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Acute Promyelocytic Leukemia (APL)

Acute Promyelocytic Leukemia (APL). By Maged Abd El Fattah Amine Assistant Lecturer Of Medical Oncology South Egypt Cancer Institute 3.2014. *Outline: - Hematopoiesis. - Introduction and Epidemiology of APL. - Pathogenesis of APL. - Diagnosis of APL. - Treatment of APL. - Conclusions.

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Acute Promyelocytic Leukemia (APL)

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  1. Acute Promyelocytic Leukemia (APL) By MagedAbd El Fattah Amine Assistant Lecturer Of Medical Oncology South Egypt Cancer Institute 3.2014

  2. *Outline:- Hematopoiesis.- Introduction and Epidemiology of APL.- Pathogenesis of APL.- Diagnosis of APL.- Treatment of APL. - Conclusions. APL

  3. Hematopoiesis APL

  4. - Hematopoiesis is a term describing the formation and development of blood cells.- The hematopoietic system must have the capacity for self renewal, which involves:1- Proliferation of progeny stem cells.2- Differentiation and maturation of the stem cells into the functional cellular elements.- Normally hematopoiesis is limited to the bone marrow and the widespread lymphatic system and only mature cells are released into the peripheral blood. APL

  5. APL

  6. - All cells are derived from a pool of stem cells thatare self-renewing.- Pluripotential & multipotential stem cells give riseto committed stem cells for each cell line.- Committed stem cells have receptors for specific growth factors, respond to stimulation by division & maturation (precursor cell stages) into end-stage cells.- Growth factor stimulation increases with need. APL

  7. APL

  8. APL

  9. APL

  10. IntroductionAnd Epidemiology of APL APL

  11. - Acute promyelocytic leukemia (APL), is a distinct subtype of acute myeloid leukemia, represents about 10-12% of adult AML cases, and 8% - 15% of pediatric AML.- The median age is approximately 30-40 years, which is considerably younger than the other subtypes of AML (70 yrs).- Itwas first described in 1957 by “Hillestad (Sweden)”,as a hyperacute fatal illness.- laboratory evidence of DIC is present in 70% to 90% of patients at diagnosis or shortly after.- Hemorrhagic events contribute 10% to 15% excess mortality during induction chemotherapy for APL. APL

  12. -Morphologically, it is identified as AML-M3 by the French-American-British (FAB) classification. -Cytogenetically (WHO), APL is characterized by a balanced reciprocal translocation abnormality, t(15;17)(q22;q12); PML-RARA. - Currently it is one of the most treatable forms of leukemia with a 12-yr PFS rate, is estimated to be approximately 70%. APL

  13. Pathogenesis of APL APL

  14. - In Acute promyelocytic leukemia (APL), there is an abnormal accumulation of immature granulocytes called promyelocytes.- APL is characterized a balanced reciprocal translocation abnormality, t(15;17)(q22;q12); PML-RARA, which results in fusion of the retinoic acid receptor (RARA) gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. - 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. APL

  15. Physiologic quantities of retinoic acid no longer sufficient to allow for cell differentiation. t(15;17); PML-RARA APL

  16. - PML/RARa gene product forms homodimer.- Homodimer represses target genes needed for differentiation.- Mechanisms act via aberrant histone modification and DNA methylation.- Proliferation via FLT3 and KIT as well are required. APL

  17. - Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for the development of leukemia. - This translocation abnormality could be detected by karyotyping, FISH or PCR techniques, which is useful for both diagnosis and evaluation of minimal residual disease. -Eight other rare gene rearrangements have been described in APL fusing RARA to other genes “Variant chromosomal translocations” [e.g., t(11;17), t(5;17)], can be detected in no less than 5% of APL patients. APL

  18. APL

  19. APL: Molecular Variants PML-RARa t(15;17)(q22;q21) 92% 4. Grimwade D, et al. Leukemia. 2002;16:1959-1973.

  20. Diagnosis of APL APL

  21. Diagnosis of APL Clinical Morphological Immunophenotyping Cytogenetics Molecular genetics APL

  22. APL

  23. # Karyotype:- Detects translocation variant.# FISH or immunostaining:- Fast – often within 2-4 hours.- Immunostaining is inexpensive and can be done at smaller centers.# RT-PCR:- Can detect minimal residual disease (MRD).- “Gold Standard”. APL

  24. APL

  25. APL

  26. APL

  27. APL

  28. Anti-PML Immunofluorescent Antibody Test (“POD” Test) APL Sensitivity and specificity of 98.7% and 98.9% 5. Dimov N, et al. Cancer. 2010;116:369-376.

