Acute promyelocytic leukemia medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{Acute promyelocytic leukemia}}
{{Acute promyelocytic leukemia}}
{{CMG}} {{shyam}}
{{CMG}}; {{AE}} {{shyam}}, {{S.G.}}; {{GRR}} {{Nat}}


==Overview==
==Overview==
The treatment of acute promyelocytic leukemia is broadly divided into anti-[[leukemia]] therapies and supportive therapies. Anti-[[leukemia]] therapies function to eliminate [[cancer]] [[Cell (biology)|cells]], whereas supportive therapies are temporizing measures that can control the [[disease]] for a short time until anti-[[Leukemia|leukemic]] [[therapy]] takes effect. Anti-[[Leukemia|leukemic]] therapies include all-''[[trans]]'' [[retinoic acid]], [[arsenic trioxide]], [[gemtuzumab ozogamicin]], and [[cytarabine]]. Supportive therapies include [[transfusions]] (such as cryopreciptate or [[platelet]] [[transfusions]]) and [[granulocyte]] [[Colony-stimulating factor|colony stimulating factor]].
The treatment of acute promyelocytic leukemia is broadly divided into anti-leukemia therapies and supportive therapies. Anti-leukemia therapies function to eliminate cancer cells, whereas supportive therapies are temporizing measures that can control the disease for a short time until anti-leukemic therapy takes effect. Anti-leukemic therapies include all-''[[trans]]'' [[retinoic acid]], [[arsenic trioxide]], [[gemtuzumab ozogamicin]], and [[cytarabine]]. Supportive therapies include transfusions (such as cryoprecipitate or [[platelet]] [[transfusions]]) and [[granulocyte]] [[Colony-stimulating factor|colony stimulating factor]].


==Medical Therapy==
==Medical Therapy==
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===Anti-leukemic Therapies===
===Anti-leukemic Therapies===
*'''All-''trans'' retinoic acid''':
*'''All-''trans'' retinoic acid''':
**Acute promyelocytic leukemia is unique among the leukemias distinguished by its sensitivity to all-''trans'' retinoic acid, a derivative of [[vitamin A]]. Treatment with all-''trans'' retinoic acid causes differentiation of the immature leukemic promyelocytes into mature granulocytes. This is typically combined with [[anthracycline]]-based chemotherapy resulting in a clinical remission in approximately 90% of patients. The introduction of all-''trans'' retinoic acid has revolutionized the treatment paradigm and outcomes in acute promyelocytic leukemia. The 5-year mortality has decreased from 82% to 36% since the introduction of all-''trans'' retinoic acid.<ref name="pmid28003274">{{cite journal| author=Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E et al.| title=Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. | journal=Blood | year= 2017 | volume= 129 | issue= 10 | pages= 1275-1283 | pmid=28003274 | doi=10.1182/blood-2016-09-736686 | pmc=5413297 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28003274  }} </ref>
**Acute promyelocytic leukemia is unique among the leukemias distinguished by its sensitivity to all-''[[trans]]'' [[retinoic acid]], a [[Derivative (chemistry)|derivative]] of [[vitamin A]]. Treatment with all-''trans'' retinoic acid causes [[differentiation]] of the immature [[Leukemia|leukemic]] promyelocytes into mature granulocytes. This is typically combined with [[anthracycline]]-based [[chemotherapy]] resulting in a clinical [[Remission (medicine)|remission]] in approximately 90% of patients. The introduction of all-''[[trans]]'' [[retinoic acid]] has revolutionized the treatment [[paradigm]] and outcomes in acute promyelocytic leukemia. The 5-year mortality has decreased from 82% to 36% since the introduction of all-''trans'' retinoic acid.<ref name="pmid28003274">{{cite journal| author=Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E et al.| title=Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. | journal=Blood | year= 2017 | volume= 129 | issue= 10 | pages= 1275-1283 | pmid=28003274 | doi=10.1182/blood-2016-09-736686 | pmc=5413297 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28003274  }} </ref>
**''Mechanism of action'': Induction of differentiation in leukemic blasts
**''Mechanism of action'':
**''Dosing'': 45mg/m2 PO daily (typically 22.5mg/m2 PO divided twice daily), given on days 1-14 of a 28-day cycle (2 weeks on, 2 weeks off), for a total of 7 cycles
***[[Induction (biology)|Induction]] of differentiation in leukemic [[Blast|blasts]]
**''Adverse effects'':   
**''Dosing'':
**The most unique adverse effect of all-''trans'' retinoic acid is differentiation syndrome. This was formerly known as retinoic acid syndrome, until it was noted that [[arsenic trioxide]] could also result in a similar phenomenon. The etiology of differentiation syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. Differentiation syndrome is characterized by the development of dyspnea, fever, weight gain, peripheral edema and is treated with [[dexamethasone]].  
