Acute promyelocytic leukemia natural history, complications and prognosis: Difference between revisions

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


==Overview==
==Overview==
The [[Natural history of disease|natural history]] of acute promyelocytic leukemia is characterized by [[Symptom|symptoms]] related to defective normal [[blood cell]] production. These [[Symptom|symptoms]] include [[fatigue]], [[bleeding]], and [[infection]]. [[Complication (medicine)|Complications]] include [[thrombosis]] and [[hemorrhage]], which eventually occur in a significant proportion of [[Patient|patients]]. Early death is common and is related to [[bleeding]] [[Complication (medicine)|complications]]. Therapy-related [[Complication (medicine)|complications]] include [[differentiation]] [[syndrome]], [[QT prolongation|QT interval prolongation]], and [[cardiomyopathy]]. The [[prognosis]] of acute promyelocytic leukemia was previously poor, but the advent of [[arsenic trioxide]] and all-''[[trans]]'' [[retinoic acid]] has rendered the [[prognosis]] to be far more favorable in the recent years.
The natural history of acute promyelocytic leukemia is characterized by symptoms related to defective normal blood cell production. These symptoms include [[fatigue]], [[bleeding]], and [[infection]]. [[Complication (medicine)|Complications]] include [[thrombosis]] and [[hemorrhage]], which eventually occur in a significant proportion of patients. Early death is common and is related to [[bleeding]] [[Complication (medicine)|complications]]. Therapy-related [[Complication (medicine)|complications]] include [[differentiation]] [[syndrome]], [[QT prolongation|QT interval prolongation]], and [[cardiomyopathy]]. The [[prognosis]] of acute promyelocytic leukemia was previously poor, but the advent of [[arsenic trioxide]] and all-''[[trans]]'' [[retinoic acid]] has rendered the prognosis to be far more favorable in the recent years.


==Natural History==
==Natural History==
* Acute promyelocytic leukemia typically begins with a combination of [[Symptom|symptoms]] including [[fatigue]], [[bleeding]], and [[Infection|infections]] (such as upper [[respiratory tract infection]]). [[Patient|Patients]] typically present to their [[primary care physician]] with such [[Symptom|symptoms]], and a [[complete blood count]] usually reveals a low [[white blood cell]] count, low [[hemoglobin]], and low [[platelet count]]. A [[bone marrow biopsy]] is usually done to work up the [[abnormal]] [[laboratory]] values, and a [[diagnosis]] of acute promyelocytic leukemia is made. In the first few days to weeks of the [[disease]], there is a high risk of [[bleeding]] due to [[disseminated intravascular coagulation]], a condition characterized by [[abnormal]] [[thrombus]] formation and breakdown.<ref name="pmid16504043">{{cite journal| author=Franchini M, Lippi G, Manzato F| title=Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation. | journal=Thromb J | year= 2006 | volume= 4 | issue=  | pages= 4 | pmid=16504043 | doi=10.1186/1477-9560-4-4 | pmc=1402263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16504043  }} </ref>
* Acute promyelocytic leukemia typically begins with a combination of symptoms including [[fatigue]], [[bleeding]], and [[Infection|infections]] (such as upper [[respiratory tract infection]]).  
* The median survival in the absence of treatment is typically one week, due to [[bleeding]] [[Complication (medicine)|complications]] contributing to [[Mortality rate|mortality]].<ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>
* Patients typically present to their [[primary care physician]] with such symptoms and a diagnosis of acute promyelocytic leukemia is made using [[complete blood count]] and a [[bone marrow biopsy]].
* The high early [[mortality]] rate was previously a major part of the [[Natural history of disease|natural history of the disease]], prior to the advent of rapid [[diagnostic]] and [[therapeutic]] interventions for this [[disease]].<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref> In areas of the United States with limited [[Health care|healthcare]] or highly specialized academic centers, [[bleeding]] diathesis continues to remain a major part of the [[Natural history of disease|natural history of the disease]]. Such [[bleeding]] [[Complication (medicine)|complications]] include [[gingival bleeding]] (very common), [[Bruise|bruising]] (very common), [[epistaxis]], [[menorrhagia]] (less common). In areas of the United States with readily available [[Health care|healthcare]] and specialized academic medical centers, the [[Natural history of disease|natural history of the disease]] takes a favorable trajectory, as the cure rate is quite high if appropriate [[Induction (biology)|induction]] [[therapy]] is initiated.<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref>
* In the first few days to weeks of the disease, there is a high risk of [[bleeding]] due to [[disseminated intravascular coagulation]].<ref name="pmid16504043">{{cite journal| author=Franchini M, Lippi G, Manzato F| title=Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation. | journal=Thromb J | year= 2006 | volume= 4 | issue=  | pages= 4 | pmid=16504043 | doi=10.1186/1477-9560-4-4 | pmc=1402263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16504043  }} </ref>
* The median survival in the absence of treatment is typically one week, due to [[bleeding]] [[Complication (medicine)|complications]] contributing to mortality.<ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>
* The high early [[mortality]] rate was previously a major part of the [[Natural history of disease|natural history of the disease]], prior to the advent of rapid [[diagnostic]] and [[therapeutic]] interventions for this disease.<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref>  
* In areas of the United States  
** '''With limited healthcare or highly specialized academic centers''': [[Bleeding diathesis]] continues to remain a major part of the [[Natural history of disease|natural history of the disease]]. Such bleeding complications include [[gingival bleeding]], [[Bruise|bruising]], [[epistaxis]], and [[menorrhagia]].
** '''With readily available healthcare and specialized academic medical centers:''' The natural history of the disease takes a favorable trajectory, as the cure rate is quite high if appropriate induction therapy is initiated.<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref>


