Acute promyelocytic leukemia

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

Synonyms and keywords: Acute progranulocytic leukemia; APL; AML with t(15;17)(q22;q12); PML-RARA and variants; FAB subtype M3; M3 variant

Overview

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

Acute promyelocytic leukemia is a sub-type of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. In acute promyelocytic leukemia, there is an abnormal accumulation of immature granulocytes called promyelocytes. A diagnosis is made when there are greater than 20% blasts, or immature cancerous cells, in the bone marrow. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα or RARA) gene and is unique from other forms of acute myeloid leukemia in its responsiveness to all trans retinoic acid (ATRA) therapy.

Historical Perspective

The first documentation of the successful treatment of acute promyelocytic leukemia occurred in the late 19th century, at which time physicians and scientists explored the role of arsenic as an anti-leukemic agent. Since that time, multiple advances have been made over the years. Specifically, the use of cytotoxic chemotherapy (anthracycline and cytarabine) has been explored extensively. The use of all-”trans” retinoic acid in the 20th century has revolutionized the treatment paradigm for acute promyelocytic leukemia. In the early 21st century, a landmark study showed that the combination of arsenic trioxide plus all-”trans” retinoic acid was superior to conventional chemotherapy for low-risk acute promyelocytic leukemia.

Classification

There are several broad classification schemes for acute promyelocytic leukemia. The most well-accepted classification scheme is risk-based classification, which categories patients into low-risk, intermediate-risk, or high-risk based on the white blood cell count and platelet count. Another classification scheme is based on the origin of the leukemia, which categorized patients as having de novo or therapy-related disease. A final classification scheme is cytogenetic-based, in which case specific chromosomal abnormalities are used to stratify patients.

Pathophysiology

The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

Causes

The cause of acute promyelocytic leukemia is sporadic rather than hereditary. It is caused by a reciprocal translocation between chromosomes 15 and 17, which creates a novel protein known as PML-RARA, leading to a differentiation block. In general, the causes of acute leukemia of myeloid origin include chemicals, radiation, cytotoxic chemotherapeutic agents, and specific mutations.

Differential Diagnosis

The differential diagnosis of acute promyelocytic leukemia includes a variety of other hematologic malignancies, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Each of these conditions has distinct causes and therapies. There is some overlap between the causes and laboratory abnormalities amongst these diseases.

Epidemiology and Demographics

Acute promyelocytic leukemia is relatively rare compared to other diseases. It predominantly affects people of Latin American descent and least commonly affects African Americans. It is more common in older adults.

Risk Factors

Risk factors for acute promyelocytic leukemia are similar to risk factors for acute myeloid leukemia. These include advanced age, benzene exposure, prior myelodysplastic syndrome, and germline mutations.

Natural History, Complications, and Prognosis

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.

History and Symptoms

Signs and symptoms of acute promyelocytic leukemia are similar to other forms of leukemia, but bleeding and hemorrhagic events are more specific for acute promyelocytic leukemia since these patients are more likely to present with disseminated intravascular coagulation (coagulopathy).

Physical Examination

The physical examination findings in acute promyelocytic leukemia include petechiae, ecchymoses, mucosal bleeding, splenomegaly, and/or pallor. The bleeding-related physical examination findings have a higher specificity for acute promyelocytic leukemia compared to other types of leukemia.

Laboratory Findings

The laboratory abnormalities in acute promyelocytic leukemia can be broadly divided into abnormalities of the complete blood count and abnormalities of the coagulation system. The complete blood count usually shows anemia, thrombocytopenia, leukopenia, and elevated blast count. The coagulation profile usually shows elevated prothrombin time, elevated partial thromboplastin time, elevated thrombin time, elevated reptilase time, and low fibrinogen. This combination of coagulation parameters accounts for high hemorrhagic risk in patients with acute promyelocytic leukemia.

Other Imaging Studies

Additional imaging studies that can be useful in acute promyelocytic leukemia include echocardiogram, chest X-ray, and brain MRI.

