1=Saitakis|first1=Michael|last2=Dogniaux|first2=Stéphanie|last3=Goudot|first3=Christel|last4=Bufi|first4=Nathalie|last5=Asnacios|first5=Sophie|last6=Maurin|first6=Mathieu|last7=Randriamampita|first7=Clotilde|last8=Asnacios|first8=Atef|last9=Hivroz|first9=Claire|title=Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity|journal=eLife|volume=6|year=2017|issn=2050-084X|doi=10.7554/eLife.23190}}</ref>
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity<ref name="pmid360370">{{cite journal| author=Haneberg B, Wesenberg F, Aarskog D| title=Lymphocyte multiplication in vitro induced by mitogens and antigens. | journal=Scand J Immunol | year= 1978 | volume= 8 | issue= 1 | pages= 9-13 | pmid=360370 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=360370 }} </ref>
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells<ref name="pmid24292902">{{cite journal| author=Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM| title=T cell responses: naive to memory and everything in between. | journal=Adv Physiol Educ | year= 2013 | volume= 37 | issue= 4 | pages= 273-83 | pmid=24292902 | doi=10.1152/advan.00066.2013 | pmc=4089090 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24292902 }} </ref>

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T17:52:09Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis<ref name="SaitakisDogniaux2017">{{cite journal|last1=Saitakis|first1=Michael|last2=Dogniaux|first2=Stéphanie|last3=Goudot|first3=Christel|last4=Bufi|first4=Nathalie|last5=Asnacios|first5=Sophie|last6=Maurin|first6=Mathieu|last7=Randriamampita|first7=Clotilde|last8=Asnacios|first8=Atef|last9=Hivroz|first9=Claire|title=Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity|journal=eLife|volume=6|year=2017|issn=2050-084X|doi=10.7554/eLife.23190}}</ref>
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity<ref name="pmid360370">{{cite journal| author=Haneberg B, Wesenberg F, Aarskog D| title=Lymphocyte multiplication in vitro induced by mitogens and antigens. | journal=Scand J Immunol | year= 1978 | volume= 8 | issue= 1 | pages= 9-13 | pmid=360370 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=360370 }} </ref>
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells<ref name="pmid24292902">{{cite journal| author=Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM| title=T cell responses: naive to memory and everything in between. | journal=Adv Physiol Educ | year= 2013 | volume= 37 | issue= 4 | pages= 273-83 | pmid=24292902 | doi=10.1152/advan.00066.2013 | pmc=4089090 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24292902 }} </ref>