***45 mg/m2 PO daily (typically 22.5 mg/m2 PO divided twice daily), given on days 1-14 of a 28-day cycle (2 weeks on, 2 weeks off), for a total of 7 cycles
**''[[Adverse effect (medicine)|Adverse effects]]'':   
***The most unique adverse effect of all-''trans'' retinoic acid is differentiation syndrome. This was formerly known as [[retinoic acid syndrome]], until it was noted that arsenic trioxide could also result in a similar phenomenon. The [[etiology]] of differentiation syndrome has been attributed to [[capillary leak syndrome]] from [[cytokine]] release from the differentiating promyelocytes. Differentiation syndrome is characterized by the development of [[dyspnea]], [[fever]], [[weight gain]], [[peripheral edema]] and is treated with [[dexamethasone]].<ref name="MontesinosSanz2011">{{cite journal|last1=Montesinos|first1=Pau|last2=Sanz|first2=Miguel A|title=THE DIFFERENTIATION SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA: EXPERIENCE OF THE PETHEMA GROUP AND REVIEW OF THE LITERATURE.|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=3|issue=1|year=2011|pages=e2011059|issn=2035-3006|doi=10.4084/mjhid.2011.059}}</ref><ref name="MontesinosBergua2008">{{cite journal|last1=Montesinos|first1=P.|last2=Bergua|first2=J. M.|last3=Vellenga|first3=E.|last4=Rayon|first4=C.|last5=Parody|first5=R.|last6=de la Serna|first6=J.|last7=Leon|first7=A.|last8=Esteve|first8=J.|last9=Milone|first9=G.|last10=Deben|first10=G.|last11=Rivas|first11=C.|last12=Gonzalez|first12=M.|last13=Tormo|first13=M.|last14=Diaz-Mediavilla|first14=J.|last15=Gonzalez|first15=J. D.|last16=Negri|first16=S.|last17=Amutio|first17=E.|last18=Brunet|first18=S.|last19=Lowenberg|first19=B.|last20=Sanz|first20=M. A.|title=Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors|journal=Blood|volume=113|issue=4|year=2008|pages=775–783|issn=0006-4971|doi=10.1182/blood-2008-07-168617}}</ref>
*'''Arsenic trioxide''':
*'''Arsenic trioxide''':
**Arsenic trioxide is commonly used in the treatment of acute promyelocytic leukemia in combination with all-''trans'' retinoic acid.<ref name="pmid24887205">{{cite journal| author=Kumar S, Yedjou CG, Tchounwou PB| title=Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. | journal=J Exp Clin Cancer Res | year= 2014 | volume= 33 | issue=  | pages= 42 | pmid=24887205 | doi=10.1186/1756-9966-33-42 | pmc=4049373 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24887205  }} </ref>
**[[Arsenic trioxide]] is commonly used in the treatment of acute promyelocytic leukemia in combination with all-''trans'' retinoic acid.<ref name="pmid24887205">{{cite journal| author=Kumar S, Yedjou CG, Tchounwou PB| title=Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. | journal=J Exp Clin Cancer Res | year= 2014 | volume= 33 | issue=  | pages= 42 | pmid=24887205 | doi=10.1186/1756-9966-33-42 | pmc=4049373 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24887205  }} </ref>
**''Mechanism of action'': Induction of apoptosis via the mitochondrial pathway in leukemic blasts; induction of oxidative stress; induction of DNA damage<ref name="pmid24887205">{{cite journal| author=Kumar S, Yedjou CG, Tchounwou PB| title=Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. | journal=J Exp Clin Cancer Res | year= 2014 | volume= 33 | issue=  | pages= 42 | pmid=24887205 | doi=10.1186/1756-9966-33-42 | pmc=4049373 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24887205  }} </ref>
**''Mechanism of action'':
**''Dosing'': 0.15mg/kg IV daily for days 1-30 of a 60-day cycle (4 weeks on, 4 weeks off), for a total of 4 cycles
***Induction of [[apoptosis]] via the mitochondrial pathway in leukemic [[Blast|blasts]]; induction of oxidative [[Stress (medicine)|stress]]; induction of DNA damage<ref name="pmid24887205">{{cite journal| author=Kumar S, Yedjou CG, Tchounwou PB| title=Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. | journal=J Exp Clin Cancer Res | year= 2014 | volume= 33 | issue=  | pages= 42 | pmid=24887205 | doi=10.1186/1756-9966-33-42 | pmc=4049373 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24887205  }} </ref>
**''Adverse effects'': The adverse effects of arsenic trioxide include myelosuppression, QT interval prolongation, and liver dysfunction.<ref name="pmid28352191">{{cite journal| author=McCulloch D, Brown C, Iland H| title=Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives. | journal=Onco Targets Ther | year= 2017 | volume= 10 | issue=  | pages= 1585-1601 | pmid=28352191 | doi=10.2147/OTT.S100513 | pmc=5359123 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28352191  }} </ref> Liver dysfunction occurs in approximately one-third of patients.<ref name="pmid26716387">{{cite journal| author=Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM| title=The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. | journal=Cancer | year= 2016 | volume= 122 | issue= 8 | pages= 1160-8 | pmid=26716387 | doi=10.1002/cncr.29852 | pmc=5042140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26716387  }} </ref>
**''Dosing'':
***0.15 mg/kg IV daily for days 1-30 of a 60-day cycle (4 weeks on, 4 weeks off), for a total of 4 cycles.<ref name="IlandSeymour2013">{{cite journal|last1=Iland|first1=Harry J.|last2=Seymour|first2=John F.|title=Role of Arsenic Trioxide in Acute Promyelocytic Leukemia|journal=Current Treatment Options in Oncology|volume=14|issue=2|year=2013|pages=170–184|issn=1527-2729|doi=10.1007/s11864-012-0223-3}}</ref>
**''Adverse effects'':
***The [[Adverse effect (medicine)|adverse effects]] of arsenic trioxide include [[myelosuppression]], [[QT interval prolongation]], and liver dysfunction.<ref name="pmid28352191">{{cite journal| author=McCulloch D, Brown C, Iland H| title=Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives. | journal=Onco Targets Ther | year= 2017 | volume= 10 | issue=  | pages= 1585-1601 | pmid=28352191 | doi=10.2147/OTT.S100513 | pmc=5359123 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28352191  }} </ref>
***Liver dysfunction occurs in approximately one-third of patients.<ref name="pmid26716387">{{cite journal| author=Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM| title=The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. | journal=Cancer | year= 2016 | volume= 122 | issue= 8 | pages= 1160-8 | pmid=26716387 | doi=10.1002/cncr.29852 | pmc=5042140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26716387  }} </ref>
*'''Gemtuzumab ozogamycin''':
*'''Gemtuzumab ozogamycin''':
*This is an anti-CD33 antibody conjugated to the anti-tumor antibiotic calicheamicin. Gemtuzumab ozogamycin is FDA-approved for the treatment of patients with newly diagnosed [[acute myeloid leukemia]] expressing the CD33 antigen. Gemtuzumab ozogamycin shows efficacy in acute promyelocytic leukemia. This medication was originally approved in the year 2000 for relapsed [[acute myeloid leukemia]], then was withdrawn from the marker a few years later, then re-introduced to the marker in 2017.