==Complications==
==Complications==
*'''Hemorrhage''': Acute promyelocytic leukemia is frequently associated with [[bleeding]] caused by [[disseminated intravascular coagulation]] ([[DIC]]). [[Hemorrhagic]] and [[bleeding diathesis]] is the major cause of early [[Complication (medicine)|complications]] that can lead to immediate death in [[Patient|patients]] with acute promyelocytic leukemia. For this reason, [[prompt]] treatment of the [[disease]] is required.<ref name="ChoudhryDeLoughery2012">{{cite journal|last1=Choudhry|first1=Aditi|last2=DeLoughery|first2=Thomas G.|title=Bleeding and thrombosis in acute promyelocytic leukemia|journal=American Journal of Hematology|volume=87|issue=6|year=2012|pages=596–603|issn=03618609|doi=10.1002/ajh.23158}}</ref><ref name="ChoudhryDeLoughery20122">{{cite journal|last1=Choudhry|first1=Aditi|last2=DeLoughery|first2=Thomas G.|title=Bleeding and thrombosis in acute promyelocytic leukemia|journal=American Journal of Hematology|volume=87|issue=6|year=2012|pages=596–603|issn=03618609|doi=10.1002/ajh.23158}}</ref>
*'''Hemorrhage''': Acute promyelocytic leukemia is frequently associated with [[bleeding]] caused by [[disseminated intravascular coagulation]] (DIC). [[Hemorrhagic]] and [[bleeding diathesis]] are the major causes of early [[Complication (medicine)|complications]] that can lead to immediate death in patients with acute promyelocytic leukemia. For this reason, prompt treatment of the disease is required.<ref name="ChoudhryDeLoughery2012">{{cite journal|last1=Choudhry|first1=Aditi|last2=DeLoughery|first2=Thomas G.|title=Bleeding and thrombosis in acute promyelocytic leukemia|journal=American Journal of Hematology|volume=87|issue=6|year=2012|pages=596–603|issn=03618609|doi=10.1002/ajh.23158}}</ref><ref name="ChoudhryDeLoughery20122">{{cite journal|last1=Choudhry|first1=Aditi|last2=DeLoughery|first2=Thomas G.|title=Bleeding and thrombosis in acute promyelocytic leukemia|journal=American Journal of Hematology|volume=87|issue=6|year=2012|pages=596–603|issn=03618609|doi=10.1002/ajh.23158}}</ref>
*'''Venous thromboembolism''': [[Thrombus]] formation is a major cause of [[morbidity]] in acute promyelocytic leukemia. [[Thrombosis]] in the setting of acute promyelocytic leukemia is associated with a worse outcome compared to non-cancer-related thrombosis. Studies have shown that rate of [[venous]] [[thromboembolism]] was 10.8 % in [[Patient|patients]] with acute promyelocytic leukemia . The reason for this [[correlation]] between [[thrombosis]] and death in acute promyelocytic leukemia is that [[thrombosis]] is a surrogate marker for [[disease]] progression.<ref name="BreenGrimwade2012">{{cite journal|last1=Breen|first1=Karen A.|last2=Grimwade|first2=David|last3=Hunt|first3=Beverley J.|title=The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia|journal=British Journal of Haematology|volume=156|issue=1|year=2012|pages=24–36|issn=00071048|doi=10.1111/j.1365-2141.2011.08922.x}}</ref><ref name="pmid25487644">{{cite journal| author=Vu K, Luong NV, Hubbard J, Zalpour A, Faderl S, Thomas DA et al.| title=A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center. | journal=Cancer Med | year= 2015 | volume= 4 | issue= 1 | pages= 27-35 | pmid=25487644 | doi=10.1002/cam4.332 | pmc=4312115 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25487644  }} </ref><ref>Al-Ani, F., Ahrari, A., Wang, Y. P., Iansavitchene, A., & Lazo-Langner, A. (2017). Incidence of Venous Thromboembolism in Acute Leukemia: A Systematic Review and Meta-Analysis. Blood, 130(Suppl 1), 5634. Accessed January 15, 2019. Retrieved from http://www.bloodjournal.org/content/130/Suppl_1/5634.</ref><ref name="DickeAmirkhosravi2015">{{cite journal|last1=Dicke|first1=Christina|last2=Amirkhosravi|first2=Ali|last3=Spath|first3=Brigitte|last4=Jiménez-Alcázar|first4=Miguel|last5=Fuchs|first5=Tobias|last6=Davila|first6=Monica|last7=Francis|first7=John L|last8=Bokemeyer|first8=Carsten|last9=Langer|first9=Florian|title=Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study|journal=Experimental Hematology & Oncology|volume=4|issue=1|year=2015|issn=2162-3619|doi=10.1186/s40164-015-0018-x}}</ref>
*'''Venous thromboembolism''': [[Thrombus]] formation is a major cause of [[morbidity]] in acute promyelocytic leukemia. [[Thrombosis]] in the setting of acute promyelocytic leukemia is associated with a worse outcome compared to non-cancer-related thrombosis. Studies have shown that rate of [[venous]] [[thromboembolism]] was 10.8 % in patients with acute promyelocytic leukemia . The reason for this [[correlation]] between thrombosis and death in acute promyelocytic leukemia is that thrombosis is a surrogate marker for disease progression.<ref name="BreenGrimwade2012">{{cite journal|last1=Breen|first1=Karen A.|last2=Grimwade|first2=David|last3=Hunt|first3=Beverley J.|title=The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia|journal=British Journal of Haematology|volume=156|issue=1|year=2012|pages=24–36|issn=00071048|doi=10.1111/j.1365-2141.2011.08922.x}}</ref><ref name="pmid25487644">{{cite journal| author=Vu K, Luong NV, Hubbard J, Zalpour A, Faderl S, Thomas DA et al.| title=A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center. | journal=Cancer Med | year= 2015 | volume= 4 | issue= 1 | pages= 27-35 | pmid=25487644 | doi=10.1002/cam4.332 | pmc=4312115 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25487644  }} </ref><ref>Al-Ani, F., Ahrari, A., Wang, Y. P., Iansavitchene, A., & Lazo-Langner, A. (2017). Incidence of Venous Thromboembolism in Acute Leukemia: A Systematic Review and Meta-Analysis. Blood, 130(Suppl 1), 5634. Accessed January 15, 2019. Retrieved from http://www.bloodjournal.org/content/130/Suppl_1/5634.</ref><ref name="DickeAmirkhosravi2015">{{cite journal|last1=Dicke|first1=Christina|last2=Amirkhosravi|first2=Ali|last3=Spath|first3=Brigitte|last4=Jiménez-Alcázar|first4=Miguel|last5=Fuchs|first5=Tobias|last6=Davila|first6=Monica|last7=Francis|first7=John L|last8=Bokemeyer|first8=Carsten|last9=Langer|first9=Florian|title=Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study|journal=Experimental Hematology & Oncology|volume=4|issue=1|year=2015|issn=2162-3619|doi=10.1186/s40164-015-0018-x}}</ref>