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T17:50:49Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis<ref name="SaitakisDogniaux2017">{{cite journal|last1=Saitakis|first1=Michael|last2=Dogniaux|first2=Stéphanie|last3=Goudot|first3=Christel|last4=Bufi|first4=Nathalie|last5=Asnacios|first5=Sophie|last6=Maurin|first6=Mathieu|last7=Randriamampita|first7=Clotilde|last8=Asnacios|first8=Atef|last9=Hivroz|first9=Claire|title=Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity|journal=eLife|volume=6|year=2017|issn=2050-084X|doi=10.7554/eLife.23190}}</ref>
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity<ref name="pmid360370">{{cite journal| author=Haneberg B, Wesenberg F, Aarskog D| title=Lymphocyte multiplication in vitro induced by mitogens and antigens. | journal=Scand J Immunol | year= 1978 | volume= 8 | issue= 1 | pages= 9-13 | pmid=360370 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=360370 }} </ref>
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T17:49:18Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis<ref name="SaitakisDogniaux2017">{{cite journal|last1=Saitakis|first1=Michael|last2=Dogniaux|first2=Stéphanie|last3=Goudot|first3=Christel|last4=Bufi|first4=Nathalie|last5=Asnacios|first5=Sophie|last6=Maurin|first6=Mathieu|last7=Randriamampita|first7=Clotilde|last8=Asnacios|first8=Atef|last9=Hivroz|first9=Claire|title=Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity|journal=eLife|volume=6|year=2017|issn=2050-084X|doi=10.7554/eLife.23190}}</ref>
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T14:12:47Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology<ref name="DaveyWillcox2018">{{cite journal|last1=Davey|first1=Martin S.|last2=Willcox|first2=Carrie R.|last3=Baker|first3=Alfie T.|last4=Hunter|first4=Stuart|last5=Willcox|first5=Benjamin E.|title=Recasting Human Vδ1 Lymphocytes in an Adaptive Role|journal=Trends in Immunology|volume=39|issue=6|year=2018|pages=446–459|issn=14714906|doi=10.1016/j.it.2018.03.003}}</ref>
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T14:09:27Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:<ref name="pmid26700440">{{cite journal| author=Hoffman W, Lakkis FG, Chalasani G| title=B Cells, Antibodies, and More. | journal=Clin J Am Soc Nephrol | year= 2016 | volume= 11 | issue= 1 | pages= 137-54 | pmid=26700440 | doi=10.2215/CJN.09430915 | pmc=4702236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26700440 }} </ref>
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction<ref name="pmid26015501">{{cite journal| author=Gao R, Stock AM| title=Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. | journal=MBio | year= 2015 | volume= 6 | issue= 3 | pages= e00686-15 | pmid=26015501 | doi=10.1128/mBio.00686-15 | pmc=4447250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26015501 }} </ref>
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-04-02T14:01:11Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process<ref name="pmid27763252">{{cite journal| author=Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J et al.| title=Myeloid Cell Origins, Differentiation, and Clinical Implications. | journal=Microbiol Spectr | year= 2016 | volume= 4 | issue= 5 | pages= | pmid=27763252 | doi=10.1128/microbiolspec.MCHD-0031-2016 | pmc=5119546 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27763252 }} </ref>
*In the development of B cells, which includes development initiated at the level of the following cells:
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-03-05T21:07:22Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process
*In the development of B cells, which includes development initiated at the level of the following cells:
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**Chemicals
**Drugs
**Radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**Hyperdiploidy (>50 chromosomes)
**Hypodiploidy (<44 chromosomes)
**[[Chromosomal translocation|Translocations]] t{[12;21], [1;19], [9;22], [4;11]}
**Rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, [[Tumor suppressor gene|tumor suppression]] and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal [[Deletion (genetics)|deletions]], limited to one or few genes that take part in normal lymphoid development:
**[[Transcriptional regulation|Transcriptional]] regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**[[Tumor suppressor gene|Tumor suppressors]] (CDKN2A, CDKN2B, RB1, TP53)
**Lymphoid signaling genes (BTLA, CD200 TOX)
**[[Transcriptional regulation|Transcriptional regulators]] and [[Coactivator (genetics)|coactivators]] (TBL1XR1, ERG)
**Regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of [[NOTCH1]] and rearrangements of transcription factors which are the follwoing
**[[TLX1]] (HOX11)
**[[TLX3]] (HOX11L2)
**[[LYL1]]
**[[TAL1]]
**[[MLL (gene)|MLL]]

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**[[Cytokine receptor]] and [[Ras|Ras signaling]]
**[[Tumor suppressor gene|Tumor suppression]]
**Lymphoid development
**Epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*[[BCR/ABL|BCR-ABL1]]-like acute lymphoblastic leukemia has the gene expression signature similar to that of [[BCR/ABL|BCR-ABL1]] acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**[[IKZF1]]
**[[PAX5]]
**[[VPREB1]]
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia pathophysiology

2019-03-05T20:55:39Z

Kamal Akbar: /* Physiology */

<div style="-webkit-user-select: none;">
{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=itkRVTqfPsE|350}}
|-
|}
__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{AE}} {{RT}}{{SM}} {{CLG}}
== Overview ==
Acute lymphoid leukemia arises from [[lymphoblasts]], which are hematologic white cells that are normally involved in the [[hematopoiesis]]. [[Chromosomal translocations]] involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) ''BCR-ABL1'', translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) ''TEL-AML1'', translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)''IL3-IGH'' and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) ''TCF3-PBX1''.

== Pathophysiology ==
===Physiology===
The normal physiology of lymphoblast formation can be understood as follows:<ref name="pmid25184049">{{cite journal| author=Zuckerman T, Rowe JM| title=Pathogenesis and prognostication in acute lymphoblastic leukemia. | journal=F1000Prime Rep | year= 2014 | volume= 6 | issue= | pages= 59 | pmid=25184049 | doi=10.12703/P6-59 | pmc=4108947 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25184049 }} </ref>
*Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process
*In the development of B cells, which includes development initiated at the level of the following cells:
**Lymphoid-primed multipotent progenitors
**Common lymphoid progenitors
**Pro–B cells
**Pre–B cells
**Mature B cells
*This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction
*A lymphoblast is a altered naive lymphocyte with recasted cell morphology
*This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
*The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
*Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.