Other Diagnostic Studies

There is no significant role for other diagnostic studies in acute promyelocytic leukemia. However, lumbar puncture can be done to assess for central nervous system involvement.

Medical Therapy

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 ozogamycin, and cytarabine. Supportive therapies include transfusions (such as cryopreciptate or platelet transfusions) and granulocyte colony stimulating factor.

Cost-Effectiveness of Therapy

A limited number of cost-effective studies have been done. In summary, these studies showed that all-trans retinoic acid-based therapy is more cost effective than chemotherapy.

Future or Investigational Therapies

Investigational therapies for acute promyelocytic leukemia include bromodomain inhibitors and RNA-based silencing approaches (gene therapy).

References

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Historical Perspective

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 first documentation of the successful treatment of acute promyelocytic leukemia occurred in the late 19th century, at which time physicians and scientists explored the role of arsenic as an anti-leukemic agent. Since that time, multiple advances have been made over the years. Specifically, the use of cytotoxic chemotherapy (anthracycline and cytarabine) has been explored extensively. The use of all-trans retinoic acid in the 20th century has revolutionized the treatment paradigm for acute promyelocytic leukemia. In the early 21st century, a landmark study showed that the combination of arsenic plus all-trans retinoic acid was superior to conventional chemotherapy for low-risk acute promyelocytic leukemia.

Historical perspective

In 1882, A.C. Doyle reported on the efficacy of arsenic in acute promyelocytic leukemia.^[1]
In 1957, Leif Hillestad described acute promyelocytic leukemia as a distinct clinical condition for the first time. He noted the syndrome of low fibrinogen levels, fibrin degradation, and life-threatening hemorrhage.^[2] It was noted that this condition carried a high mortality rate due to severe hemorrhage.^[3]
In 1970, scientists in Harbin showed that arsenic trioxide and mercury chloride could treat acute and chronic leukemia.^[4]
In 1973, Bernard and colleagues showed in clinical studies that therapeutic efficacy of daunorubicin, an chemotherapy agent of the anthracycline class. This medication was shown to induce remission in the majority of patients, with an increase in remission rate from 13% to 58%. The median duration of remission with daunorubicin was more than 2 years. Compared to 6-mercaptopurine, daunorubicin was shown to reduce mortality from bleeding after 5 days.^[3]
In the early 1990s, it was noted that arsenic trioxide could induce remission in a high proportion of patients.^[3]^[5]
In 1980, Breitman and colleagues showed that all-trans retinoic acid could lead to the differentiation of the HL-60 cell line of myeloid leukemia. This was the first demonstration that differentiation therapy could treat leukemia. This concept was based on the fact that most cancers are primitive and stem-like, which leads to aggressive and chemo-resistant cellular behavior. Blockade of stemness and induction of differentiation could lead to anti-cancer effect.^[2]^[6]
In 1988, Huang and colleagues showed that all-trans retinoic acid could successfully treat acute promyelocytic leukemia in 24 patients. The complete remission rate was more tan 90%.^[2]
In 1995, D. Head and colleagues showed that higher remission rates and higher survival rates could be achieved with higher doses of daunorubicin, with a survival rate of 61% after 9 years and a 0% relapse after 36 months.^[7]
In 1997, scientists in Harbin and Shanghai showed that single-agent arsenic trioxide could induce response rates of 90% in patients who relapsed after receiving all-trans retinoic acid and chemotherapy.^[2]
In 2000, the United States Food and Drug Administration approved arsenic trioxide for treatment of acute promyelocytic leukemia.^[8]
In 2001, Soignet and colleagues showed that a single, 5-week course of arsenic trioxide carried a complete remission rate of 50%. It was shown that 2 cycles of arsenic trioxide could induce remission in 86% of patients.^[9]
In 2013, LoCoco and colleagues showed that, in a randomized phase 3 multi-center clinical trial, a non-chemotherapy-based regimen was superior to a chemotherapy-based regimen for low-risk acute promyelocytic leukemia. Specifically, the combination of all-”trans” retinoic acid and arsenic trioxide resulted in improved overall survival compared to the combination of all-trans retinoic acid plus chemotherapy. This landmark clinical trial, which was conducted by the Italian and German-Austrian Leukemia Study Groups, altered the treatment paradigm for low-risk acute promyelocytic leukemia.^[10]

