Multidisciplinary approach to the management of leukemias aml
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The document discusses the multidisciplinary approach to managing leukemias like AML and MDS. It presents the case of a 68-year old male patient presenting with fever and fatigue, and details the diagnostic workup showing features consistent with acute myeloid leukemia. The document then reviews classification, prognostic factors, recent treatment trials, and the role of allogeneic stem cell transplantation for AML patients.
![Molecular Profiles of
Cytogenetically Normal AML
Döhner H, et al. Blood. 2009 Oct 30. [Epub ahead of print]. This research was originally published in Blood. © 2009
the American Society of Hematology.](https://image.slidesharecdn.com/multidisciplinaryapproachtothemanagementofleukemias-aml-141222102032-conversion-gate02/85/Multidisciplinary-approach-to-the-management-of-leukemias-aml-26-320.jpg)
![Recent Randomized Trials of Dose-
Intensification in AML
• ECOG E1900: daunorubicin 90 mg/m2 x 3 superior to 45
mg/m2 x 3 in pts < 60 yrs[1]
– But not in patients with adverse cytogenetics, FLT3-
ITD, or aged 50 yrs or older
• HOVON: daunorubicin 90 mg/m2 x 3 = 45 mg/m2 x 3 in
pts ≥ 60 yrs[2]
– But superior in patients aged 60-65 yrs
• ALFA-9801: idarubicin 12 mg/m2 x 3 and x 4 superior to
daunorubicin 80 x 3 for CR[3]
– But not for EFS and OS
• MRC AML15: more durable CR in patients receiving
FLAG-Ida than ADE/DA[4]
– But higher initial toxicity
• HOVON: high-dose cytarabine = intermediate-dose
cytarabine in induction[5]
– Unknown whether intermediate dose = “standard
dose”
1.](https://image.slidesharecdn.com/multidisciplinaryapproachtothemanagementofleukemias-aml-141222102032-conversion-gate02/85/Multidisciplinary-approach-to-the-management-of-leukemias-aml-34-320.jpg)
Multidisciplinary approach to the management of leukemias aml
- 1. MULTIDISCIPLINARY APPROACH TO THE MANAGEMENT OF LEUKEMIAS- AML/MDS DR. R. RAJKUMAR M.D., D.M. ASST PROF MADURAI MEDICAL COLLEGE & CONSULTANT MEDICAL ONCOLOGIST
- 2. CASE HISTORY MR. X 68/M PRESENTING C/O FEVER, FATIGUE - 20DAYS O/E– pallor + Comorbidities- Nil P.S. 1 COMPLETE HAEMOGRAM- HB—7.6 TOTAL WBC COUNT -1300 D.C. – P-20%, L-76%, E- 04%, M-00% PLATELET—1.04 LAKHS/cu mm PACKED CELL VOL- 25.7% MCV- 101.8 fl MCH- 30.0 pg RED BLOOD CELL COUNT- 2.53 million
- 3. LAB0RATORY VALUES UREA- 30.0 CREATININE- 0.90 TOTAL BILIRUBIN- 0.70 DIRECT- 0.30 INDIRECT-0.40 SERUM ELECTROLYTES SODIUM- 149 POTASSIUM- 4.0 CHLORIDE-106
- 4. PERIPHEREAL SMEAR RBCS SHOW MICROCYTES AND NORMOCHROMIC NORMOCYTE WBCS SHOW LEUKOPENIA. OCC ATYPICAL CELLS SEEN.PLATELETS ARE REDUCED. BONE MARROW PARTICLES: APARTICULATE CELLULARITY: HYPOCELLULAR MEGAKARYOCYTES: NOT SEEN NONERYTHYROID:ERYTHROID RATIO >100:1
- 5. BONE MARROW DIFFERENTIAL COUNT: BLASTS: 73% PROMYELOCYTES: 00% MYELOCYTES: 01% METAMYELOCYTES: 01% POLYMORPHS: 02% LYMPHOCYTES: 23% PLASMA CELLS: 00% EOSINOPHILS : 00% MONOCYTES:00% ERYTHROID: 00%
- 9. BONE MARROW MORPHOLOGY: Blasts are 2-3 times the size of lymphocytes with high N:C ratio, opened up chromatin , 1-2 conspicuous to prominent nucleoli, nuclear foldings, nuclear groovings and moderate agranular basophilic cytoplasm with absence of auer rods. IMPRESSION: SUGGESTIVE OF ACUTE MYELOID LEUKEMIA.
- 10. QUESTION 1. Cytochemistry 2. Periphereal blood flowcytometry 3. Bone marrow flowcytometry 4. All the above
- 11. FLOW CYTOMETRY
- 12. FLOW CYTOMETRY
- 16. QUESTION FURTHER EVALUATION- 1. B.M. CYTOGENETICS - FISH 2. MOLECULAR DIAGNOSTICS-RT PCR 3. L.P. 4. 1&2 5. ALL THE ABOVE
- 18. AML Classification FAB Classification M0 Minimally differentiated M1 Without maturation M2 With maturation M3 Acute promyelocytic leukemia M4 Acute myelomonocytic leukemia M5 Acute monoblastic leukemia M6 Acute erythroleukemia M7 Acute megakaryoblastic leukemia 2008 WHO Classification
- 19. AML ALOGORITHM
- 23. Prognostic/predictive factors in AML Factor Comment Age Major impact at diagnosis WBC Continuous variable Prior therapy or MDS? Karyotype may be more important Extramedullary disease Variable Day 14 blast count Higher percentage worse # cycles of induction One better than two Cytogenetic/molecular profile Major Impact at diagnosis Gene expression profile Can further subdivide patients MicroRNA expression Needs validation by other groups Gene sequencing Future application MRD detection at CR ??; seems like it should be useful
- 26. Molecular Profiles of Cytogenetically Normal AML Döhner H, et al. Blood. 2009 Oct 30. [Epub ahead of print]. This research was originally published in Blood. © 2009 the American Society of Hematology.