===Pathogenesis===
*The cause of most acute lymphoblastic leukemia is not known
*In general, cancer is caused by damage to [[Deoxyribonucleic Acid|DNA]] that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
*This damage may be caused by environmental factors such as:<ref name="pmid23523389">{{cite journal |vauthors=Inaba H, Greaves M, Mullighan CG |title=Acute lymphoblastic leukaemia |journal=Lancet |volume=381 |issue=9881 |pages=1943–55 |date=June 2013 |pmid=23523389 |pmc=3816716 |doi=10.1016/S0140-6736(12)62187-4 |url=}}</ref>
**chemicals
**drugs
**radiation
*In leukemias including acute lymphoblastic leukemia, [[chromosomal translocation]] occur regularly
*It is thought that most translocations occur before birth during fetal development
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia.
*It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
**hyperdiploidy (>50 chromosomes)
**hypodiploidy (<44 chromosomes)
**translocations t{[12;21], [1;19], [9;22], [4;11]}
**rearrangements (MYC, MLL)
*However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
*For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
*Many of these genes are encoding proteins with key roles in lymphoid development
*It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to formation of the leukemic clone
*Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
*More than 50 recurring regions of DNA copy number changes have been discovered
*They are commonly focal deletions, limited to one or few genes that take part in normal lymphoid development:
**transcriptional regulators of lymphoid development(PAX5, IKZF1, EBF1, LEF1)
**tumor suppressors (CDKN2A, CDKN2B, RB1, TP53)
**lymphoid signaling genes (BTLA, CD200 TOX)
**transcriptional regulators and coactivators (TBL1XR1, ERG)
**regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP)
*T-lineage acute lymphoblastic leukemia is understood as activated mutations of NOTCH1 and rearrangements of transcription factors which are the follwoing
**TLX1 (HOX11)
**TLX3 (HOX11L2)
**LYL1
**TAL1
**MLL

*Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
**cytokine receptor and Ras signaling
**tumor suppression
**lymphoid development
**epigenetic regulation
*The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

===BCR-ABL1-like B-ALL and IKZF1 transformation===
*BCR-ABL1-like acute lymphoblastic leukemia has the gene expression signature similar to that of BCR-ABL1 acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
*More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
**IKZF1
**PAX5
**VPREB1
*The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia
===CRLF2 over expression and JAK mutations===
*Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping

*Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
*The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
**Cytokine
**Chemokine
**Growth factor receptors
*Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
*These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
*Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .
===Hypodiploid acute lymphoblastic leukemia===
Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:
*Near-haploid cases with 24 to 31 chromosomes
*Low-hypodiploid cases with 32 to 39 chromosomes

*There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
*A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
*In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
**TP53 (91.2%)
**IKZF2 (53%)
**RB1 (41%)
*Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia
===T cell acute lymphoblastic leukemia===
*T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
*As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
*The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor

*Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
*Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
**Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
**Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
**Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
*The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
*Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
*Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
*Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated
===WHO and FAB classification===
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:

:*B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), ''BCR-ABL1''
:*B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
:*B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) ''TEL-AML1'' (ETV6-RUNX1)
:*B lymphoblastic leukemia/lymphoma with hyperdiploidy
:*B lymphoblastic leukemia/lymphoma with hypodiploidy
:*B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) ''IL3-IGH''
:*B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) ''TCF3-PBX1''

*According with the [[French-American-British classification | French-American-British (FAB) classification]] of acute lymphoblastic leukemia is divided into 3 subtypes:
**ALL-L1: small uniform cells
**ALL-L2: large varied cells
**ALL-L3: large varied cells with [[vacuole]]s (bubble-like features)

*[[Malignant]], immature [[lymphoblasts|white blood cells]] continuously multiply and are overproduced in the [[bone marrow]]
*Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading ([[metastasis|metastasizing]]) to other organs

==Markers==

B-cell acute lymphoblastic leukemia:<ref name=ALL>{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>
:*Typically express [[CD10]], [[CD19]], and [[CD34]] on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)
T-cell acute lymphoblastic leukemia:
:*Typically express [[CD2]], [[CD3]], [[CD7]], [[CD34]], and TdT.