References

↑ Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). “The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy”. Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
↑ ^2.0 ^2.1 ^2.2 ^2.3 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.
↑ ^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.
↑ Chen, Sai-Juan; Zhou, Guang-Biao (2012). “Targeted therapy: The new lease on life for acute promyelocytic leukemia, and beyond”. IUBMB Life. 64 (8): 671–675. doi:10.1002/iub.1055. ISSN 1521-6543.
↑ 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.
↑ Frank, Natasha Y.; Schatton, Tobias; Frank, Markus H. (2010). “The therapeutic promise of the cancer stem cell concept”. Journal of Clinical Investigation. 120 (1): 41–50. doi:10.1172/JCI41004. ISSN 0021-9738.
↑ Head D, Kopecky KJ, Weick J, Files JC, Ryan D, Foucar K; et al. (1995). “Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia”. Blood. 86 (5): 1717–28. PMID 7655004.
↑ 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.
↑ Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E; et al. (2001). “United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia”. J Clin Oncol. 19 (18): 3852–60. doi:10.1200/JCO.2001.19.18.3852. PMID 11559723.
↑ Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S; et al. (2013). “Retinoic acid and arsenic trioxide for acute promyelocytic leukemia”. N Engl J Med. 369 (2): 111–21. doi:10.1056/NEJMoa1300874. PMID 23841729.

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Classification

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

There are several broad classification schemes for acute promyelocytic leukemia. The most well-accepted classification scheme is risk-based classification, which categories patients into low-risk, intermediate-risk, or high-risk based on the white blood cell count and platelet count. Another classification scheme is based on the origin of the leukemia, which categorized patients as having de novo or therapy-related disease. A final classification scheme is cytogenetic-based, in which case specific chromosomal abnormalities are used to stratify patients.

Classification

Based on Risk

Low-risk disease:
- Low-risk disease is defined as the presence of less than 10000 white blood cells per microliter and greater than 40000 platelets per microliter in the peripheral blood.^[1]
- Treatment of low-risk disease involves non-chemotherapy-based regimens, such as the combination of all trance retinoic acid and arsenic trioxide.^[2]
Intermediate-risk disease:
- Intermediate-risk disease is defined as the presence of less than 10000 white blood cells per microliter and less than 40000 plate lets per microliter in peripheral blood.^[3]
High-risk disease:
- High-risk disease is defined as the presence of greater than 10000 white blood cells per microliter in peripheral blood, regardless of the platelet count.
- Platelet count is typically less than 40000 cells per microliter, though platelet count is not a formal criterion in the classification of acute promyelocytic leukemia.^[2]

Based on etiology

De novo disease:
- De novo acute promyelocytic leukemia is the most common subtype.
- This refers to development of the disease in the absence of prior cytotoxic therapy or prior precursor conditions.
- De novo acute promyelocytic leukemia is due to a sporadic events in cells, without prior DNA damaging insults. This is in contrast to therapy-related disease.

Therapy-related disease:
- Therapy-related disease refers to the development of acute promyelocytic leukemia in patients who were previously treated with DNA-damaging or genotoxic agents for other conditions, such as other cancers.
- The most common DNA-damaging agents that cause therapy-associated acute promyelocytic leukemia are topoisomerase inhibitors and alkylating agents.
- Therapy-related acute promyelocytic leukemia is typically seen in patients with a history of breast cancer who received cyclophosphamide or patients with a history of a germ cell tumor who have received etoposide.
- The prognosis of therapy-related disease is worse than that of de novo disease, with a 5-year survival of less than 10 years. The 4-year overall survival for therapy-related disease is 24.5%, compared to 39.5% for de novo disease.^[4]


