Acute promyelocytic leukemia

Source: Wikipedia, the free encyclopedia.
Acute promyelocytic leukemia
promyelocytes[2]
FrequencyDevelops in about 600 to 800 people per year (United States)[2]

Acute promyelocytic leukemia (APML, APL) is a subtype of

all-trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957[4][5] by French and Norwegian physicians as a hyperacute fatal illness,[3] with a median survival time of less than a week.[6] Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.[7][6][8]

Signs and symptoms

The symptoms tend to be similar to AML in general with the following being possible symptoms:[9]

Easy bleeding from low platelets may include:

  • Bruising (
    ecchymosis
    )
  • Gingival bleeding
  • Nose bleeds (
    epistaxis
    )
  • Bleeding from the gums
  • Increased menstrual bleeding (
    menorrhagia
    )
  • Brain bleed (intracerebral hemorrhage)

Pathogenesis

Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the

promyelocytic leukemia gene (PML) on chromosome 15, a translocation denoted as t(15;17)(q22;q21).[3] The RAR receptor is dependent on retinoic acid for regulation of transcription.[3]

Eight other rare gene rearrangements have been described in APL fusing RARA to

signal transducer and activator of transcription 5b (STAT5B), protein kinase A regulatory subunit 1α (PRKAR1A), factor interacting with PAPOLA and CPSF1 (FIP1L1), BCL-6 corepressor or oligonucleotide/oligosaccharide-binding fold containing 2A (NABP1) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA.[3]

The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC). Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for the development of leukemia.[3]

RARA/PLZF gene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracycline chemotherapy hence leading to poorer long-term outcomes in this subset of patients.[3]

Diagnosis

Acute promyelocytic leukemia may also have a hypogranular variant, which can have very scant Auer rods.[11] Wright's stain.

Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the

cytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis.[3]

Hypogranular variant of APL. Giemsa stain, 1000x.

Treatment

Initial treatment

Tretinoin
Mitozantrone
Methotrexate

APL is unique among leukemias due to its sensitivity to

malignant cells.[3] ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy.[3] As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide, which combined with ATRA is referred to ATRA-ATO;[12][13] before 2013 the standard of treatment was anthracycline (e.g. daunorubicin, doxorubicin, idarubicin or mitoxantrone)-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile.[7]

ATRA therapy is associated with the unique side effect of

dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone.[15] The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.[15]

The monoclonal antibody, gemtuzumab ozogamicin, has been used successfully as a treatment for APL,[16] although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK.[16][17] Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy.[16] It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients.[16]

Maintenance therapy

After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with

consolidation therapy.[15] In the 2000 European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy was 27% compared to 11% in those that did receive consolidation therapy (p<0.01).[19] Likewise in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance.[20]

However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this is controversial.[13]

Relapsed or refractory disease

Arsenic trioxide (As2O3) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported.[21] Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein.[21] Arsenic also increases caspase activity which then induces apoptosis.[21] It does reduce the relapse rate for high risk patients.[22] In Japan a synthetic retinoid, tamibarotene, is licensed for use as a treatment for ATRA-resistant APL.[23]

Investigational agents

Some evidence supports the potential therapeutic utility of

HL-60 cells.[27]

Prognosis

Prognosis is generally good relative to other leukemias. Because of the acuteness of onset compared to other leukemias, early death is comparatively more common. If untreated, it has median survival of less than a month. It has been transformed from a highly fatal disease to a highly curable one. The cause of early death is most commonly severe bleeding, often intracranial hemorrhage. Early death from hemorrhage occurs in 5–10% of patients in countries with adequate access to healthcare and 20–30% of patients in less developed countries. Risk factors for early death due to hemorrhage include delayed diagnosis, late treatment initiation, and high white blood cell count on admission.[28] Despite advances in treatment, early death rates have remained relatively constant, as described by several groups including Scott McClellan, Bruno Medeiros, and Ash Alizadeh at Stanford University.[29]