==Genetics==

*[[Cytogenetics]], the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.<ref>{{cite journal |author=Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G |title=Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial |journal=Blood |volume=109 |issue=8 |pages=3189-97 |year=2007 |pmid=17170120}}</ref>

*It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia

*The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*In has been documented that the incidence of chromosomal change is related with the age
*The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old<ref name="P.Borjas-Gutierrez2013">{{cite journal|last1=P.|first1=M.|last2=Borjas-Gutierrez|first2=C.|last3=M.|first3=G.|last4=E.|first4=L.|last5=M.|first5=A.|last6=R.|first6=J.|title=Pathophysiology of Acute Lymphoblastic Leukemia|year=2013|doi=10.5772/54652}}</ref>
*The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
*The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
*The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
*The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old

{| class="wikitable"
|-
! Cytogenetic change
! Target gene
! Frequency in childhood in %
! Frequency in adulthood in %
! Risk category
|-
| [[Philadelphia chromosome]]
| BCR-ABL1
| 3 to 5
| 25 to 30
| Poor prognosis
|-
| t(4;11)(q21;q23)
| MLL-AF4
| 2 to 3
| 3 to 7
| Poor prognosis
|-
| t(8;14)(q24.1;q32)
| Non-TCR(NOTCH,HOX11,JAK1)
| 60
|
| Favorable prognosis
|-
| Complex [[karyotype]] (more than four abnormalities)
|
|
|
| Poor prognosis
|-
| hypodiploidy or near [[triploidy]]
|
| 5 to 6
| 3
| Poor prognosis
|-
| High hyperdiploidy
|
| 20 to 30
| 7
| Good prognosis
|-
| T cell acute lymphoblastic leukemia
| TCR
|
|
|
|}

==Gallery==
[[Image:ALL-KM-2.jpg|thumb|Acute lymphoblastic leukemia cells|center]]

==References==
{{Reflist|2}}

[[Category:Lymphocytic leukemia]]
[[Category:Leukemia]]

{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia historical perspective

2019-03-05T20:38:27Z

Kamal Akbar:

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{CLG}}, {{kakbar}}

==Overview==
Leukemia was first described in 1827 by [[Alfred-Armand-Louis-Marie Velpeau]], a french physician.

==Historical perspective==
* The first published illustration of a case of leukemia in medical text dates to 1827, when a French physician named [[Alfred-Armand-Louis-Marie Velpeau]] described a 63-year-old florist who developed an sickness denoted by [[fever]], [[weakness]], [[nephrolithiasis|urinary stones]], and substantial [[hepatosplenomegaly|enlargement of the liver and spleen]]<ref name="Piller2001">{{cite journal|last1=Piller|first1=Gordon J.|title=Leukaemia - a brief historical review from ancient times to 1950|journal=British Journal of Haematology|volume=112|issue=2|year=2001|pages=282–292|issn=0007-1048|doi=10.1046/j.1365-2141.2001.02411.x}}</ref>

*Velpeau saw that the blood of this patient had a texture that was "like gruel", and thought that the blood appeared white due to the white corpuscles.<ref>{{cite book |last = Hoffman |first = Ronald ''et al.'' |title= Hematology: Basic Principles and Practice |year= 2005 |publisher= Elsevier Churchill Livingstone |location= St. Louis, Mo. |edition = 4th. ed. |pages = p. 1071 |id= ISBN 0-443-06629-9}}</ref>

* In 1845, a number of patients who passed away with enlarged spleens and changes in the "colors and consistencies of their blood" was publicized by the Edinburgh-based [[pathologist]] J.H. Bennett; he used the term "leucocythemia" to outline this pathological condition.<ref name="Piller2001">{{cite journal|last1=Piller|first1=Gordon J.|title=Leukaemia - a brief historical review from ancient times to 1950|journal=British Journal of Haematology|volume=112|issue=2|year=2001|pages=282–292|issn=0007-1048|doi=10.1046/j.1365-2141.2001.02411.x}}</ref><ref>Bennett JH. Two cases of hypertrophy of the spleen and liver, where death took place from suppuration of blood. ''Edinburgh Med Surg J.'' (1845)64:413.</ref>