Chemotherapeutic agents
Topoisomerase II inhibitors:^[5]	This class of chemotherapeutics causes early-onset leukemia, with a typical latency of 2-3 years from the receipt of the topoisomerase inhibitor. Cytogenetics from the leukemia diagnosis typically shows the MLL rearrangement (chromosome 11q23). There is usually no preceding myelodysplastic phase; the onset of leukemia is relatively sudden.
Alkylating agents:^[5]	This class of chemotherapeutics causes late-onset leukemia, with a typical latency of greater than 7 years from the receipt of the alkylating agent. Cytogenetics from the leukemia diagnosis typically shows monosomy 5 or monosomy 7. Mutational analyses can show a TP53 mutation. There is usually a preceding myelodysplastic phase.
Other chemotherapeutic agents:^[4]	Although other chemotherapy medications are not classically associated with therapy-related promyelocytleukemiamiaiamia, there have been cases of such associations. In a patient with gastric cancer treated with oxaliplatin and capecitabine, acute promyleukemia leukemia developed after a latency period of 4 years. The leukemic cells had chromosomal abnormalities, suggesting that the secondary neoplasm was chemotherapy-induced rather than de novo.

Based on cytogenetics

The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia.^[6]


Cytogenetics
Complex karyotype	Complex karyotype is defined as the presence of two or more chromosomal abnormities. Complex karyotype acute promyelocytic leukemia is associated with worse prognosis and lower rates of complete remission, similar to complex karyotype acute myeloid leukemia^[6]. Patients with complex karyotype are more likely to have a TP53 mutation and are more likely to be resistant to chemotherapy.^[6]
Trisomy 8	Trisomy 8 is characterized by three copies of chromosome 8 in cells. This chromosomal abnormality is commonly found in patients with myelodysplastic syndrome, which is a precursor condition for acute myeloid leukemia. Aside from t(15;17), trisomy 8 is the most frequent chromosomal abnormality in acute promyelocytic leukemia.^[6]
Tetraploidy	Tetraploidy is defined as the presence of four sets of chromosomes in a cell. Tetraploidy is generally rare in acute promyelocytic leukemia and accounts for approximately 0.75% of cases. The karyotype of most cases of acute promyelocytic leukemia involves the t(15;17) translocation between the PML and RARA genes. However, complex karyotypes may co-exist in some cases of acute promyelocytic leukemia. Tetraploidy in acute promyelocytic leukemia is more commonly associated with CD2 expression in the malignant cells. Tetraploid acute promyelocytic leukemia is mostly sensitive to all-trans retinoic acid.^[6]
t(8;21)	The t(8;21) translocation sometimes co-exists with the t(15;17) translocation. The t(8;21) translocation is more commonly found in acute myeloid leukemia and involves the juxtaposition of the ETO (RUNX1T1) gene on chromosome 8 with AML1 (RUNX1) gene on chromosome 21. A total of six cases of coexisting t(8;21) and t(15;17) have thus far been described.^[7]

References

↑ Song, Yu-hua; Peng, Peng; Qiao, Chun; Zhang, Run; Li, Jian-yong; Lu, Hua (2017). “Low platelet count is potentially the most important contributor to severe bleeding in patients newly diagnosed with acute promyelocytic leukemia”. OncoTargets and Therapy. Volume 10: 4917–4924. doi:10.2147/OTT.S144438. ISSN 1178-6930.
↑ ^2.0 ^2.1 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.
↑ 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.
↑ ^4.0 ^4.1 Zhang YC, Zhou YQ, Yan B, Shi J, Xiu LJ, Sun YW; et al. (2015). “Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report”. World J Gastroenterol. 21 (14): 4402–7. doi:10.3748/wjg.v21.i14.4402. PMC 4394105. PMID 25892894.
↑ ^5.0 ^5.1 Zahid MF, Parnes A, Savani BN, Litzow MR, Hashmi SK (2016). “Therapy-related myeloid neoplasms – what have we learned so far?”. World J Stem Cells. 8 (8): 231–42. doi:10.4252/wjsc.v8.i8.231. PMC 4999650. PMID 27621757.
↑ ^6.0 ^6.1 ^6.2 ^6.3 ^6.4 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.
↑ Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y, Kamada N, Ohki M (July 1993). “The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript”. EMBO J. 12 (7): 2715–21. PMC 413521. PMID 8334990.