**''Procoagulants'': There is increased production of procoagulant [[Molecule|molecules]] such as [[thrombin]] from [[cancer]] [[Cell (biology)|cells]]. Furthermore, [[Mucin|mucins]] and [[Cytokine|cytokines]] produced by [[malignant]] [[Promyelocyte|promyelocytes]] can induce [[endothelial cells]] to increase [[tissue]] factor production, and [[tissue factor]] functions in the [[extrinsic pathway]] to promote [[coagulation]].<ref name="LimaMonteiro2013">{{cite journal|last1=Lima|first1=Luize G.|last2=Monteiro|first2=Robson Q.|title=Activation of blood coagulation in cancer: implications for tumour progression|journal=Bioscience Reports|volume=33|issue=5|year=2013|pages=701–710|issn=0144-8463|doi=10.1042/BSR20130057}}</ref>
**''Procoagulants'': There is increased production of procoagulant molecules such as [[thrombin]] from cancer cells. Furthermore, [[Mucin|mucins]] and [[Cytokine|cytokines]] produced by [[malignant]] [[Promyelocyte|promyelocytes]] can induce [[endothelial cells]] to increase tissue factor production, and [[tissue factor]] functions in the [[extrinsic pathway]] to promote [[coagulation]].<ref name="LimaMonteiro2013">{{cite journal|last1=Lima|first1=Luize G.|last2=Monteiro|first2=Robson Q.|title=Activation of blood coagulation in cancer: implications for tumour progression|journal=Bioscience Reports|volume=33|issue=5|year=2013|pages=701–710|issn=0144-8463|doi=10.1042/BSR20130057}}</ref>
**''[[Platelet|Platelets]]'': There is a increased [[platelet activation]] in acute promyelocytic leukemia.<ref name="ChoudhryDeLoughery2012" />
**''[[Platelet|Platelets]]'': There is a increased [[platelet activation]] in acute promyelocytic leukemia.<ref name="ChoudhryDeLoughery2012" />
**''[[Fibrin]]'': There is decreased fibrinolytic activity in acute promyelocytic leukemia, and this results in presence of excess [[fibrin]]. Fibrin is also known as [[factor I]] of the [[coagulation]] [[cascade]] and functions to binds [[Platelet|platelets]] together via their [[GpIIb/IIIa]] [[receptors]]. This is one of the final steps in [[coagulation]].<ref>{{cite journal|doi=10.1182/blood-2016-09-739334 PMCID: PMC5374289}}</ref><ref name="pmid29340130">{{cite journal |vauthors=Periayah MH, Halim AS, Mat Saad AZ |title=Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis |journal=Int J Hematol Oncol Stem Cell Res |volume=11 |issue=4 |pages=319–327 |date=October 2017 |pmid=29340130 |pmc=5767294 |doi= |url=}}</ref>
**''[[Fibrin]]'': There is decreased fibrinolytic activity in acute promyelocytic leukemia, and this results in presence of excess [[fibrin]]. Fibrin is also known as [[factor I]] of the [[coagulation]] [[cascade]] and functions to binds [[Platelet|platelets]] together via their [[GpIIb/IIIa]] [[receptors]]. This is one of the final steps in coagulation.<ref>{{cite journal|doi=10.1182/blood-2016-09-739334 PMCID: PMC5374289}}</ref><ref name="pmid29340130">{{cite journal |vauthors=Periayah MH, Halim AS, Mat Saad AZ |title=Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis |journal=Int J Hematol Oncol Stem Cell Res |volume=11 |issue=4 |pages=319–327 |date=October 2017 |pmid=29340130 |pmc=5767294 |doi= |url=}}</ref>
**''Natural anticoagulants'': There is decreased production of natural [[Anticoagulant|anticoagulants]], and this results in increased propensity for [[thrombosis]].<ref name="FloresD Trivedi2017">{{cite journal|last1=Flores|first1=Brisas|last2=D Trivedi|first2=Hirsh|last3=C Robson|first3=Simon|last4=Bonder|first4=Alan|title=Hemostasis, bleeding and thrombosis in liver disease|journal=Journal of Translational Science|volume=3|issue=3|year=2017|issn=2059268X|doi=10.15761/JTS.1000182}}</ref>
**''Natural [[anticoagulants]]'': There is decreased production of natural anticoagulants, and this results in increased propensity for [[thrombosis]].<ref name="FloresD Trivedi2017">{{cite journal|last1=Flores|first1=Brisas|last2=D Trivedi|first2=Hirsh|last3=C Robson|first3=Simon|last4=Bonder|first4=Alan|title=Hemostasis, bleeding and thrombosis in liver disease|journal=Journal of Translational Science|volume=3|issue=3|year=2017|issn=2059268X|doi=10.15761/JTS.1000182}}</ref>
**''Catheters'': Central [[venous]] [[catheters]] can serve as a nidus for [[thrombosis]] since there is localized [[tissue]] and [[endothelial]] damage at the site of [[catheter]] [[insertion]] and along the [[Catheter|cathete]]<nowiki/>r within the [[Human body|body]]. [[Patient|Patients]] with acute promyelocytic leukemia are more likely to have central [[venous]] [[Catheter|catheters]], compared to [[Patient|patients]] with other conditions, since [[chemotherapy]] usually requires the presence of a [[central]] [[catheter]] to be placed.<ref name="pmid25487644" /><ref name="Avvisati2011">{{cite journal|last1=Avvisati|first1=Giuseppe|title=HOW I TREAT NEWLY DIAGNOSED ACUTE PROMYELOCYTIC LEUKEMIA|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=3|issue=1|year=2011|pages=e2011064|issn=2035-3006|doi=10.4084/mjhid.2011.064}}</ref><ref name="FangYang2017">{{cite journal|last1=Fang|first1=Shirong|last2=Yang|first2=Jinhong|last3=Song|first3=Lei|last4=Jiang|first4=Yan|last5=Liu|first5=Yuxiu|title=Comparison of three types of central venous catheters in patients with malignant tumor receiving chemotherapy|journal=Patient Preference and Adherence|volume=Volume 11|year=2017|pages=1197–1204|issn=1177-889X|doi=10.2147/PPA.S142556}}</ref>
**''Catheters'': Central venous [[catheters]] can serve as a nidus for thrombosis since there is localized [[tissue]] and [[endothelial]] damage at the site of catheter insertion and along the cathete<nowiki/>r within the body. Patients with acute promyelocytic leukemia are more likely to have central venous catheters, compared to patients with other conditions, since chemotherapy usually requires the presence of a central catheter to be placed.