*The term "leukemia" was introduced by [[Rudolf Virchow]], the acclaimed German [[pathologist]], in 1856

*As a visionary in the use of the [[light microscope]] in pathology, Virchow was the first to talk about the abnormal overabundance of [[white blood cells]] in patients with the clinical syndrome reported by Velpeau and Bennett<ref name="Piller2001">{{cite journal|last1=Piller|first1=Gordon J.|title=Leukaemia - a brief historical review from ancient times to 1950|journal=British Journal of Haematology|volume=112|issue=2|year=2001|pages=282–292|issn=0007-1048|doi=10.1046/j.1365-2141.2001.02411.x}}</ref>

*As Virchow was not certain of the [[etiology|cause]] of the white blood cell excess, he used the exclusively depictive term "leukemia" (Greek: "white blood") to refer to the condition.<ref>Virchow R: Die Leukämie. In Virchow R (ed): Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Meidinger, 1856, p 190.</ref>

* [[Wilhelm Ebstein]] invented the term ''"acute leukemia"'' in 1889 to decipher rapidly progressive and fatal leukemias from the more indolent [[chronic leukemia]]s.<ref>Ebstein W. Ueber die acute Leukämie und Pseudoleukämie. ''Deutsch Arch Klin Med''. (1889)44:343.</ref>

* The technique of [[bone marrow examination]] to diagnose leukemia was first narrated in 1879 by Mosler.<ref>Mosler F. Klinische Symptome und Therapie der medullären Leukämie. ''Berl Klin Wochenschr''. (1876)13:702. </ref>

* Finally, in 1900 the [[lymphoblast]], which is the malignant cell in acute lymphoid leukemia, was described by Naegeli, who seperated the leukemias into ''myeloid'' and ''lymphocytic''.<ref>Naegeli O. Über rothes Knochenmark und Myeloblasten. ''Deutsch Med Wochenschr''. (1900) 26:287.</ref><ref>{{cite journal | author = Zhen-yi, Wang |title = Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis | year=2003 | journal = Hematology | pmid = 14633774}}</ref>

==References==
{{Reflist|2}}

[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T16:28:32Z

Kamal Akbar: /* Late Effects of Treatment for Adult acute lymphocytic leukemia */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
*With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
*There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
*Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings
*This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses
*The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population
*The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene
*The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies."
*In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker
*The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia

=== Radiation Therapy ===
*[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation)
*[[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain
*Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia
*Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects
*As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

*Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies
*Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T16:27:27Z

Kamal Akbar: /* Radiation Therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
*With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
*There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
*Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings
*This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses
*The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population
*The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene
*The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies."
*In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker
*The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia

=== Radiation Therapy ===
*[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation)
*[[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain
*Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia
*Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects
*As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T16:14:39Z

Kamal Akbar: /* Chimeric antigen receptor T (CAR-T) cell therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
*With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
*There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
*Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings
*This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses
*The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population
*The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene
*The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref>
*CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies."
*In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker
*The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T16:07:31Z

Kamal Akbar: /* Chimeric antigen receptor T (CAR-T) cell therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
*With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
*There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
*Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T15:32:29Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
*With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
*There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T15:08:59Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with KMT2A rearrangements, and infants with acute lymphoblastic luekemia
*With the exception of patients <1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation (HCT) during first remission
*There is evidence that HCT offers a survival advantage to those >10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL [102], induction failure, and patients >1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-05T14:17:49Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an high incidence of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with KMT2A rearrangements, and infants with ALL
*With the exception of patients <1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation (HCT) during first remission
*There is evidence that HCT offers a survival advantage to those >10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL [102], induction failure, and patients >1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-01T17:05:57Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
*Selected patients with high-risk disease have an high incidence of relapse during delayed intensification chemotherapy
*This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with KMT2A rearrangements, and infants with ALL
*With the exception of patients <1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation (HCT) during first remission
There is evidence that HCT offers a survival advantage to those >10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL [102], induction failure, and patients >1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-01T16:37:30Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===
Selected patients with high-risk disease have an increased incidence of relapse during delayed intensification chemotherapy [69,103,104]. This includes patients with severe hypodiploid ALL (less than 46 chromosomes), those with KMT2A rearrangements, and infants with ALL. With the exception of patients <1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation (HCT) during first remission. There is evidence that HCT offers a survival advantage to those >10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL [102], induction failure, and patients >1 year of age with 11q23 rearrangements