  29. Treatment of APL APL

  30. APL Leukemic Infiltration Coagulopathy APL

  31. Coagulopathy *Coagulopathy:- It occurs in 70% to 90% of cases.- It occurs due to release of several procoagulants, mainly tissue factor (TF), and cancer procoagulant (CP).# Def:- Fibrinogen level < 150 mg / dl.OR 2 of the following criteria;(1) Fibrinogen 150-200 mg / dl.(2) FDP (D-dimer).(3) PT 3 sec. Longer than control. APL

  32. # TTT of Coagulopathy:1- Keep PLT count > 50 000.2- Maintain fibrinogen level > 150 mg/dl, by-FFP 15 ml/kg (max infusion rate = 200 ml/hr). - Cryoprecipitate. - Fibrinogen (2 gm I.V) may be given instead of plasma if available.- Heparin is of no documented value. - packed RBCs transfusion may worsen the condition. - Avoid invasive procedures if possible (leukapheresis, LP, and central line placement). Note: APL

  33. APL

  34. - Using “Sanz” criteria (Sanz score).- Depending on WBCs and Platelets count at presentation. Risk stratification of APL APL

  35. APL

  36. APL Therapy: History Discovery t(15;17) in APL ATO frontline ATRA therapy First description: Hyperacute fatal illness associated with hemorrhagic syndrome Daunorubicin in APL Differentiation of APL cells with RA ATO in relapse ATRA + ATO ± GO In vivo leukemic cell differentiation ATRA + CT • 1960 1970 1980 1990 2000 HIGHLY FATAL HIGHLY CURABLE 6. Chen Y, et al. Cancer. 2012;118:5811-5818. 7. Nowak D, et al. Blood. 2009;113:3655-3665.

  37. Consolidation Induction Therapy TTT of APL Maintenance APL

  38. Induction/Consolidation therapy in APL - Several established treatment protocols offer excellent outcomes.- Important not to “mix and match” induction from one trial with consolidation from another.- ATRA(all-trans retinoic acid) is the cornerstone in each protocol, whatever the risk status.- Treatment must begin before the diagnosis is confirmed in patients with suspected APL, as early tttis the key for survival. APL

  39. APL

  40. Treatment of APL APL

  41. Induction Therapy in APL # ATRA [Vesanoid Caps.(10 mg)]:- 45 mg/m2 P.O. daily in 2 divided/12hs, till CR or for a max. of90 days.#Anthracyclines ( DAN or IDA):- Daunorubicin (50 mg/m2 I.V. x 4d), or (60 mg/m2 I.V. x 3d).- Idarubicin (12 mg/m2 I.V. x 2,4,6,8 days). # Cytarabine (Ara-C):200 mg/m2 CIVI x 7 days, could be added according to the protocol. APL

  42. Consolidation Treatment in APL - 2 or 3 cycles of an anthracycline (daunorubicin or idarubicin) plus 1 to 2 weeks of ATRA are administered until molecular CR.- Intermediate- or high-dose Ara-C can be administered depending on age as a first consolidation, as in (GIMEMA, APL 2000 study); or Arsenic Trioxide (ATO) for 2 courses of 25 days each as in (second North American Intergroup C9710 study).- To consider LP and IT CTR for 5 doses (weekly) in high risk patients. APL

  43. APL

  44. APL

  45. APL

  46. Maintenance Treatment in APL - ATRA and low-dose chemotherapy with 6-mercaptopurine and methotrexate is given for 2 years.-ATRA (45 mg/m2 P.O/day) for 2 weeks every 3 months.- 6-MP (60 mg/m2, P.O/day). - MTX (15 mg/m2, IM/ week).- There is some debate around maintenance ttt in APL, as some studies showed no difference in DFS and OS, but it is still the standard of care till now. APL

  47. Treatment of APL in Elderly pts - Elderly patients (> 60y) have poorer outcomes with standard treatment.- In the PETHEMA trial, the last dose of idarubicin was omitted during induction; consolidation should be altered to liposomal ATRA and ATO.- Another option is ATRA + ATO for induction without anthracyclines. APL

  48. Post- remission Monitoring in APL 1- Document complete molecular remission by PCR after consolidation.2- Monitor PCR every 3 months up to 2 years.3- If PCR was –ve, continue maintenance ttt.4- If PCR was +ve, repeat within 4 weeks to confirm.5- If PCR still +ve, proceed to ttt of relapse. APL

  49. APL

  50. Treatment of Relapsed APL - Arsenic Trioxide (ATO) is the standard ttt of relapsed APL, +/- ATRA.- If CR2 and PCR was -ve, consider ASCT, or ATO x 6 cycles.- If PCR was +ve, or No CR, consider AlloSCT or clinical trial, (Gemtuzumab followed by allo SCT).- Strongly consider CNS-directed treatment with intrathecal chemotherapy.- Gemtuzumabozogamicin (GO) is also an effective agent for patients with relapsed APL. Although this drug is no longer commercially available. APL

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