**This is an anti-[[CD33]] [[antibody]] conjugated to the anti-tumor [[antibiotic]] [[calicheamicin]]. [[Gemtuzumab ozogamicin|Gemtuzumab ozogamycin]] is [[Food and Drug Administration|FDA]]-approved for the treatment of patients with newly diagnosed [[acute myeloid leukemia]] expressing the [[CD33]] [[antigen]].<ref name="JenKo2018">{{cite journal|last1=Jen|first1=Emily Y.|last2=Ko|first2=Chia-Wen|last3=Lee|first3=Jee Eun|last4=Del Valle|first4=Pedro L.|last5=Aydanian|first5=Antonina|last6=Jewell|first6=Charles|last7=Norsworthy|first7=Kelly J.|last8=Przepiorka|first8=Donna|last9=Nie|first9=Lei|last10=Liu|first10=Jiang|last11=Sheth|first11=Christopher M.|last12=Shapiro|first12=Marjorie|last13=Farrell|first13=Ann T.|last14=Pazdur|first14=Richard|title=FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia|journal=Clinical Cancer Research|volume=24|issue=14|year=2018|pages=3242–3246|issn=1078-0432|doi=10.1158/1078-0432.CCR-17-3179}}</ref>
**''Mechanism of action'': Antibody-dependent cell-mediated cytotoxicity towards leukemic blasts expressing the cell surface marker CD33
**[[Gemtuzumab ozogamicin|Gemtuzumab ozogamycin]] shows [[efficacy]] in acute promyelocytic leukemia. This medication was originally approved in the year 2000 for relapsed [[acute myeloid leukemia]], then was withdrawn from the marker a few years later, then re-introduced to the marker in 2017.<ref name="WeiTiong2017">{{cite journal|last1=Wei|first1=Andrew H.|last2=Tiong|first2=Ing S.|title=Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML|journal=Blood|volume=130|issue=23|year=2017|pages=2469–2474|issn=0006-4971|doi=10.1182/blood-2017-08-784066}}</ref>
**''Dosing'': 3 mg/m2 IV on days 1, 4, and 7 of the induction regimen
**''Mechanism of action'':
**''Adverse effects'': The most unique adverse effect is hepatic [[venoocclusive disease]], which is due to the ozogamycin component.
***Antibody-dependent cell-mediated [[cytotoxicity]] towards leukemic [[Blast|blasts]] expressing the cell surface marker [[CD33]].<ref name="PlanqueJager2011">{{cite journal|last1=Planque|first1=Robert|last2=Jager|first2=Eva|last3=van der Velden|first3=Vincent H. J.|last4=te Marvelde|first4=Jeroen G.|last5=Walter|first5=Roland B.|last6=Agur|first6=Zvia|last7=Vainstein|first7=Vladimir|title=Targeted Drug Delivery by Gemtuzumab Ozogamicin: Mechanism-Based Mathematical Model for Treatment Strategy Improvement and Therapy Individualization|journal=PLoS ONE|volume=6|issue=9|year=2011|pages=e24265|issn=1932-6203|doi=10.1371/journal.pone.0024265}}</ref>
**''Dosing'':
***3 mg/m2 IV on days 1, 4, and 7 of the induction regimen.<ref name="pmid16562371">{{cite journal |vauthors=Lo Coco F, Ammatuna E, Noguera N |title=Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin |journal=Clin Adv Hematol Oncol |volume=4 |issue=1 |pages=57–62, 76–7 |date=January 2006 |pmid=16562371 |doi= |url=}}</ref>
**''Adverse effects'':
***The most unique adverse effect is hepatic [[venoocclusive disease]], which is due to the ozogamycin component.<ref name="BaronWang20182">{{cite journal|last1=Baron|first1=Jeffrey|last2=Wang|first2=Eunice S.|title=Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia|journal=Expert Review of Clinical Pharmacology|volume=11|issue=6|year=2018|pages=549–559|issn=1751-2433|doi=10.1080/17512433.2018.1478725}}</ref>
*'''Cytarabine''':
*'''Cytarabine''':
*This is a cytotoxic chemotherapy that is used in high-risk acute promyelocytic leukemia along with all-''trans'' retinoic acid. Importantly, cytarabine is not required for the treatment of acute promyelocytic leukemia, as studies from the GIMEMA cooperative group in Italy and the PETHEMA cooperative group in Spain showed that the combination of [[anthracycline]] plus all-''trans'' retinoic acid is equally as effective as a cytarabine-containing regimen.<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100  }} </ref>
**This is a cytotoxic chemotherapy that is used in high-risk acute promyelocytic leukemia along with all-''trans'' retinoic acid.<ref name="RavandiEstey2009">{{cite journal|last1=Ravandi|first1=Farhad|last2=Estey|first2=Eli|last3=Jones|first3=Dan|last4=Faderl|first4=Stefan|last5=O'Brien|first5=Susan|last6=Fiorentino|first6=Jackie|last7=Pierce|first7=Sherry|last8=Blamble|first8=Deborah|last9=Estrov|first9=Zeev|last10=Wierda|first10=William|last11=Ferrajoli|first11=Alessandra|last12=Verstovsek|first12=Srdan|last13=Garcia-Manero|first13=Guillermo|last14=Cortes|first14=Jorge|last15=Kantarjian|first15=Hagop|title=Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin|journal=Journal of Clinical Oncology|volume=27|issue=4|year=2009|pages=504–510|issn=0732-183X|doi=10.1200/JCO.2008.18.6130}}</ref><ref name="ZhangZou2018">{{cite