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Pathophysiology

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 pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

Pathophysiology

The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.^[1]
The chromosomal translocation involves the juxtaposition of the retinoic acid receptor– alpha gene (RARA) on the long arm of chromosome 17 with another gene, most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15. The translocation is designated as t(15;17)(q22;q12).^[2]^[3]
The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome.
The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.^[4]^[5]
This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The cells remain primitive and stem-like, which is the basis for the malignancy. The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.^[2]
In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.^[6]


Translocation Partner	Chromosomal Location	Function	Response to Therapy	Other Features

PML	15q24.1	A member of the tripartite motif (TRIM) family Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor Regulate p53 response to oncogenic growth signals Influenced by the cell cycle	Sensitive to all-trans retinoic acid^[7]	Most common translocation Found in 70-90% of cases^[8]
PLZF (ZBTB16)^[2]^[8]	11q23.2	Encodes a zinc finger transcription factor Involved in cell cycle regulation Interacts with histone deacetylases	Resistant to all-trans retinoic acid^[7]	Second most common translocation (after PML-RARA)
NPM1	5q35.1	Encodes nucleophosmin 1 (a nucleolar shuttle protein) Involved in centromere duplication Serves a protein chaperone Regulates the cell cycle Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Sensitive to all-trans retinoic acid^[7]	NPM1 mutation carries a favorable prognosis in acute myeloid leukemia Rare translocation
NUMA^[7]	11q13.4	Contributes to a structural component of the nuclear matrix Interacts with microtubules Contributes to mitotic spindle formation during cell division	Sensitive to all-trans retinoic acid^[7]	Rare translocation
STAT5B^[8]	17q21.2	Encodes a signal transducer and activator of transcription (STAT) Serves an intracellular transduction molecule for cytokine signaling Translocates to the nucleus and functions as a transcription factor Involved in T cell receptor signaling Involved in apoptosis Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation	Resistant to all-trans retinoic acid^[7]	Rare translocation

References

↑ Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D (2001). “Translocations of the RARα gene in acute promyelocytic leukemia”. Oncogene. 20 (49): 7186–7203. doi:10.1038/sj.onc.1204766. ISSN 0950-9232.
↑ ^2.0 ^2.1 ^2.2 Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A (2017). “Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia”. Case Rep Hematol. 2017: 7657393. doi:10.1155/2017/7657393. PMC 5424191. PMID 28529810.
↑ L. R. Hiorns, T. Min, G. J. Swansbury, A. Zelent, M. J. Dyer & D. Catovsky (1994). “Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17”. Blood. 83 (10): 2946–2951. PMID 8180390. Unknown parameter |month= ignored (help)
↑ Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). “The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy”. Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
↑ “RARA retinoic acid receptor alpha [Homo sapiens (human)] – Gene – NCBI”.
↑ Saeed, S; Logie, C; Stunnenberg, H G; Martens, J H A (2011). “Genome-wide functions of PML–RARα in acute promyelocytic leukaemia”. British Journal of Cancer. 104 (4): 554–558. doi:10.1038/sj.bjc.6606095. ISSN 0007-0920.
↑ ^7.0 ^7.1 ^7.2 ^7.3 ^7.4 ^7.5 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.
↑ ^8.0 ^8.1 ^8.2 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.

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Differentiating Acute promyelocytic leukemia from Other Diseases

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 differential diagnosis of acute promyelocytic leukemia includes a variety of other hematologic malignancies, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Each of these conditions has distinct causes and therapies. There is some overlap between the causes and laboratory abnormalities amongst these diseases.