<ref name="pmid25487644" /><ref name="Avvisati2011">{{cite journal|last1=Avvisati|first1=Giuseppe|title=HOW I TREAT NEWLY DIAGNOSED ACUTE PROMYELOCYTIC LEUKEMIA|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=3|issue=1|year=2011|pages=e2011064|issn=2035-3006|doi=10.4084/mjhid.2011.064}}</ref><ref name="FangYang2017">{{cite journal|last1=Fang|first1=Shirong|last2=Yang|first2=Jinhong|last3=Song|first3=Lei|last4=Jiang|first4=Yan|last5=Liu|first5=Yuxiu|title=Comparison of three types of central venous catheters in patients with malignant tumor receiving chemotherapy|journal=Patient Preference and Adherence|volume=Volume 11|year=2017|pages=1197–1204|issn=1177-889X|doi=10.2147/PPA.S142556}}</ref>
**''Immobility'': [[Patient|patients]] with acute promyelocytic leukemia are frequently confined to a hospital bed during [[Induction (biology)|induction]] [[therapy]], and [[venous stasis]] contributes to [[thrombosis]]. Obesity can also contribute to [[thrombosis]].<ref name="DallyHoffman2005">{{cite journal|last1=Dally|first1=Najib|last2=Hoffman|first2=Ron|last3=Haddad|first3=Nuhad|last4=Sarig|first4=Galit|last5=Rowe|first5=Jacob M.|last6=Brenner|first6=Benjamin|title=Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia—a single center experience in 34 patients|journal=Thrombosis Research|volume=116|issue=2|year=2005|pages=109–114|issn=00493848|doi=10.1016/j.thromres.2004.11.001}}</ref>
**''Immobility'': Patients with acute promyelocytic leukemia are frequently confined to a hospital bed during induction therapy, and [[venous stasis]] contributes to [[thrombosis]]. Obesity can also contribute to thrombosis.<ref name="DallyHoffman2005">{{cite journal|last1=Dally|first1=Najib|last2=Hoffman|first2=Ron|last3=Haddad|first3=Nuhad|last4=Sarig|first4=Galit|last5=Rowe|first5=Jacob M.|last6=Brenner|first6=Benjamin|title=Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia—a single center experience in 34 patients|journal=Thrombosis Research|volume=116|issue=2|year=2005|pages=109–114|issn=00493848|doi=10.1016/j.thromres.2004.11.001}}</ref>
**''Erythropoiesis-stimulating agents'': [[Patients Not Patents|patients]] with acute promyelocytic leukemia frequently have [[anemia]]. Some [[Patient|patients]] receive [[Erythropoiesis-stimulating agent|erythropoiesis-stimulating agents]], such as [[erythropoietin]], which can increase [[red blood cell]] production and exacerbate [[Thrombosis|thrombotic]] [[Complication (medicine)|complications]].<ref name="HandigundMalur2012">{{cite journal|last1=Handigund|first1=Rajeshwari Satish|last2=Malur|first2=Prakash R.|last3=Dhumale|first3=Annasaheb J.|last4=Bali|first4=Akshay|last5=Roy|first5=Maitrayee|last6=Inumella|first6=Suvarna|title=Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?|journal=Indian Journal of Hematology and Blood Transfusion|volume=30|issue=1|year=2012|pages=64–67|issn=0971-4502|doi=10.1007/s12288-012-0201-8}}</ref><ref name="BittencourtTeixeira Junior2011">{{cite journal|last1=Bittencourt|first1=Henrique|last2=Teixeira Junior|first2=Antonio Lucio|last3=Glória|first3=Ana Beatriz Firmato|last4=Ribeiro|first4=Ana Flávia Leonardi Tiburcio|last5=Fagundes|first5=Evandro Maranhão|title=Acute promyelocytic leukemia presenting as an extradural mass|journal=Revista Brasileira de Hematologia e Hemoterapia|volume=33|issue=6|year=2011|pages=478–480|issn=1516-8484|doi=10.5581/1516-8484.20110126}}</ref><ref name="FibachRachmilewitz2017">{{cite journal|last1=Fibach|first1=Eitan|last2=Rachmilewitz|first2=Eliezer A.|title=Iron overload in hematological disorders|journal=La Presse Médicale|volume=46|issue=12|year=2017|pages=e296–e305|issn=07554982|doi=10.1016/j.lpm.2017.10.007}}</ref>
**''Erythropoiesis-stimulating agents'': Patients with acute promyelocytic leukemia frequently have [[anemia]]. Some patients receive [[Erythropoiesis-stimulating agent|erythropoiesis-stimulating agents]], such as [[erythropoietin]], which can increase [[red blood cell]] production and exacerbate [[Thrombosis|thrombotic]] [[Complication (medicine)|complications]].<ref name="HandigundMalur2012">{{cite journal|last1=Handigund|first1=Rajeshwari Satish|last2=Malur|first2=Prakash R.|last3=Dhumale|first3=Annasaheb J.|last4=Bali|first4=Akshay|last5=Roy|first5=Maitrayee|last6=Inumella|first6=Suvarna|title=Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?|journal=Indian Journal of Hematology and Blood Transfusion|volume=30|issue=1|year=2012|pages=64–67|issn=0971-4502|doi=10.1007/s12288-012-0201-8}}</ref><ref name="BittencourtTeixeira Junior2011">{{cite journal|last1=Bittencourt|first1=Henrique|last2=Teixeira Junior|first2=Antonio Lucio|last3=Glória|first3=Ana Beatriz Firmato|last4=Ribeiro|first4=Ana Flávia Leonardi Tiburcio|last5=Fagundes|first5=Evandro Maranhão|title=Acute promyelocytic leukemia presenting as an extradural mass|journal=Revista Brasileira de Hematologia e Hemoterapia|volume=33|issue=6|year=2011|pages=478–480|issn=1516-8484|doi=10.5581/1516-8484.20110126}}</ref><ref name="FibachRachmilewitz2017">{{cite journal|last1=Fibach|first1=Eitan|last2=Rachmilewitz|first2=Eliezer A.|title=Iron overload in hematological disorders|journal=La Presse Médicale|volume=46|issue=12|year=2017|pages=e296–e305|issn=07554982|doi=10.1016/j.lpm.2017.10.007}}</ref>
In a 2015 study from MD Anderson [[Cancer]] Center, it was shown that the annual incidence of venous [[thromboembolism]], which includes [[deep vein thrombosis]] and [[pulmonary embolism]], was 6.1-42%, which is the highest amongst all [[leukemia]] subtypes. In contrast, the incidence of [[venous]] [[thromboembolism]] in [[Chronic (medical)|chronic]] [[myeloid]] [[leukemia]] was only 1.5%.<ref name="pmid25487644" />  
In a 2015 study from MD Anderson Cancer Center, it was shown that the annual incidence of venous [[thromboembolism]], which includes [[deep vein thrombosis]] and [[pulmonary embolism]], was 6.1-42%, which is the highest amongst all [[leukemia]] sub-types. In contrast, the incidence of venous [[thromboembolism]] in [[Chronic (medical)|chronic]] myeloid [[leukemia]] was only 1.5%.<ref name="pmid25487644" />  