journal|last1=Zhang|first1=Li|last2=Zou|first2=Yao|last3=Chen|first3=Yumei|last4=Guo|first4=Ye|last5=Yang|first5=Wenyu|last6=Chen|first6=Xiaojuan|last7=Wang|first7=Shuchun|last8=Liu|first8=Xiaoming|last9=Ruan|first9=Min|last10=Zhang|first10=Jiayuan|last11=Liu|first11=Tianfeng|last12=Liu|first12=Fang|last13=Qi|first13=Benquan|last14=An|first14=Wenbin|last15=Ren|first15=Yuanyuan|last16=Chang|first16=Lixian|last17=Zhu|first17=Xiaofan|title=Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial|journal=BMC Cancer|volume=18|issue=1|year=2018|issn=1471-2407|doi=10.1186/s12885-018-4280-2}}</ref>
**''Mechanism of action'': Incorporation into DNA and disruption of DNA synthesis
**Importantly, [[cytarabine]] is not required for the treatment of acute promyelocytic leukemia, as studies from the GIMEMA cooperative group in Italy and the PETHEMA cooperative group in Spain showed that the combination of [[anthracycline]] plus all-''[[trans]]'' [[retinoic acid]] is equally as effective as a cytarabine-containing regimen.<ref name="Lo-CocoAvvisati2010">{{cite journal|last1=Lo-Coco|first1=F.|last2=Avvisati|first2=G.|last3=Vignetti|first3=M.|last4=Breccia|first4=M.|last5=Gallo|first5=E.|last6=Rambaldi|first6=A.|last7=Paoloni|first7=F.|last8=Fioritoni|first8=G.|last9=Ferrara|first9=F.|last10=Specchia|first10=G.|last11=Cimino|first11=G.|last12=Diverio|first12=D.|last13=Borlenghi|first13=E.|last14=Martinelli|first14=G.|last15=Di Raimondo|first15=F.|last16=Di Bona|first16=E.|last17=Fazi|first17=P.|last18=Peta|first18=A.|last19=Bosi|first19=A.|last20=Carella|first20=A. M.|last21=Fabbiano|first21=F.|last22=Pogliani|first22=E. M.|last23=Petti|first23=M. C.|last24=Amadori|first24=S.|last25=Mandelli|first25=F.|title=Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group|journal=Blood|volume=116|issue=17|year=2010|pages=3171–3179|issn=0006-4971|doi=10.1182/blood-2010-03-276196}}</ref><ref name="OrtegaMadero2005">{{cite journal|last1=Ortega|first1=Juan J.|last2=Madero|first2=Luis|last3=Martín|first3=Guillermo|last4=Verdeguer|first4=Amparo|last5=García|first5=Purificación|last6=Parody|first6=Ricardo|last7=Fuster|first7=José|last8=Molines|first8=Antonio|last9=Novo|first9=Andrés|last10=Debén|first10=Guillermo|last11=Rodríguez|first11=Antonia|last12=Conde|first12=Eulogio|last13=de la Serna|first13=Javier|last14=Allegue|first14=María J.|last15=Capote|first15=Francisco J.|last16=González|first16=José D.|last17=Bolufer|first17=Pascual|last18=González|first18=Marcos|last19=Sanz|first19=Miguel A.|title=Treatment With All-TransRetinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group|journal=Journal of Clinical Oncology|volume=23|issue=30|year=2005|pages=7632–7640|issn=0732-183X|doi=10.1200/JCO.2005.01.3359}}</ref>
**''Dosing'': 100 mg/m2 IV infusion continuously for 7 days
**''Mechanism of action'':
**''Adverse effects'': Common adverse effects include rash; myelosuppression (infections, fatigue, bleeding); cerebellar dysfunction; [[conjunctivitis]]  
***Incorporation into DNA and disruption of [[DNA synthesis]].<ref name="Prakasha GowdaPolizzi2010">{{cite journal|last1=Prakasha Gowda|first1=A. S.|last2=Polizzi|first2=Joanna M.|last3=Eckert|first3=Kristin A.|last4=Spratt|first4=Thomas E.|title=Incorporation of Gemcitabine and Cytarabine into DNA by DNA Polymerase β and Ligase III/XRCC1|journal=Biochemistry|volume=49|issue=23|year=2010|pages=4833–4840|issn=0006-2960|doi=10.1021/bi100200c}}</ref>
**''Dosing'':
***100 mg/m2 IV infusion continuously for 7 days.<ref name="LöwenbergPabst2011">{{cite journal|last1=Löwenberg|first1=Bob|last2=Pabst|first2=Thomas|last3=Vellenga|first3=Edo|last4=van Putten|first4=Wim|last5=Schouten|first5=Harry C.|last6=Graux|first6=Carlos|last7=Ferrant|first7=Augustin|last8=Sonneveld|first8=Pieter|last9=Biemond|first9=Bart J.|last10=Gratwohl|first10=Alois|last11=de Greef|first11=Georgine E.|last12=Verdonck|first12=Leo F.|last13=Schaafsma|first13=Martijn R.|last14=Gregor|first14=Michael|last15=Theobald|first15=Matthias|last16=Schanz|first16=Urs|last17=Maertens|first17=Johan|last18=Ossenkoppele|first18=Gert J.|title=Cytarabine Dose for Acute Myeloid Leukemia|journal=New England Journal of Medicine|volume=364|issue=11|year=2011|pages=1027–1036|issn=0028-4793|doi=10.1056/NEJMoa1010222}}</ref>
**''Adverse effects'':
***Common adverse effects include [[rash]], [[myelosuppression]] ([[Infection|infections]], [[fatigue]], [[bleeding]]), [[cerebellar]] [[dysfunction]], and [[conjunctivitis]].<ref name="ShepshelovichEdel2015">{{cite journal|last1=Shepshelovich|first1=Daniel|last2=Edel|first2=Yonatan|last3=Goldvaser|first3=Hadar|last4=Dujovny|first4=Tal|last5=Wolach|first5=Ofir|last6=Raanani|first6=Pia|title=Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study|journal=British Journal of Clinical Pharmacology|volume=79|issue=4|year=2015|pages=685–691|issn=03065251|doi=10.1111/bcp.12530}}</ref>
*'''Anthacyclines''':
*'''Anthacyclines''':
*These are cytotoxic chemotherapy agents that are used in high-risk acute promyelocytic leukemia along with all-''trans'' retinoic acid.  