Differentiating Acute promyelocytic meukemia from other Diseases

The following table differentiates acute promyelocytic leukemia from other leukemias that may present with similar clinical features such as fever, fatigue, weight loss, recurrent infections and elevated leukocyte counts. The following are the differentials:

Characteristic	Causes	Laboratory abnormalities	Physical examination	Therapy	Other associations
Acute myeloid leukemia	Chromosomal instability Sporadic mutations Prior exposure to benzene Prior exposure to alkylating agents Prior exposure to topoisomerase II inhibitors Germline RUNX1 mutation	Anemia Thrombocytopenia Neutropenia Elevated LDH Elevated uric acid Elevated phosphorus Elevated potassium Low calcium Greater than 20% myeloblasts on bone marrow aspirate^[1]	Pyrexia Evidence of infection Pallor Mucosal bleeding (less common than in acute promyelocytic leukemia) Bruising (less common than in acute promyelocytic leukemia)	Cytarabine Anthracycline Enasidenib Liposomal daunorubicin plus cytarabine Gemtuzumab ozogamycin Midostaurin Enasidenib Ivosidenib Stem cell transplant	Variable prognosis based on cytogenetic and molecular profile Five new FDA-approved therapies became available in 2017-2018
Acute promyelocytic leukemia	Prior exposure to alkylating agents Prior exposure to topoisomerase II inhibitors Translocation between chromosomes 15 and 17 Creation of PML-RARalpha gene product Differentiation block in myeloid cells	Low white blood cell count (typically) Anemia Neutropenia Thrombocytopenia Low fibrinogen Elevated prothrombin time (PT) Elevated partial thromboplastin time (PTT)	Mucosal bleeding Petechiae Ecchymoses Evidence of infection Pallor Thrombosis	All-trans retinoic acid (ATRA) Arsenic trioxide Cytarabine Anthracycline	Presence of Auer rods in promyelocytes High risk for early death from hemorrhagic complications^[2]
Acute lymphoblastic leukemia	Chromosomal instability Sporadic mutations	Anemia Thrombocytopenia Neutropenia Elevated LDH Elevated uric acid Elevated phosphorus Elevated potassium Low calcium Greater than 20% lymphoblasts on bone marrow aspirate	Neurologic deficits Pallor Lymphadenopathy	HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)^[3] R-HyperCVAD (inclusion of rituximab) Peg-asparaginase Intrathecal methotrexate Intrathecal cytarabine Blinatumomab (bispecific T cell engager) Inotuzumab ozogamycin (anti-CD22 antibody) Tisagenlecleucel (chimeric antigen receptor T (CAR-T) cell therapy) Stem cell transplant	Sanctuary sites include the central nervous system (CNS) and testes^[4]
Chronic myeloid leukemia	Translocation between chromosomes 9 and 22 Creation of BCR-Abl gene product	Elevated white blood cell count Presence of white blood cell precursors at various stages of maturation Presence of excess metamyelocytes, basophils, eosinophils, and band cells	Splenomegaly Abdominal tenderness Pallor Evidence of infection	Imatinib Nilotinib Dasatinib Bosutinib Ponatinib Omacetaxine^[5]	High response rate to tyrosine kinase inhibitors Risk for development of T315I kinase domain mutation Typically does not require stem cell transplant Three phases include chronic, accelerated, and blast phase
Chronic lymphocytic leukemia^[6]	Chromosomal instability Sporadic mutations Infections	Elevated absolute lymphocyte count (in all stages) Presence of >5000 clonal B cells per microliter in peripheral blood Anemia (in Rai stage III) Thrombocytopenia (in Rai stage IV)	Lymph node enlargement in Rai stage I Splenomegaly in Rai stage II Hepatomegaly in Rai stage II Pallor Bleeding	Fludarabine Cyclophosphamide Rituximab Obinutuzumab^[7] Ofatumumab Ibrutinib Venetoclax	Associated with autoimmune hemolytic anemia, which occurs in 10-25% of patients with CLL Associated with immune thrombocytopenia purpura Associated with pure red cell aplasia Treatment with corticosteroids or anti-leukemic therapy will correct the autoimmune complications of CLL