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-01T15:36:13Z

Kamal Akbar: /* Chimeric antigen receptor T (CAR-T) cell therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

==Miscellaneous therapies==
===Allogeneic hematopoietic cell transplantation===

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-03-01T15:33:35Z

Kamal Akbar: /* Management of relapse */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-28T22:03:01Z

Kamal Akbar: /* Allogeneic hematopoietic cell transplantation */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Management of relapse===
*About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
*Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
*Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
*Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
*The following drugs are used:
**Blinatumomab
**Clofarabine
**Nelarabine
**Etoposide
**Cyclophosphamide
**Cytarabine

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-28T22:01:58Z

Kamal Akbar: /* Relapse monitoring */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

===Allogeneic hematopoietic cell transplantation===

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-28T20:43:41Z

Kamal Akbar: /* Follow-up therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks
===Allogeneic hematopoietic cell transplantation===

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-28T17:07:41Z

Kamal Akbar: /* Relapse monitoring */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T18:34:46Z

Kamal Akbar: /* Relapse monitoring */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T16:44:05Z

Kamal Akbar: /* Relapse monitoring */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
*Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
*Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
*Monitoring for the presence of measurable residual disease (MRD; also referred to as minimal residual disease) is also common practice in patients who have had a stem cell transplant as part of their treatment regimen
*Prompt referral for bone marrow examination is warranted if there is suppression of more than one cell line (white cells, red cells, platelets) or unexplained suppression of one cell line that persists for longer than three to four weeks

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T15:30:41Z

Kamal Akbar: /* Follow-up therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.
===Relapse monitoring===
ALL relapse most commonly occurs in the bone marrow and usually presents with persistent peripheral blood cytopenias. Healthcare providers should pay close attention to persistent abnormal blood counts in the ALL survivor. Monitoring for the presence of measurable residual disease (MRD; also referred to as minimal residual disease) is also common practice in patients who have had a stem cell transplant as part of their treatment regimen. Prompt referral for bone marrow examination is warranted if there is suppression of more than one cell line (white cells, red cells, platelets) or unexplained suppression of one cell line that persists for longer than three to four weeks.
A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T15:28:24Z

Kamal Akbar: /* CNS prophylaxis */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*The objective is to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial irradiation plus spinal tap or intrathecal delivery of the drug [[methotrexate]].
**High-dose systemic and intrathecal [[methotrexate]]
**Intrathecal chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T15:14:00Z

Kamal Akbar: /* Follow-up therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-27T14:34:28Z

Kamal Akbar: /* Follow-up therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., [[ofloxacin]], [[rifampin]]), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-26T17:38:09Z

Kamal Akbar: /* Maintenance therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

==Follow-up therapy==
For acute lymphoblastic leukemia patients, follow-up usually consists of:
*Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
*Regular visits to there primary care physicians who provide cousniling, vaccinations, prophlactic antibiotics
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., [[ofloxacin]], [[rifampin]]), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]
* Immunizations are given such as varicella and influenza, but live attenuated vaccines are not given, because of hypo-immune state.

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-26T17:23:51Z

Kamal Akbar: /* Maintenance therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:
**Trimethoprim-sulfamethoxazole
**Dapsone
**Pentamidine, or Atovaquone
prophylaxis is continued to prevent Pneumocystis pneumonia
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO
'''Follow-up therapy''' for acute lymphoblastic leukemia patients usually consists of:
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., [[ofloxacin]], [[rifampin]]), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-26T16:42:15Z

Kamal Akbar: /* Maintenance therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO
'''Follow-up therapy''' for acute lymphoblastic leukemia patients usually consists of:
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., [[ofloxacin]], [[rifampin]]), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
{{Reflist|2}}
[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