**These are cytotoxic [[Chemotherapy agent|chemotherapy agents]] that are used in high-risk acute promyelocytic leukemia along with all-''trans'' retinoic acid.<ref name="RavandiEstey2009" /><ref name="ZhangZou2018" />
**''Mechanism of action'': intercalation into DNA; inhibition of topoisomerase II
***''Mechanism of action'':
**''Dosing'': Idarubicin 12mg/m2 IV daily for 3 days, daunorubicin 60 mg/m2 or 90 mfg/m2 IV daily for 3 days  
****Intercalation into DNA and [[inhibition]] of [[Type II topoisomerase|topoisomerase II]]. <ref name="McGowanChung2017">{{cite journal|last1=McGowan|first1=John V|last2=Chung|first2=Robin|last3=Maulik|first3=Angshuman|last4=Piotrowska|first4=Izabela|last5=Walker|first5=J Malcolm|last6=Yellon|first6=Derek M|title=Anthracycline Chemotherapy and Cardiotoxicity|journal=Cardiovascular Drugs and Therapy|volume=31|issue=1|year=2017|pages=63–75|issn=0920-3206|doi=10.1007/s10557-016-6711-0}}</ref>
**''Adverse effects'': The most unique adverse effect is cardiomyopathy. This can include arrhythmias in the acute setting and heart failure in the long-term setting. Patients who are at highest risk for cardiomyopathy from anthracyclines include those with pre-existing heart disease, diabetes, hypertension, and elderly patients. Mucositis is also a common adverse effect.
***''Dosing'':  
****[[Idarubicin]] 12 mg/m2 IV daily for 3 days and [[daunorubicin]] 60 mg/m2 or 90 mfg/m2 IV daily for 3 days.<ref name="SunZhou2016">{{cite journal|last1=Sun|first1=Zimin|last2=Zhou|first2=Li|last3=Liu|first3=Xin|last4=Liu|first4=Huilan|last5=Zhu|first5=Weibo|last6=Cai|first6=Xiaoyan|last7=Song|first7=Kaidi|last8=Zheng|first8=Changcheng|last9=Tang|first9=Baolin|title=A comparative study of idarubicin 12 mg/m2 and 8 mg/m2 combined with cytarabine as the first induction regimen for adult acute myeloid leukemia patients|journal=OncoTargets and Therapy|year=2016|pages=985|issn=1178-6930|doi=10.2147/OTT.S96176}}</ref>
***''Adverse effects'':
****The most unique adverse effect is [[cardiomyopathy]].<ref name="VolkovaRussell2012">{{cite journal|last1=Volkova|first1=Maria|last2=Russell|first2=Raymond|title=Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment|journal=Current Cardiology Reviews|volume=7|issue=4|year=2012|pages=214–220|issn=1573403X|doi=10.2174/157340311799960645}}</ref>
****This can include [[arrhythmias]] in the acute setting and [[heart failure]] in the long-term setting. Patients who are at highest risk for cardiomyopathy from anthracyclines include those with pre-existing [[heart]] [[disease]], [[diabetes]], [[hypertension]], and [[elderly]] [[Patient|patients]].<ref name="HerrmannLerman2014">{{cite journal|last1=Herrmann|first1=Joerg|last2=Lerman|first2=Amir|last3=Sandhu|first3=Nicole P.|last4=Villarraga|first4=Hector R.|last5=Mulvagh|first5=Sharon L.|last6=Kohli|first6=Manish|title=Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology|journal=Mayo Clinic Proceedings|volume=89|issue=9|year=2014|pages=1287–1306|issn=00256196|doi=10.1016/j.mayocp.2014.05.013}}</ref>
****[[Mucositis]] is also a common adverse effect.<ref name="pmid19679009">{{cite journal |vauthors=Fathi AT, Karp JE |title=New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines |journal=Curr Oncol Rep |volume=11 |issue=5 |pages=346–52 |date=September 2009 |pmid=19679009 |pmc=3066101 |doi= |url=}}</ref>


===Supportive Therapies===
===Supportive Therapies===
*'''[[Cryoprecipitate]] transfusion''': [[Cryoprecipitate]] is commonly given to patients with acute promyelocytic leukemia who have [[disseminated intravascular coagulation]]. Low [[fibrinogen]] levels (less than 100 mg/dl) warrant transfusion of [[cryoprecipitate]]. [[Cryoprecipitate]] contains [[factor I]], [[factor VIII]], and [[von Willebrand factor]].
*'''Cryoprecipitate transfusion''':
**''Adverse effects'': Risks of cryoprecipitate transfusion include volume overload (low risk) and transfusion reaction. In rare cases, sepsis can occur from contaminated product.
**[[Cryoprecipitate]] is commonly given to patients with acute promyelocytic leukemia who have [[disseminated intravascular coagulation]]. Low [[fibrinogen]] levels (less than 100 mg/dl) warrant [[transfusion]] of cryoprecipitate. Cryoprecipitate contains [[factor I]], [[factor VIII]], and [[von Willebrand factor]].<ref name="pmid24972790">{{cite journal |vauthors=Nascimento B, Goodnough LT, Levy JH |title=Cryoprecipitate therapy |journal=Br J Anaesth |volume=113 |issue=6 |pages=922–34 |date=December 2014 |pmid=24972790 |pmc=4627369 |doi=10.1093/bja/aeu158 |url=}}</ref>
*'''Packed red blood cell transfusion''': [[Red blood cell]] transfusion is commonly done in patients with acute promyelocytic leukemia. Transfusion is indicated when the hemoglobin level decreases below 7 g/dl.
**''Adverse effects'':
**''Adverse effects'': Risks of [[red blood cell]] transfusion include volume overload, alloimmunization, iron overload, and infection (if the product is contaminated). Alloimmunization is usually prevents with clerical checks and proper blood banking techniques. Iron overload occurs after many repeated transfusion and can be prevented via the use of iron chelators such as [[deferiprone]], [[deferasirox]], and [[deferoxamine]].