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*'''Therapy-related complications:''' Treatment of acute promyelocytic leukemia can result in a variety of [[Complication (medicine)|complications]] which are somewhat unique to the [[disease]].
*'''Therapy-related complications:''' Treatment of acute promyelocytic leukemia can result in a variety of complications, which are somewhat unique to the disease.
**''Differentiation syndrome'':<ref name="SanzMontesinos2014">{{cite journal|last1=Sanz|first1=M. A.|last2=Montesinos|first2=P.|title=How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia|journal=Blood|volume=123|issue=18|year=2014|pages=2777–2782|issn=0006-4971|doi=10.1182/blood-2013-10-512640}}</ref><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="RegoDe Santis2011">{{cite journal|last1=Rego|first1=Eduardo Magalhães|last2=De Santis|first2=Gil Cunha|title=DIFFERENTIATION SYNDROME IN PROMYELOCYTIC LEUKEMIA : CLINICAL PRESENTATION, PATHOGENESIS AND TREATMENT|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=3|issue=1|year=2011|pages=e2011048|issn=2035-3006|doi=10.4084/mjhid.2011.048}}</ref><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><ref name="SanzMontesinos20142">{{cite journal|last1=Sanz|first1=M. A.|last2=Montesinos|first2=P.|title=How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia|journal=Blood|volume=123|issue=18|year=2014|pages=2777–2782|issn=0006-4971|doi=10.1182/blood-2013-10-512640}}</ref><ref name="MontesinosSanz20112">{{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>
**''Differentiation syndrome'':<ref name="SanzMontesinos2014">{{cite journal|last1=Sanz|first1=M. A.|last2=Montesinos|first2=P.|title=How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia|journal=Blood|volume=123|issue=18|year=2014|pages=2777–2782|issn=0006-4971|doi=10.1182/blood-2013-10-512640}}</ref><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="RegoDe Santis2011">{{cite journal|last1=Rego|first1=Eduardo Magalhães|last2=De Santis|first2=Gil Cunha|title=DIFFERENTIATION SYNDROME IN PROMYELOCYTIC LEUKEMIA : CLINICAL PRESENTATION, PATHOGENESIS AND TREATMENT|journal=Mediterranean Journal of Hematology and Infectious Diseases|volume=3|issue=1|year=2011|pages=e2011048|issn=2035-3006|doi=10.4084/mjhid.2011.048}}</ref><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><ref name="SanzMontesinos20142">{{cite journal|last1=Sanz|first1=M. A.|last2=Montesinos|first2=P.|title=How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia|journal=Blood|volume=123|issue=18|year=2014|pages=2777–2782|issn=0006-4971|doi=10.1182/blood-2013-10-512640}}</ref><ref name="MontesinosSanz20112">{{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>
***[[Differentiation]] [[syndrome]] is a clinical condition that results from treatment with all-''[[trans]]'' [[retinoic acid]].  
***Differentiation syndrome is a clinical condition that results from treatment with all-''[[trans]]'' [[retinoic acid]].  
***[[Differentiation]] [[syndrome]] This condition is characterized by weight gain, [[peripheral edema]], [[hypoxia]], [[dyspnea]], [[renal]] [[failure]], [[fever]], and [[hypotension]].  
***Differentiation syndrome This condition is characterized by weight gain, [[peripheral edema]], [[hypoxia]], [[dyspnea]], [[renal]] [[failure]], [[fever]], and [[hypotension]].  
***The [[syndrome]] is thought to be due to [[systemic]] [[inflammation]] induced by the release of [[Cytokine|cytokines]] from [[malignant]] promyelocytes. This results in [[endothelial cell]] damage with resultant [[capillary]] leakage. [[Malignant]] [[Promyelocyte|promyelocytes]] are then able to adhere to [[Tissue (biology)|tissue]] that is perfused by the [[microcirculation]]. [[Patient|Patients]] with a high [[white blood cell]] count are at highest risk for differentiation syndrome, since all-''[[trans]]'' [[retinoic acid]] will result in release of a large amount of [[Cytokine|cytokines]] if there is a high leukemia burden. Differentiation syndrome is a major [[Complication (medicine)|complication]] that must be recognized early on, such that proper corrective measures can be taken. These include the use of [[dexamethasone]] 10 mg PO twice daily, plus supportive treatment for any underlying respiratory distress. Diruesis may be needed to help eliminate excess fluid accumulation.
***The syndrome is thought to be due to [[systemic]] [[inflammation]] induced by the release of [[Cytokine|cytokines]] from [[malignant]] promyelocytes. This results in [[endothelial cell]] damage with resultant capillary leakage. [[Malignant]] promyelocytes are then able to adhere to tissue that is perfused by the [[microcirculation|micro-circulation]]. Patients with a high [[white blood cell]] count are at highest risk for differentiation syndrome, since all-''[[trans]]'' [[retinoic acid]] will result in release of a large amount of [[Cytokine|cytokines]] if there is a high leukemia burden. Differentiation syndrome is a major complication that must be recognized early on, such that proper corrective measures can be taken. These include the use of [[dexamethasone]] 10 mg PO twice daily, plus supportive treatment for any underlying respiratory distress. [[Diuresis]] may be needed to help eliminate excess fluid accumulation.
**''[[QT prolongation|QT interval prolongation]]'':<ref name="Porta‐SánchezGilbert2017">{{cite journal|last1=Porta‐Sánchez|first1=Andreu|last2=Gilbert|first2=Cameron|last3=Spears|first3=Danna|last4=Amir|first4=Eitan|last5=Chan|first5=Joyce|last6=Nanthakumar|first6=Kumaraswamy|last7=Thavendiranathan|first7=Paaladinesh|title=Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review|journal=Journal of the American Heart Association|volume=6|issue=12|year=2017|issn=2047-9980|doi=10.1161/JAHA.117.007724}}</ref><ref name="BarbeyPezzullo2003">{{cite journal|last1=Barbey|first1=Jean T.|last2=Pezzullo|first2=John C.|last3=Soignet|first3=Steven L.|title=Effect of Arsenic Trioxide on QT Interval in Patients With Advanced Malignancies|journal=Journal of Clinical Oncology|volume=21|issue=19|year=2003|pages=3609–3615|issn=0732-183X|doi=10.1200/JCO.2003.10.009}}</ref><ref name="McCullochBrown2017">{{cite journal|last1=McCulloch|first1=Derek|last2=Brown|first2=Christina|last3=Iland|first3=Harry|title=Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives|journal=OncoTargets and Therapy|volume=Volume 10|year=2017|pages=1585–1601|issn=1178-6930|doi=10.2147/OTT.S100513}}</ref>  
**''[[QT prolongation|QT interval prolongation]]'':<ref name="Porta‐SánchezGilbert2017">{{cite journal|last1=Porta‐Sánchez|first1=Andreu|last2=Gilbert|first2=Cameron|last3=Spears|first3=Danna|last4=Amir|first4=Eitan|last5=Chan|first5=Joyce|last6=Nanthakumar|first6=Kumaraswamy|last7=Thavendiranathan|first7=Paaladinesh|title=Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review|journal=Journal of the American Heart Association|volume=6|issue=12|year=2017|issn=2047-9980|doi=10.1161/JAHA.117.007724}}</ref><ref name="BarbeyPezzullo2003">{{cite journal|last1=Barbey|first1=Jean T.|last2=Pezzullo|first2=John C.|last3=Soignet|first3=Steven L.|title=Effect of Arsenic Trioxide on QT Interval in Patients With Advanced Malignancies|journal=Journal of Clinical Oncology|volume=21|issue=19|year=2003|pages=3609–3615|issn=0732-183X|doi=10.1200/JCO.2003.10.009}}</ref><ref name="McCullochBrown2017">{{cite journal|last1=McCulloch|first1=Derek|last2=Brown|first2=Christina|last3=Iland|first3=Harry|title=Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives|journal=OncoTargets and Therapy|volume=Volume 10|year=2017|pages=1585–1601|issn=1178-6930|doi=10.2147/OTT.S100513}}</ref>  
***[[Arsenic trioxide]] can result in [[prolonged QT interval]], which carries a risk for [[cardiac]]-related [[Complication (medicine)|complications]] such as [[arrhythmias]]. [[Patient|Patients]] who are treated with [[arsenic trioxide]] must have routine [[Electrocardiogram|electrocardiograms (EKGs)]] done to ensure that the corrected [[QT interval]] remains less than 500 milliseconds.
***[[Arsenic trioxide]] can result in [[prolonged QT interval]], which carries a risk for cardiac-related complications such as [[arrhythmias]]. Patients who are treated with arsenic trioxide must have routine [[Electrocardiogram|electrocardiograms (EKGs)]] done to ensure that the corrected [[QT interval]] remains less than 500 milliseconds.
***In [[patients]] who are treated with concomitant [[chemotherapy]] and [[arsenic trioxide]], such as [[Patient|patients]] with high-risk acute promyelocytic leukemia, there is a higher risk for [[cardiac]]-related [[Complication (medicine)|complications]]. [[Chemotherapy]] and intravenous fluids can alter [[electrolyte]] such as [[potassium]] levels. [[Hypokalemia]] (low [[potassium]]) can exacerbate [[QT prolongation]].
***In patients who are treated with concomitant [[chemotherapy]] and arsenic trioxide, such as patients with high-risk acute promyelocytic leukemia, there is a higher risk for cardiac-related complications. Chemotherapy and intravenous fluids can alter [[electrolyte]] such as [[potassium]] levels. [[Hypokalemia]] (low potassium) can exacerbate QT prolongation.
**''[[Cardiomyopathy]]'':<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>
**''[[Cardiomyopathy]]'':<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><ref name="Shakir2009">{{cite journal|last1=Shakir|first1=Douraid|title=Chemotherapy Induced Cardiomyopathy: Pathogenesis, Monitoring and Management|journal=Journal of Clinical Medicine Research|year=2009|issn=19183003|doi=10.4021/jocmr2009.02.1225}}</ref>
***[[Patient|Patients]] receiving [[chemotherapy]] with [[Anthracycline|anthracyclines]], such as [[idarubicin]] or [[daunorubicin]], are at risk for short-term [[cardiac]]-related [[Complication (medicine)|complications]] such as [[arrhythmias]] and long-term [[cardiac]]-related [[Complication (medicine)|complications]] such as [[systolic dysfunction]] and [[heart failure]].  
***Patients receiving [[chemotherapy]] with [[Anthracycline|anthracyclines]], such as [[idarubicin]] or [[daunorubicin]], are at risk for short-term cardiac-related complications such as arrhythmias and long-term cardiac-related complications such as [[systolic dysfunction]] and [[heart failure]].  
***The highest risk of these [[Complication (medicine)|complications]] occurs in [[Patient|patients]] with underlying [[cardiomyopathy]] such as [[congestive heart failure]], [[atrial fibrillation]], or other [[Heart|cardiac]] issues. The [[cardiotoxicity]] of [[anthracyclines]] is [[dose]]-dependent and generally [[irreversible]].
***The highest risk of these complications occurs in patients with underlying [[cardiomyopathy]] such as [[congestive heart failure]], [[atrial fibrillation]], or other cardiac issues. The [[cardiotoxicity]] of anthracyclines is dose-dependent and generally [[irreversible]].