Acute lymphoblastic leukemia medical therapy

2019-02-26T16:34:13Z

Kamal Akbar: /* Maintenance therapy */

__NOTOC__
{{Acute lymphoblastic leukemia}}

{{CMG}} {{shyam}} {{AE}} {{RT}} {{CLG}}

==Overview==
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS [[prophylaxis]] and maintenance treatments with chemotherapeutic drugs such as [[Prednisone]] plus [[Vincristine]] plus [[Cyclophosphamide]] plus [[Doxorubicin]] or [[Methotrexate]] plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]]. Drugs approved for acute lymphoblastic leukemia include: [[Methotrexate]], [[Nelarabine]], [[Blinatumomab]], [[Cyclophosphamide]], [[Clofarabine]], [[Cytarabine]], [[Dasatinib]], [[Doxorubicin hydrochloride]], [[Mercaptopurine]], [[Nelarabine]], [[Pegaspargase]], [[Prednisone]] and [[Mercaptopurine]]. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

==Medical Therapy==
===Chemotherapy===
*The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting [[remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:
*[[chemotherapy]]
*[[steroid]]s
*[[radiation therapy]]
*Intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants)
*Growth factors

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
*Induction chemotherapy
*Consolidation therapy
*CNS prophylaxis
*Maintenance treatment
*Follow-up therapy

==Induction chemotherapy==
*To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
*For adult acute lymphoblastic leukemia standard induction plans include:
**[[Prednisone]]
**[[Vincristine]]
**Anthracycline drug
*Other drug plans may include:
**[[L-asparaginase]]
**[[Cyclophosphamide]]
*Patients will undergo this regimen for the first month of treatment

===Low risk therapy===
* '''Low risk therapy'''
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
***Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.

**'''1.2 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
***Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
***Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
***Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
***Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28

**'''1.3 Renal impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
*****Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
*****Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
****Alternative regimen(1): Dexamethasone
*****No adjustments required
****Alternative regimen(2):Daunorubicin
*****CrCl <30 mL/minute: Administer 50% of dose
*****Hemodialysis: Administer 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****No adjustment required
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****No adjustment required
****Preferred regimen(4): Imatinib
*****Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
*****Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
*****Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
****Alternative regimen(1): Dexamethasone
*****No adjustments required

**'''1.4 Hepatic impairment'''
***'''Pediatric'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
****Preferred regimen(2): Prednisone
*****There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
****Preferred regimen(3): Asparaginase
*****Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
****ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
****ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
****ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
*****Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
*****Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
****Alternative regimen(1): Dexamethasone
*****No adjustment required
****Alternative regimen(2):Daunorubicin
*****Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
*****Serum bilirubin >3 mg/dL: Give 50% of dose

***'''Adult'''
****Preferred regimen(1): Vincristine
*****Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
*****Serum bilirubin >3 mg/dL: Do not use
****Preferred regimen(2): Prednisone
*****No adjustment required
****Preferred regimen(3): Asparaginase
*****ALT/AST >3 to 5 times ULN: Continue use
*****ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
*****ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
*****Direct bilirubin <3 mg/dL: Continue use
*****Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
*****Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
****Preferred regimen(4): Imatinib
*****Mild-to-moderate impairment: No dosage adjustment required
*****Severe impairment: Decrease dose by 25%
****Alternative regimen(1): Dexamethasone
*****No adjustments required

===High risk therapy===
*High-risk children may receive these drugs listed above plus an [[anthracycline]] such as [[daunorubicin]].<ref name="pmid20033052">{{cite journal |vauthors=Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R |title=Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999 |journal=Leukemia |volume=24 |issue=2 |pages=383–96 |date=February 2010 |pmid=20033052 |doi=10.1038/leu.2009.260 |url=}}</ref><ref name="pmid18388178">{{cite journal |vauthors=Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM |title=Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study |journal=Blood |volume=111 |issue=12 |pages=5477–85 |date=June 2008 |pmid=18388178 |pmc=2424148 |doi=10.1182/blood-2008-01-132837 |url=}}</ref>

==Consolidation therapy==
*It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
*A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
*Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as [[methotrexate]] and [[6-mercaptopurine]] (6-MP)
*High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.<ref name="pmid25435112">{{cite journal |vauthors=Cooper SL, Brown PA |title=Treatment of pediatric acute lymphoblastic leukemia |journal=Pediatr. Clin. North Am. |volume=62 |issue=1 |pages=61–73 |date=February 2015 |pmid=25435112 |pmc=4366417 |doi=10.1016/j.pcl.2014.09.006 |url=}}</ref>

**'''1.1 Pediatric'''
***Preferred regimen(1): Methotraxate:
****High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
****Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
***Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
***Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
***Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
***Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
***Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle

**'''1.2 Adult'''
***Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
***Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
***Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
***Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
***Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
***Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