***Risks of cryoprecipitate transfusion include volume overload (low risk) and transfusion reaction. In rare cases, [[sepsis]] can occur from a contaminated product.<ref name="pmid22578374">{{cite journal |vauthors=Pandey S, Vyas GN |title=Adverse effects of plasma transfusion |journal=Transfusion |volume=52 Suppl 1 |issue= |pages=65S–79S |date=May 2012 |pmid=22578374 |pmc=3356109 |doi=10.1111/j.1537-2995.2012.03663.x |url=}}</ref>
*'''Platelet transfusion''': Platelet transfusion is indicated when the platelet count decreases to less than 10,000 cells per microliter. This low platelet count occurs especially when a patient received induction chemotherapy, such as cytarabine or anthacycline.
*'''Packed red blood cell transfusion''':
**''Adverse effects'': Risks include sepsis (since platelet units are stored at room temperature and there is a high risk for contamination), volume overload, and thrombosis (less likely).
**[[Red blood cell]] transfusion is commonly done in patients with acute promyelocytic leukemia. [[Transfusion]] is indicated when the [[hemoglobin]] level decreases below 7 g/dl.<ref name="Ikezoe2013">{{cite journal|last1=Ikezoe|first1=Takayuki|title=Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin|journal=International Journal of Hematology|volume=100|issue=1|year=2013|pages=27–37|issn=0925-5710|doi=10.1007/s12185-013-1463-0}}</ref>
*'''Granulocyte colony stimulating factor (G-CSF)''': G-CSF is sometimes uses to help improve the neutrophil count in patients with acute promyelocytic leukemia. It is important to use G-CSF only when there is no active leukemia, as G-CSF can stimulate the proliferation of leukemic blasts. Patients who receive G-CSF are usually those who have had a favorable anti-tumor response to chemotherapy but have not recovered their normal blood counts. G-CSF helps enhance normal blood cell count recovery.
**''Adverse effects'':
**''Adverse effects'': The most common adverse effects are bone pain, leukocytosis, and injection site erythema and pain. Bone pain can be alleviated via loratadine or other histamine receptor blockers.
***Risks of [[red blood cell]] transfusion include volume overload, [[alloimmunization]], [[iron]] overload, and [[infection]] (if the product is contaminated).<ref name="pmid25535415">{{cite journal |vauthors=Sahu S, Hemlata, Verma A |title=Adverse events related to blood transfusion |journal=Indian J Anaesth |volume=58 |issue=5 |pages=543–51 |date=September 2014 |pmid=25535415 |pmc=4260299 |doi=10.4103/0019-5049.144650 |url=}}</ref>
***Alloimmunization is usually prevented with clerical checks and proper blood banking techniques. [[Iron]] overload can occur after many repeated [[transfusion]], but it can be prevented via the use of iron [[Chelator|chelators]] such as [[deferiprone]], [[deferasirox]], and [[deferoxamine]].<ref name="pmid21226580">{{cite journal |vauthors=Brittenham GM |title=Iron-chelating therapy for transfusional iron overload |journal=N. Engl. J. Med. |volume=364 |issue=2 |pages=146–56 |date=January 2011 |pmid=21226580 |pmc=3078566 |doi=10.1056/NEJMct1004810 |url=}}</ref>
*'''Platelet transfusion''':  
**[[Platelet transfusions|Platelet transfusion]] is indicated when the [[platelet]] count decreases to less than 10,000 cells per microliter. This low platelet count occurs especially when a patient received induction chemotherapy, such as [[cytarabine]] or anthacycline.<ref name="pmid29062237">{{cite journal |vauthors=Song YH, Peng P, Qiao C, Zhang R, Li JY, Lu H |title=Low platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia |journal=Onco Targets Ther |volume=10 |issue= |pages=4917–4924 |date=2017 |pmid=29062237 |pmc=5640392 |doi=10.2147/OTT.S144438 |url=}}</ref>
**''Adverse effects'':  
***Risks include [[sepsis]] (since platelet units are stored at room temperature where there is a high risk for [[contamination]]), volume overload, and [[thrombosis]] (less likely).<ref name="pmid225783742">{{cite journal |vauthors=Pandey S, Vyas GN |title=Adverse effects of plasma transfusion |journal=Transfusion |volume=52 Suppl 1 |issue= |pages=65S–79S |date=May 2012 |pmid=22578374 |pmc=3356109 |doi=10.1111/j.1537-2995.2012.03663.x |url=}}</ref>
*'''Granulocyte colony stimulating factor (G-CSF)''':  
**[[Granulocyte colony stimulating factor|G-CSF]] is sometimes uses to help improve the [[neutrophil]] count in patients with acute promyelocytic leukemia. It is important to use G-CSF only when there is no active leukemia, as G-CSF can stimulate the proliferation of leukemic [[Blast|blasts]].<ref name="pmid8923783">{{cite journal |vauthors=Usuki K, Nishizawa Y, Endo M, Osawa M, Kitazume K, Iki S, Watanabe M, Urabe A |title=Administration of granulocyte colony-stimulating factor during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia |journal=Int. J. Hematol. |volume=64 |issue=3-4 |pages=213–9 |date=October 1996 |pmid=8923783 |doi= |url=}}</ref>
**Patients who receive [[Granulocyte colony stimulating factor|G-CSF]] are usually those who have had a favorable anti-tumor response to chemotherapy but have not recovered their normal blood counts. G-CSF helps enhance normal blood cell count recovery.<ref name="pmid20495576">{{cite journal |vauthors=Metcalf D |title=The colony-stimulating factors and cancer |journal=Nat. Rev. Cancer |volume=10 |issue=6 |pages=425–34 |date=June 2010 |pmid=20495576 |pmc=3345291 |doi=10.1038/nrc2843 |url=}}</ref>
**''Adverse effects'':  
***The most common adverse effects are [[bone pain]], [[leukocytosis]], and injection site [[erythema]] and [[pain]]. Bone pain can be alleviated via [[loratadine]] or other histamine receptor blockers.<ref name="pmid10532609">{{cite journal |vauthors=McCullough J, Clay M, Herr G, Smith J, Stroncek D |title=Effects of granulocyte-colony-stimulating factor on potential normal granulocyte donors |journal=Transfusion |volume=39 |issue=10 |pages=1136–40 |date=October 1999 |pmid=10532609 |doi= |url=}}</ref>


==References==
==References==

Latest revision as of 13:12, 11 April 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2], Sogand Goudarzi, MD [3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Overview

The treatment of acute promyelocytic leukemia is broadly divided into anti-leukemia therapies and supportive therapies. Anti-leukemia therapies function to eliminate cancer cells, whereas supportive therapies are temporizing measures that can control the disease for a short time until anti-leukemic therapy takes effect. Anti-leukemic therapies include all-trans retinoic acid, arsenic trioxide, gemtuzumab ozogamicin, and cytarabine. Supportive therapies include transfusions (such as cryoprecipitate or platelet transfusions) and granulocyte colony stimulating factor.