==Prognosis==
==Prognosis==
Prior to the introduction of readily available diagnostics and targeted therapeutics, the prognosis of acute promyelocytic leukemia was previously very poor, especially in the early phase of the disease. The poor prognosis was due to high bleeding risk and death from hemorrhagic complications due to [[disseminated intravascular coagulation]]. Death typically occurs with a few days to weeks in the absence of treatment. The early death rate is estimated to be 17.3%, based on a large population-based analysis conducted in the United Stated between 1992-2007.<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> <ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref> The 5-year survival rate is only 30-40% after 5 years in younger patients.<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> In the current era of medicine (after the introduction of all-''trans'' retinoic acid and arsenic trioxide, the prognosis of acute promyelocytic leukemia carries a much better prognosis.<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref> Patients can achieve long-term, durable remission if treated appropriately in an expedited manner with medications such as [[all-''trans'' retinoic acid]], [[arsenic trioxide]], or cytotoxic chemotherapy. The current overall survival rate is 86-97%, and the complete remission rate is 90-100%.<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> In a multicenter study published in 2017 evaluating long-term outcomes of patients with acute promyelocytic leukemia, the complete remission rate was 96%.<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> Induction mortality if low at 4%.<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>
* Prior to the introduction of readily available [[Diagnosis|diagnostics]] and targeted [[therapeutics]], the [[prognosis]] of acute promyelocytic leukemia was previously very poor, especially in the early phase of the disease.<ref name="CoombsTavakkoli2015">{{cite journal|last1=Coombs|first1=C C|last2=Tavakkoli|first2=M|last3=Tallman|first3=M S|title=Acute promyelocytic leukemia: where did we start, where are we now and the future|journal=Blood Cancer Journal|volume=5|issue=4|year=2015|pages=e304–e304|issn=2044-5385|doi=10.1038/bcj.2015.25}}</ref><ref name="EfficaceBreccia2018">{{cite journal|last1=Efficace|first1=Fabio|last2=Breccia|first2=Massimo|last3=Avvisati|first3=Giuseppe|last4=Cottone|first4=Francesco|last5=Intermesoli|first5=Tamara|last6=Borlenghi|first6=Erika|last7=Carluccio|first7=Paola|last8=Rodeghiero|first8=Francesco|last9=Fabbiano|first9=Francesco|last10=Luppi|first10=Mario|last11=Romani|first11=Claudio|last12=Sborgia|first12=Marco|last13=D’Ardia|first13=Stefano|last14=Nobile|first14=Francesco|last15=Cantore|first15=Nicola|last16=Crugnola|first16=Monica|last17=Nadali|first17=Gianpaolo|last18=Vignetti|first18=Marco|last19=Amadori|first19=Sergio|last20=Lo Coco|first20=Francesco|title=Health-related quality of life, symptom burden, and comorbidity in long-term survivors of acute promyelocytic leukemia|journal=Leukemia|year=2018|issn=0887-6924|doi=10.1038/s41375-018-0325-4}}</ref>
* The poor prognosis was due to high bleeding risk and death from [[hemorrhagic]] [[Complication (medicine)|complications]] due to [[disseminated intravascular coagulation]]. Death typically occurs within a few days to weeks in the absence of treatment. The early death rate is estimated to be 17.3%, based on a large population-based [[analysis]] that was conducted in the United Stated between 1992-2007.<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> <ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>  
* The 5-year survival rate is only 30-40% after 5 years in younger patients.<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> In the current era of medicine (after the introduction of all-''trans'' retinoic acid and arsenic trioxide), the prognosis of acute promyelocytic leukemia carries a much better prognosis.<ref name="pmid25885425">{{cite journal| author=Coombs CC, Tavakkoli M, Tallman MS| title=Acute promyelocytic leukemia: where did we start, where are we now, and the future. | journal=Blood Cancer J | year= 2015 | volume= 5 | issue=  | pages= e304 | pmid=25885425 | doi=10.1038/bcj.2015.25 | pmc=4450325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25885425  }} </ref>
* Patients can achieve long-term, durable remission if treated appropriately in an expedited manner with medications such as [[all-''trans'' retinoic acid]], [[arsenic trioxide]], or cytotoxic chemotherapy. The current overall survival rate is 86-97%, and the complete remission rate is 90-100%.<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>  
* In a multi-center study published in 2017 that evaluated the long-term outcomes of patients with acute promyelocytic leukemia, the complete remission rate was 96% <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> and [[Induction (biology)|induction]] mortality if low at 4%.<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>