==CNS prophylaxis==
*(preventive therapy) to stop the cancer from spreading to the brain and nervous system
*Standard prophylaxis may consist of:<ref name="pmid20209620">{{cite journal |vauthors=Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S |title=Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies |journal=Cancer |volume=116 |issue=10 |pages=2290–300 |date=May 2010 |pmid=20209620 |doi=10.1002/cncr.25008 |url=}}</ref>
**Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug [[methotrexate]].
**High-dose systemic and IT [[methotrexate]], without cranial irradiation
**IT chemotherapy.
*Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
**'''1.1 Pediatric'''
***Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

**'''1.2 Adult'''
***Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
***Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
===Radiotherapy in CNS prophylaxis===
* Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
* Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
* Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
* When an MRI was done the following was seen:
**atrophy
**leukoencephalopathy
**calcifications, or grey matter abnormalities
* The irradiation would also cause secondary brain tumors to arise, causing further complications during the treatment

==Maintenance therapy==
*Treatment with chemotherapeutic drugs (e.g., [[prednisone]] plus [[vincristine]] plus [[cyclophosphamide]] plus [[doxorubicin]]; [[methotrexate]] plus 6-MP) to prevent disease recurrence once remission has been achieved
*Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
*In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
*Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
**'''1.1 Pediatric'''
***Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 20 mg/m2 once weekly, given PO
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous
infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide
***Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO

**'''1.1 Adult'''
***Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
***Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
***Preferred regimen(1): Methotraxate 10 mg/m2/day IV for 5 days every month for 2 years
***Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
***Preferred regimen (6): Cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous
infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide
***Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO
'''Follow-up therapy''' for acute lymphoblastic leukemia patients usually consists of:
* Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., [[ofloxacin]], [[rifampin]]), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
* Transfusions with [[red blood cells]] and [[platelets]]

A laboratory test known as [[polymerase chain reaction]] (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. [[PCR]] testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia [[cyclophosphamide]]-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and [[sterilization]] of the microorganisms in the gut, until their total [[White blood cells|white blood cell]] (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by [[Allogeneic bone marrow transplantation|allogeneic bone marrow transplant]] (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the [[chemotherapy regimens]] can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an [[intravenous]] catheter inserted into a large vein (termed a [[central venous catheter]] or a [[Hickman line]]), or a [[Portacath]] (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System [[CNS]], most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the [[CNS]] fluid and to extract [[CNS]] fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

===Chimeric antigen receptor T (CAR-T) cell therapy===
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."<ref name="pmid28301076">{{cite journal| author=Makita S, Yoshimura K, Tobinai K| title=Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. | journal=Cancer Sci | year= 2017 | volume= 108 | issue= 6 | pages= 1109-1118 | pmid=28301076 | doi=10.1111/cas.13239 | pmc=5480083 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28301076 }} </ref> CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.

=== Radiation Therapy ===
[[Radiation therapy]] is used on painful bony areas in severe disease or as part of the preparations for a [[bone marrow transplant]] (total body irradiation). [[Radiation]] in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that [[CNS]] chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.<ref name="pmid8262820">{{cite journal |vauthors=Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD |title=The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group |journal=Int. J. Radiat. Oncol. Biol. Phys. |volume=27 |issue=5 |pages=1001–9 |date=December 1993 |pmid=8262820 |doi= |url=}}</ref>

=== Drugs Approved for acute lymphoblastic leukemia ===
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:<ref name="ALL">{{cite web | title =National Cancer Institurte| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq#link/_14_toc }}</ref>
*[[Methotrexate]]
*[[Nelarabine]]
*[[Asparaginase Erwinia chrysanthemi]]
*[[Blinatumomab]]
*[[Cyclophosphamide]]
*[[Clofarabine]]
*[[Cytarabine]]
*[[Dasatinib]]
*[[Doxorubicin Hydrochloride]]
*[[Mercaptopurine]]
*[[Nelarabine]]
*[[Pegaspargase]]
*[[Prednisone]]
*[[Mercaptopurine]]

===Late Effects of Treatment for Adult acute lymphocytic leukemia ===

Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.<ref name="ALL">{{cite web | title = National Cancer Institute| url =http://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq }}</ref>

==References==
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[[Category:Leukemia]]
[[Category:Lymphocytic leukemia]]
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[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]