Medical Therapy

Anti-leukemic Therapies

Supportive Therapies

  • Cryoprecipitate transfusion:
  • Packed red blood cell transfusion:
  • Platelet transfusion:
    • Platelet transfusion is indicated when the platelet count decreases to less than 10,000 cells per microliter. This low platelet count occurs especially when a patient received induction chemotherapy, such as cytarabine or anthacycline.[30]
    • Adverse effects:
      • Risks include sepsis (since platelet units are stored at room temperature where there is a high risk for contamination), volume overload, and thrombosis (less likely).[31]
  • Granulocyte colony stimulating factor (G-CSF):
    • G-CSF is sometimes uses to help improve the neutrophil count in patients with acute promyelocytic leukemia. It is important to use G-CSF only when there is no active leukemia, as G-CSF can stimulate the proliferation of leukemic blasts.[32]
    • Patients who receive G-CSF are usually those who have had a favorable anti-tumor response to chemotherapy but have not recovered their normal blood counts. G-CSF helps enhance normal blood cell count recovery.[33]
    • Adverse effects:

References

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  2. Montesinos, Pau; Sanz, Miguel A (2011). "THE DIFFERENTIATION SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA: EXPERIENCE OF THE PETHEMA GROUP AND REVIEW OF THE LITERATURE". Mediterranean Journal of Hematology and Infectious Diseases. 3 (1): e2011059. doi:10.4084/mjhid.2011.059. ISSN 2035-3006.
  3. Montesinos, P.; Bergua, J. M.; Vellenga, E.; Rayon, C.; Parody, R.; de la Serna, J.; Leon, A.; Esteve, J.; Milone, G.; Deben, G.; Rivas, C.; Gonzalez, M.; Tormo, M.; Diaz-Mediavilla, J.; Gonzalez, J. D.; Negri, S.; Amutio, E.; Brunet, S.; Lowenberg, B.; Sanz, M. A. (2008). "Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors". Blood. 113 (4): 775–783. doi:10.1182/blood-2008-07-168617. ISSN 0006-4971.
  4. 4.0 4.1 Kumar S, Yedjou CG, Tchounwou PB (2014). "Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells". J Exp Clin Cancer Res. 33: 42. doi:10.1186/1756-9966-33-42. PMC 4049373. PMID 24887205.
  5. Iland, Harry J.; Seymour, John F. (2013). "Role of Arsenic Trioxide in Acute Promyelocytic Leukemia". Current Treatment Options in Oncology. 14 (2): 170–184. doi:10.1007/s11864-012-0223-3. ISSN 1527-2729.
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  9. Wei, Andrew H.; Tiong, Ing S. (2017). "Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML". Blood. 130 (23): 2469–2474. doi:10.1182/blood-2017-08-784066. ISSN 0006-4971.
  10. Planque, Robert; Jager, Eva; van der Velden, Vincent H. J.; te Marvelde, Jeroen G.; Walter, Roland B.; Agur, Zvia; Vainstein, Vladimir (2011). "Targeted Drug Delivery by Gemtuzumab Ozogamicin: Mechanism-Based Mathematical Model for Treatment Strategy Improvement and Therapy Individualization". PLoS ONE. 6 (9): e24265. doi:10.1371/journal.pone.0024265. ISSN 1932-6203.
  11. Lo Coco F, Ammatuna E, Noguera N (January 2006). "Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin". Clin Adv Hematol Oncol. 4 (1): 57–62, 76–7. PMID 16562371.
  12. Baron, Jeffrey; Wang, Eunice S. (2018). "Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia". Expert Review of Clinical Pharmacology. 11 (6): 549–559. doi:10.1080/17512433.2018.1478725. ISSN 1751-2433.
  13. 13.0 13.1 Ravandi, Farhad; Estey, Eli; Jones, Dan; Faderl, Stefan; O'Brien, Susan; Fiorentino, Jackie; Pierce, Sherry; Blamble, Deborah; Estrov, Zeev; Wierda, William; Ferrajoli, Alessandra; Verstovsek, Srdan; Garcia-Manero, Guillermo; Cortes, Jorge; Kantarjian, Hagop (2009). "Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin". Journal of Clinical Oncology. 27 (4): 504–510. doi:10.1200/JCO.2008.18.6130. ISSN 0732-183X.
  14. 14.0 14.1 Zhang, Li; Zou, Yao; Chen, Yumei; Guo, Ye; Yang, Wenyu; Chen, Xiaojuan; Wang, Shuchun; Liu, Xiaoming; Ruan, Min; Zhang, Jiayuan; Liu, Tianfeng; Liu, Fang; Qi, Benquan; An, Wenbin; Ren, Yuanyuan; Chang, Lixian; Zhu, Xiaofan (2018). "Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial". BMC Cancer. 18 (1). doi:10.1186/s12885-018-4280-2. ISSN 1471-2407.
  15. Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Breccia, M.; Gallo, E.; Rambaldi, A.; Paoloni, F.; Fioritoni, G.; Ferrara, F.; Specchia, G.; Cimino, G.; Diverio, D.; Borlenghi, E.; Martinelli, G.; Di Raimondo, F.; Di Bona, E.; Fazi, P.; Peta, A.; Bosi, A.; Carella, A. M.; Fabbiano, F.; Pogliani, E. M.; Petti, M. C.; Amadori, S.; Mandelli, F. (2010). "Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group". Blood. 116 (17): 3171–3179. doi:10.1182/blood-2010-03-276196. ISSN 0006-4971.