==References==
==References==

Latest revision as of 16:15, 8 April 2019

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

Overview

The natural history of acute promyelocytic leukemia is characterized by symptoms related to defective normal blood cell production. These symptoms include fatigue, bleeding, and infection. Complications include thrombosis and hemorrhage, which eventually occur in a significant proportion of patients. Early death is common and is related to bleeding complications. Therapy-related complications include differentiation syndrome, QT interval prolongation, and cardiomyopathy. The prognosis of acute promyelocytic leukemia was previously poor, but the advent of arsenic trioxide and all-trans retinoic acid has rendered the prognosis to be far more favorable in the recent years.

Natural History

Complications

In a 2015 study from MD Anderson Cancer Center, it was shown that the annual incidence of venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, was 6.1-42%, which is the highest amongst all leukemia sub-types. In contrast, the incidence of venous thromboembolism in chronic myeloid leukemia was only 1.5%.[7]

Disease Thrombotic Incidence

Acute promyelocytic leukemia

6.1-48%

Acute myeloid leukemia

3.7%

Chronic lymphocytic leukemia

2.7%

Acute lymphoblastic leukemia

2.1-13%

Chronic myeloid leukemia

1.5%

Prognosis

  • Prior to the introduction of readily available diagnostics and targeted therapeutics, the prognosis of acute promyelocytic leukemia was previously very poor, especially in the early phase of the disease.[31][32]
  • The poor prognosis was due to high bleeding risk and death from hemorrhagic complications due to disseminated intravascular coagulation. Death typically occurs within a few days to weeks in the absence of treatment. The early death rate is estimated to be 17.3%, based on a large population-based analysis that was conducted in the United Stated between 1992-2007.[33] [2]
  • The 5-year survival rate is only 30-40% after 5 years in younger patients.[23] In the current era of medicine (after the introduction of all-trans retinoic acid and arsenic trioxide), the prognosis of acute promyelocytic leukemia carries a much better prognosis.[3]
  • Patients can achieve long-term, durable remission if treated appropriately in an expedited manner with medications such as all-''trans'' retinoic acid, arsenic trioxide, or cytotoxic chemotherapy. The current overall survival rate is 86-97%, and the complete remission rate is 90-100%.[23]
  • In a multi-center study published in 2017 that evaluated the long-term outcomes of patients with acute promyelocytic leukemia, the complete remission rate was 96% [34] and induction mortality if low at 4%.[34]