References

↑ Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T; et al. (2017). “Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel”. Blood. 129 (4): 424–447. doi:10.1182/blood-2016-08-733196. PMC 5291965. PMID 27895058.
↑ McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA; et al. (2012). “Treatment advances have not improved the early death rate in acute promyelocytic leukemia”. Haematologica. 97 (1): 133–6. doi:10.3324/haematol.2011.046490. PMC 3248942. PMID 21993679.
↑ Terwilliger T, Abdul-Hay M (2017). “Acute lymphoblastic leukemia: a comprehensive review and 2017 update”. Blood Cancer J. 7 (6): e577. doi:10.1038/bcj.2017.53. PMC 5520400. PMID 28665419.
↑ Inaba H, Greaves M, Mullighan CG (2013). “Acute lymphoblastic leukaemia”. Lancet. 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716. PMID 23523389.
↑ Chen Y, Li S (2014). “Omacetaxine mepesuccinate in the treatment of intractable chronic myeloid leukemia”. Onco Targets Ther. 7: 177–86. doi:10.2147/OTT.S41786. PMC 3916637. PMID 24516334.
↑ Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG; et al. (2017). “Chronic lymphocytic leukaemia”. Nat Rev Dis Primers. 3: 16096. doi:10.1038/nrdp.2016.96. PMC 5336551. PMID 28102226.
↑ Al-Sawaf O, Fischer K, Engelke A, Pflug N, Hallek M, Goede V (2017). “Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy”. Drug Des Devel Ther. 11: 295–304. doi:10.2147/DDDT.S104869. PMC 5279834. PMID 28182141.

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Epidemiology and Demographics

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

Acute promyelocytic leukemia is relatively rare compared to other diseases. It predominantly affects people of Latin American descent and least commonly affects African Americans. It is more common in older adults.

Epidemiology

Incidence

Acute promyelocytic leukemia represents 10-15%% of all cases of acute myeloid leukemia in adults.^[1]
Acute promyelocytic leukemia affects approximately 1,500 people per year in the United States.^[2]
The incidence of acute promyelocytic leukemia is 0.2 to 0.26 per 100,000 annually in the United States, which corresponds to 600-800 cases of acute promyelocytic leukemia per year.^[3]
The incidence in Caucasians is 0.18 per 100,000. The incidence is African Americans is 0.14 per 100,000.^[3]
The incidence in men is 0.19 per 100,000, while the incidence in women is 0.17 per year.^[3]
The incidence of acute promyelocytic leukemia in people above age 60 is 0.36 per 100,000.
The incidence in people under age 20 is 0.06 per 100,000.
The incidence of acute promyelocytic leukemia has increased over time from 1975-2008.^[3]

Demographics

Race

Caucasians are more commonly affected by acute promyelocytic leukemia than African Americans.
Asians and Pacific islanders are more commonly affected by acute promyelocytic leukemia than African Americans.^[3]
The incidence is higher in people of Latin American descent compared to Caucasian descent.^[3]

Gender

Men are more commonly affected by acute promyelocytic leukemia than women.

Age

Older patients are more likely to develop acute promyelocytic leukemia than younger patients.
The median age is approximately 40 years, which is considerably younger than the other sub-types of acute myeloid leukemia (70 years).

References

↑ 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.
↑ 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.
↑ ^3.0 ^3.1 ^3.2 ^3.3 ^3.4 ^3.5 Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F (2012). “Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008”. Cancer. 118 (23): 5811–8. doi:10.1002/cncr.27623. PMC 4180246. PMID 22707337.

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Risk Factors

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

Risk factors for acute promyelocytic leukemia are similar to risk factors for acute myeloid leukemia. These include advanced age, benzene exposure, prior myelodysplastic syndrome, and germline mutations.