  16. Ortega, Juan J.; Madero, Luis; Martín, Guillermo; Verdeguer, Amparo; García, Purificación; Parody, Ricardo; Fuster, José; Molines, Antonio; Novo, Andrés; Debén, Guillermo; Rodríguez, Antonia; Conde, Eulogio; de la Serna, Javier; Allegue, María J.; Capote, Francisco J.; González, José D.; Bolufer, Pascual; González, Marcos; Sanz, Miguel A. (2005). "Treatment With All-TransRetinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group". Journal of Clinical Oncology. 23 (30): 7632–7640. doi:10.1200/JCO.2005.01.3359. ISSN 0732-183X.
  17. Prakasha Gowda, A. S.; Polizzi, Joanna M.; Eckert, Kristin A.; Spratt, Thomas E. (2010). "Incorporation of Gemcitabine and Cytarabine into DNA by DNA Polymerase β and Ligase III/XRCC1". Biochemistry. 49 (23): 4833–4840. doi:10.1021/bi100200c. ISSN 0006-2960.
  18. Löwenberg, Bob; Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C.; Graux, Carlos; Ferrant, Augustin; Sonneveld, Pieter; Biemond, Bart J.; Gratwohl, Alois; de Greef, Georgine E.; Verdonck, Leo F.; Schaafsma, Martijn R.; Gregor, Michael; Theobald, Matthias; Schanz, Urs; Maertens, Johan; Ossenkoppele, Gert J. (2011). "Cytarabine Dose for Acute Myeloid Leukemia". New England Journal of Medicine. 364 (11): 1027–1036. doi:10.1056/NEJMoa1010222. ISSN 0028-4793.
  19. Shepshelovich, Daniel; Edel, Yonatan; Goldvaser, Hadar; Dujovny, Tal; Wolach, Ofir; Raanani, Pia (2015). "Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study". British Journal of Clinical Pharmacology. 79 (4): 685–691. doi:10.1111/bcp.12530. ISSN 0306-5251.
  20. McGowan, John V; Chung, Robin; Maulik, Angshuman; Piotrowska, Izabela; Walker, J Malcolm; Yellon, Derek M (2017). "Anthracycline Chemotherapy and Cardiotoxicity". Cardiovascular Drugs and Therapy. 31 (1): 63–75. doi:10.1007/s10557-016-6711-0. ISSN 0920-3206.
  21. Sun, Zimin; Zhou, Li; Liu, Xin; Liu, Huilan; Zhu, Weibo; Cai, Xiaoyan; Song, Kaidi; Zheng, Changcheng; Tang, Baolin (2016). "A comparative study of idarubicin 12 mg/m2 and 8 mg/m2 combined with cytarabine as the first induction regimen for adult acute myeloid leukemia patients". OncoTargets and Therapy: 985. doi:10.2147/OTT.S96176. ISSN 1178-6930.
  22. Volkova, Maria; Russell, Raymond (2012). "Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment". Current Cardiology Reviews. 7 (4): 214–220. doi:10.2174/157340311799960645. ISSN 1573-403X.
  23. Herrmann, Joerg; Lerman, Amir; Sandhu, Nicole P.; Villarraga, Hector R.; Mulvagh, Sharon L.; Kohli, Manish (2014). "Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology". Mayo Clinic Proceedings. 89 (9): 1287–1306. doi:10.1016/j.mayocp.2014.05.013. ISSN 0025-6196.
  24. Fathi AT, Karp JE (September 2009). "New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines". Curr Oncol Rep. 11 (5): 346–52. PMC 3066101. PMID 19679009.
  25. Nascimento B, Goodnough LT, Levy JH (December 2014). "Cryoprecipitate therapy". Br J Anaesth. 113 (6): 922–34. doi:10.1093/bja/aeu158. PMC 4627369. PMID 24972790.
  26. Pandey S, Vyas GN (May 2012). "Adverse effects of plasma transfusion". Transfusion. 52 Suppl 1: 65S–79S. doi:10.1111/j.1537-2995.2012.03663.x. PMC 3356109. PMID 22578374.
  27. Ikezoe, Takayuki (2013). "Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin". International Journal of Hematology. 100 (1): 27–37. doi:10.1007/s12185-013-1463-0. ISSN 0925-5710.
  28. Sahu S, Hemlata, Verma A (September 2014). "Adverse events related to blood transfusion". Indian J Anaesth. 58 (5): 543–51. doi:10.4103/0019-5049.144650. PMC 4260299. PMID 25535415.
  29. Brittenham GM (January 2011). "Iron-chelating therapy for transfusional iron overload". N. Engl. J. Med. 364 (2): 146–56. doi:10.1056/NEJMct1004810. PMC 3078566. PMID 21226580.
  30. Song YH, Peng P, Qiao C, Zhang R, Li JY, Lu H (2017). "Low platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia". Onco Targets Ther. 10: 4917–4924. doi:10.2147/OTT.S144438. PMC 5640392. PMID 29062237.
  31. Pandey S, Vyas GN (May 2012). "Adverse effects of plasma transfusion". Transfusion. 52 Suppl 1: 65S–79S. doi:10.1111/j.1537-2995.2012.03663.x. PMC 3356109. PMID 22578374.
  32. Usuki K, Nishizawa Y, Endo M, Osawa M, Kitazume K, Iki S, Watanabe M, Urabe A (October 1996). "Administration of granulocyte colony-stimulating factor during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia". Int. J. Hematol. 64 (3–4): 213–9. PMID 8923783.
  33. Metcalf D (June 2010). "The colony-stimulating factors and cancer". Nat. Rev. Cancer. 10 (6): 425–34. doi:10.1038/nrc2843. PMC 3345291. PMID 20495576.
  34. McCullough J, Clay M, Herr G, Smith J, Stroncek D (October 1999). "Effects of granulocyte-colony-stimulating factor on potential normal granulocyte donors". Transfusion. 39 (10): 1136–40. PMID 10532609.

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