References

  1. ↑ Franchini M, Lippi G, Manzato F (2006). "Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation". Thromb J. 4: 4. doi:10.1186/1477-9560-4-4. PMC 1402263. PMID 16504043.
  2. ↑ 2.0 2.1 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). "Early mortality in acute promyelocytic leukemia: Potential predictors". Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.
  3. ↑ 3.0 3.1 3.2 Coombs CC, Tavakkoli M, Tallman MS (2015). "Acute promyelocytic leukemia: where did we start, where are we now, and the future". Blood Cancer J. 5: e304. doi:10.1038/bcj.2015.25. PMC 4450325. PMID 25885425.
  4. ↑ 4.0 4.1 Choudhry, Aditi; DeLoughery, Thomas G. (2012). "Bleeding and thrombosis in acute promyelocytic leukemia". American Journal of Hematology. 87 (6): 596–603. doi:10.1002/ajh.23158. ISSN 0361-8609.
  5. ↑ Choudhry, Aditi; DeLoughery, Thomas G. (2012). "Bleeding and thrombosis in acute promyelocytic leukemia". American Journal of Hematology. 87 (6): 596–603. doi:10.1002/ajh.23158. ISSN 0361-8609.
  6. ↑ Breen, Karen A.; Grimwade, David; Hunt, Beverley J. (2012). "The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia". British Journal of Haematology. 156 (1): 24–36. doi:10.1111/j.1365-2141.2011.08922.x. ISSN 0007-1048.
  7. ↑ 7.0 7.1 7.2 Vu K, Luong NV, Hubbard J, Zalpour A, Faderl S, Thomas DA; et al. (2015). "A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center". Cancer Med. 4 (1): 27–35. doi:10.1002/cam4.332. PMC 4312115. PMID 25487644.
  8. ↑ Al-Ani, F., Ahrari, A., Wang, Y. P., Iansavitchene, A., & Lazo-Langner, A. (2017). Incidence of Venous Thromboembolism in Acute Leukemia: A Systematic Review and Meta-Analysis. Blood, 130(Suppl 1), 5634. Accessed January 15, 2019. Retrieved from http://www.bloodjournal.org/content/130/Suppl_1/5634.
  9. ↑ Dicke, Christina; Amirkhosravi, Ali; Spath, Brigitte; Jiménez-Alcázar, Miguel; Fuchs, Tobias; Davila, Monica; Francis, John L; Bokemeyer, Carsten; Langer, Florian (2015). "Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study". Experimental Hematology & Oncology. 4 (1). doi:10.1186/s40164-015-0018-x. ISSN 2162-3619.
  10. ↑ Lima, Luize G.; Monteiro, Robson Q. (2013). "Activation of blood coagulation in cancer: implications for tumour progression". Bioscience Reports. 33 (5): 701–710. doi:10.1042/BSR20130057. ISSN 0144-8463.
  11. ↑ . doi:10.1182/blood-2016-09-739334 PMCID: PMC5374289 Check |doi= value (help). Missing or empty |title= (help)
  12. ↑ Periayah MH, Halim AS, Mat Saad AZ (October 2017). "Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis". Int J Hematol Oncol Stem Cell Res. 11 (4): 319–327. PMC 5767294. PMID 29340130.
  13. ↑ Flores, Brisas; D Trivedi, Hirsh; C Robson, Simon; Bonder, Alan (2017). "Hemostasis, bleeding and thrombosis in liver disease". Journal of Translational Science. 3 (3). doi:10.15761/JTS.1000182. ISSN 2059-268X.
  14. ↑ Avvisati, Giuseppe (2011). "HOW I TREAT NEWLY DIAGNOSED ACUTE PROMYELOCYTIC LEUKEMIA". Mediterranean Journal of Hematology and Infectious Diseases. 3 (1): e2011064. doi:10.4084/mjhid.2011.064. ISSN 2035-3006.
  15. ↑ Fang, Shirong; Yang, Jinhong; Song, Lei; Jiang, Yan; Liu, Yuxiu (2017). "Comparison of three types of central venous catheters in patients with malignant tumor receiving chemotherapy". Patient Preference and Adherence. Volume 11: 1197–1204. doi:10.2147/PPA.S142556. ISSN 1177-889X.
  16. ↑ Dally, Najib; Hoffman, Ron; Haddad, Nuhad; Sarig, Galit; Rowe, Jacob M.; Brenner, Benjamin (2005). "Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia—a single center experience in 34 patients". Thrombosis Research. 116 (2): 109–114. doi:10.1016/j.thromres.2004.11.001. ISSN 0049-3848.
  17. ↑ Handigund, Rajeshwari Satish; Malur, Prakash R.; Dhumale, Annasaheb J.; Bali, Akshay; Roy, Maitrayee; Inumella, Suvarna (2012). "Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?". Indian Journal of Hematology and Blood Transfusion. 30 (1): 64–67. doi:10.1007/s12288-012-0201-8. ISSN 0971-4502.
  18. ↑ Bittencourt, Henrique; Teixeira Junior, Antonio Lucio; Glória, Ana Beatriz Firmato; Ribeiro, Ana Flávia Leonardi Tiburcio; Fagundes, Evandro Maranhão (2011). "Acute promyelocytic leukemia presenting as an extradural mass". Revista Brasileira de Hematologia e Hemoterapia. 33 (6): 478–480. doi:10.5581/1516-8484.20110126. ISSN 1516-8484.
  19. ↑ Fibach, Eitan; Rachmilewitz, Eliezer A. (2017). "Iron overload in hematological disorders". La Presse Médicale. 46 (12): e296–e305. doi:10.1016/j.lpm.2017.10.007. ISSN 0755-4982.
  20. ↑ Sanz, M. A.; Montesinos, P. (2014). "How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia". Blood. 123 (18): 2777–2782. doi:10.1182/blood-2013-10-512640. ISSN 0006-4971.
  21. ↑ 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.
  22. ↑ Rego, Eduardo Magalhães; De Santis, Gil Cunha (2011). "DIFFERENTIATION SYNDROME IN PROMYELOCYTIC LEUKEMIA : CLINICAL PRESENTATION, PATHOGENESIS AND TREATMENT". Mediterranean Journal of Hematology and Infectious Diseases. 3 (1): e2011048. doi:10.4084/mjhid.2011.048. ISSN 2035-3006.
  23. ↑ 23.0 23.1 23.2 McCulloch D, Brown C, Iland H (2017). "Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives". Onco Targets Ther. 10: 1585–1601. doi:10.2147/OTT.S100513. PMC 5359123. PMID 28352191.
  24. ↑ Sanz, M. A.; Montesinos, P. (2014). "How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia". Blood. 123 (18): 2777–2782. doi:10.1182/blood-2013-10-512640. ISSN 0006-4971.
  25. ↑ 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.
  26. ↑ Porta‐Sánchez, Andreu; Gilbert, Cameron; Spears, Danna; Amir, Eitan; Chan, Joyce; Nanthakumar, Kumaraswamy; Thavendiranathan, Paaladinesh (2017). "Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review". Journal of the American Heart Association. 6 (12). doi:10.1161/JAHA.117.007724. ISSN 2047-9980.
  27. ↑ Barbey, Jean T.; Pezzullo, John C.; Soignet, Steven L. (2003). "Effect of Arsenic Trioxide on QT Interval in Patients With Advanced Malignancies". Journal of Clinical Oncology. 21 (19): 3609–3615. doi:10.1200/JCO.2003.10.009. ISSN 0732-183X.
  28. ↑ McCulloch, Derek; Brown, Christina; Iland, Harry (2017). "Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives". OncoTargets and Therapy. Volume 10: 1585–1601. doi:10.2147/OTT.S100513. ISSN 1178-6930.
  29. ↑ 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.
  30. ↑ Shakir, Douraid (2009). "Chemotherapy Induced Cardiomyopathy: Pathogenesis, Monitoring and Management". Journal of Clinical Medicine Research. doi:10.4021/jocmr2009.02.1225. ISSN 1918-3003.
  31. ↑ Coombs, C C; Tavakkoli, M; Tallman, M S (2015). "Acute promyelocytic leukemia: where did we start, where are we now and the future". Blood Cancer Journal. 5 (4): e304–e304. doi:10.1038/bcj.2015.25. ISSN 2044-5385.
  32. ↑ Efficace, Fabio; Breccia, Massimo; Avvisati, Giuseppe; Cottone, Francesco; Intermesoli, Tamara; Borlenghi, Erika; Carluccio, Paola; Rodeghiero, Francesco; Fabbiano, Francesco; Luppi, Mario; Romani, Claudio; Sborgia, Marco; D’Ardia, Stefano; Nobile, Francesco; Cantore, Nicola; Crugnola, Monica; Nadali, Gianpaolo; Vignetti, Marco; Amadori, Sergio; Lo Coco, Francesco (2018). "Health-related quality of life, symptom burden, and comorbidity in long-term survivors of acute promyelocytic leukemia". Leukemia. doi:10.1038/s41375-018-0325-4. ISSN 0887-6924.
  33. ↑ Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). "Emerging new approaches for the treatment of acute promyelocytic leukemia". Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
  34. ↑ 34.0 34.1 Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E; et al. (2017). "Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab". Blood. 129 (10): 1275–1283. doi:10.1182/blood-2016-09-736686. PMC 5413297. PMID 28003274.

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