- 27. Heterogeneity within Cytogenetically Normal AML Category Gene Mutation Prognostic Impact NPM1 Favorable in absence of Flt3 ITD Flt3 ITD/allele ratio Unfavorable Flt3 TKD Controversial CEBPA Favorable MLL PTD Unfavorable Ras Neutral WT-1 Controversial Runx1 Unfavorable
- 28. Impact of Gene Expression in Cytogenetically Normal AML Category Gene Impact of Overexpression BAALC Unfavorable ERG Unfavorable MN1 Unfavorable Mir181 Favorable
- 29. Current State of AML Therapy • Excluding the roughly 20-30% of good risk patients, 40-90% of younger patients (age 18-59) achieving remission are destined to relapse
- 30. Current State of AML Therapy • Excluding the roughly 20-30% of good risk patients, 40-90% of younger patients (age 18-59) achieving remission are destined to relapse • All but a very select subset of older AML patients (> 60) will die due to relapsed or refractory disease
- 31. QUESTION Which of the following option would be your choice for initial treatment in this patient 1. 3+7 regimen 2. high dose cytarabine+ idarubicin 3. ADE(3+7+Etop) 4. 3+7 plus cladribine 5. Low dose cytrabine
- 34. Recent Randomized Trials of Dose- Intensification in AML • ECOG E1900: daunorubicin 90 mg/m2 x 3 superior to 45 mg/m2 x 3 in pts < 60 yrs[1] – But not in patients with adverse cytogenetics, FLT3- ITD, or aged 50 yrs or older • HOVON: daunorubicin 90 mg/m2 x 3 = 45 mg/m2 x 3 in pts ≥ 60 yrs[2] – But superior in patients aged 60-65 yrs • ALFA-9801: idarubicin 12 mg/m2 x 3 and x 4 superior to daunorubicin 80 x 3 for CR[3] – But not for EFS and OS • MRC AML15: more durable CR in patients receiving FLAG-Ida than ADE/DA[4] – But higher initial toxicity • HOVON: high-dose cytarabine = intermediate-dose cytarabine in induction[5] – Unknown whether intermediate dose = “standard dose” 1.
- 35. QUESTION Which Consolidation Regimen would you choose? 1. 3-4 cycles of high dose cytrabine 2. 5+2 regimen 3. Allogenic stem cell transplantation 4. Autologous stem cell transplantation
- 43. Current Role of Allografts for AML Patients <60 years in CR1
- 44. Current Role of Allografts for AML Patients <60 years in CR1 • Adverse risk cytogenetics – Most agree allograft appropriate consolidation at least up to 55-60 years of age
- 45. Current Role of Allografts for AML Patients <60 years in CR1 • Adverse risk cytogenetics – Most agree allograft appropriate consolidation at least up to 55-60 years of age • Favorable risk cytogenetics – No role in general • Intermediate risk cytogenetics – This is where it gets complicated – Recent meta-analyses suggest benefit • Cornellison et al, Blood, 2007 • Koreth at al, JAMA, 2009
- 46. BMT versus Conventional therapy for AML with normal cytogenetics Schlenk RF, et al. New Engl J Med. 2008;358:1909-1918. Reprinted with permission © 2009 Massachusetts Medical Society.
- 47. What recommendations should be made for Flt3 ITD group? • Should all of these patients be referred for allograft? On what basis?
- 48. Lestaurtinib Midostaurin Tandutinib QuizartinibSunitinib Sorafenib Prescott H, et al. Expert Opin Emerg Drugs. 2011;16:407-423. FLT3 Kinase Inhibitors
- 49. What defines a “suitable donor” allograft for a high risk AML patient in first remission? Matched sibling: Yes Matched unrelated donor: Yes Mismatched unrelated donor (KIR mismatched?) – Cooley et al, Blood, 2009 Mismatched umbilical cord blood? – Gutman et al, BBMT, 2009 Haploidentical related? – Perugia approach (ex vivo T-cell depletion) – Hopkins approach (in vivo alloreactive T-cell depletion)
- 52. Acute Promyelocytic Leukemia (M-3) • A) a severe bleeding tendency due to fibrinogenopenia and disseminated intravascular coagulation • (B) accumulation of abnormal promyelocytes in bone marrow and chromosomal translocation t(15;17)(q22;q21) • (C) with the resultant fusion transcripts between PML and RAR detected by FISH using PML-RAR dual- color, dual-fusion translocation probes • D) Schematics representing the formation of 15;17 reciprocal chromosomal translocations and fusion transcripts
- 57. ROLE OF SUPPORTIVE CARE Will you use G-csf in AML ? 1. Prophylactically 2. Myelosupresssion following chemo 3. Fear of Clonal Myeloproliferation Will you use ESA ? 1. HB- <10% 2. HB- <8% 3. Only if donor unavailable