Relapse rates are extremely low. Most deaths following remission are from other causes, such as second malignancies, which in one study occurred in 8% of patients. In this study, second malignancies accounted for 41% of deaths, and heart disease, 29%. Survival rates were 88% at 6.3 years and 82% at 7.9 years.[30]

In another study, 10-year survival rate was estimated to be approximately 77%.[7]

Epidemiology

Acute promyelocytic leukemia represents 10–12% of AML cases.

topoisomerase II inhibitors (such as the anthracyclines and etoposide) due to the carcinogenic effects of these agents, with patients with breast cancer representing the majority of such patients.[34][35][36] Around 40% of patients with APL also have a chromosomal abnormality such as trisomy 8 or isochromosome 17 which do not appear to impact on long-term outcomes.[3]

References

  1. ^ Image by Mikael Häggström, MD. Reference for findings: Syed Zaidi, M.D. "APL with PML-RARA". APL with PML-RARA. Last author update: 1 February 2013
    Source image: File:Faggot cell in AML-M3.jpg from PEIR Digital Library (Pathology image database) Archived 2009-03-01 at the Wayback Machine (Public Domain)
  2. ^ a b c "Acute Promyelocytic Leukemia". National Organization for Rare Disorders. Retrieved March 9, 2023.
  3. ^ a b c d e f g h i j k l m n Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia". Medscape Reference. WebMD. Retrieved 14 January 2014.
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  6. ^
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  7. ^
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  9. ^ Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia Clinical Presentation". Medscape Reference. WebMD. Retrieved 14 January 2014.
  10. PMID 8384553
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  11. ^ Image by Mikael Häggström, MD. Source for findings: Syed Zaidi, M.D. "Bone marrow neoplastic, APL with PML-RARA". Pathology Outlines. Last author update: 1 February 2013 Last staff update: 29 November 2022
  12. PMID 23841729
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  13. ^
    PMID 29083825
    , retrieved 2018-12-11, Hence, ATRA-ATO for induction and consolidation has emerged as the new standard of care for patients with low-(to-intermediate) risk acute promyelocytic leukemia. ATRA-ATO therapy is also a reasonable choice for patients with severe comorbidities, older adults, patients with cardiac dysfunction who cannot tolerate anthracycline-based regimens or overall poor functional status. Maintenance therapy after the initial consolidation is widely debated. Maintenance may not be necessary for patients receiving intensive induction/consolidation including ATO.
  14. PMID 18945746
    .
  15. ^ a b c Kotiah, SD; Besa, EC (3 June 2013). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; McKenna, R; Besa, EC (eds.). "Acute Promyelocytic Leukemia Treatment & Management". Medscape Reference. WebMD. Retrieved 14 January 2014.
  16. ^
    PMID 22987091
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  17. ^ Martindale: The Complete Drug Reference. Pharmaceutical Press. 23 September 2011.
  18. ^ Kotiah, SD (28 October 2013). Anand, J; Braden, CD; Harris, JE (eds.). "Acute Promyelocytic Leukema Treatment Protocols". Medscape Reference. WebMD. Retrieved 14 January 2014.
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  20. PMID 12393590
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  21. ^
    PMID 9801394
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  22. ^ "Arsenic Compound Improves Survival in Acute Promyelocytic Leukemia Patients". Oncology. 21 (10). 2007.
  23. PMID 17925887
    .
  24. PMID 20159609
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  26. PMID 11696577
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  27. PMID 23977653
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  28. PMID 20015875
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  30. ISSN 0006-4971
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  31. ^ Schiffer, CA; Stone, RM (2000). "Chapter 124: Acute Myeloid Leukemia in Adults". In Bast, RC; Kufe, DW; Pollock, RE (eds.). Holland-Frei Cancer Medicine (5th ed.). Hamilton, ON: BC Decker. Retrieved 15 January 2014.
  32. S2CID 238748395
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  33. S2CID 20065990
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  34. PMID 21454880
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  35. S2CID 42345682
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  36. S2CID 5454988
    .

External links
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