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Hematologic Malignancies CON 616, 2009

Hematologic Malignancies CON 616, 2009. William H. Fleming, M.D., Ph.D. Division of Hematology & Medical Oncology Hematologic Malignancies Section Knight Cancer Institute OHSU. Blood Cell Formation. Acute vs. Chronic Leukemia. Acute Leukemia (AML and ALL)

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Hematologic Malignancies CON 616, 2009

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  1. Hematologic MalignanciesCON 616, 2009 William H. Fleming, M.D., Ph.D. Division of Hematology & Medical Oncology Hematologic Malignancies Section Knight Cancer Institute OHSU

  2. Blood Cell Formation

  3. Acute vs. Chronic Leukemia • Acute Leukemia (AML and ALL) • excess myeloblasts or lymphoblasts • short clinical course (weeks to months) • Chronic Leukemia (CML and CLL) • accumulation of mature granulocytes or lymphocytes • longer clinical course (several to many years)

  4. Acute Leukemia • A clonal, molecular abnormality of hematopoietic blast cells resulting in a failure of differentiation & uncontrolled cell proliferation • Accumulation of leukemic blast cells results in marrow replacement, organ infiltration and metabolic effects

  5. Acute Leukemia:AML versus ALL • Adults - 85% of acute leukemia is AML • Children-85% of acute leukemia is ALL • Leukemic Blast morphology • AML: cytoplasmic granules, Auer rods, more cytoplasm, 2-5 nucleoli • ALL: no cytoplasmic granules, minimal cytoplasm, 1-2 nucleoli

  6. Acute Leukemia:Clinical Manifestations • Constitutional & Metabolic effects: • Weight loss • Fever • Hyperkalemia • Hyperuricemia

  7. Acute Leukemia:Hematology Laboratory Findings • Decreased, normal or elevated WBC • Anemia • Thrombocytopenia • Blasts on peripheral blood smear (often) • Hypercellular bone marrow with 20% or more blasts (normal is < 5%)

  8. Acute Leukemia:Clinical Manifestations • Marrow replacement, organ infiltration & metabolic effects • Marrow replacement • Neutropenia: infection • Anemia: pallor, fatigue, dyspnea • Thrombocytopenia: abnormal bruising and bleeding

  9. Acute Leukemia:Clinical Manifestations • Organ infiltration • Bone pain • Hepatosplenomegaly • Lymphadenopathy • Gingival hypertrophy • Leukemic meningitis

  10. AML With Minimal Differentiation(M0/M1)

  11. Acute LeukemiaAML vs. ALL • Cell Surface Markers by Flow cytometry • AML • CD13, CD33, glycophorin (M6), platelet antigens (M7) • ALL B lineage: CD19, CD22, CD10 (+/-), surface Ig, T lineage: CD2, CD3, CD5, CD7

  12. AML:FAB classification • French American British classification • M0-M7 based on morphology, and special cytochemical studies • Historically, distinguishing AML M0 from ALL was a major clinical problem

  13. AMLFAB classification • M0,M1, M2: Myeloblasts with no, little or some granulocytic maturation • M3: Promyelocytic leukemia • M4: Myelomonocytic or eosinophilic • M5: Monocytic • M6: Erythroleukemia • M7: Megakaryoblastic Not all that useful except for M3 or APL

  14. Acute Leukemia:Blasts with Auer Rods

  15. Auer rods = AML

  16. Acute Leukemia:AML vs. ALL • Cytochemistry AML ALL • Myeloperoxidase + - • Sudan black + - • Non-specific esterase + (M4,5) - • PAS + (M6) + • Acid phosphatase + (M6) +

  17. FAB is Supplemented by Cytogenetic and Molecular analysis

  18. Flow Cytometry & FISH Analysis

  19. Gingival Hyperplasia

  20. Chloroma (Granulocytic Sarcoma)

  21. Leukemia Cutis

  22. AMLClinical Features & Prognosis • Age • < 60 years: >80% remission, 20-30% DFS • > 60 years: ~60% remission, 5-15% DFS • Prior marrow disorder: Myelodysplasia (MDS) • Secondary AML (prior chemo or radiotherapy) • Response to induction therapy

  23. AMLCytogenetics & Prognosis • Favorable t(8;21), t(15;17), inv(16) • Intermediate (Most patients) normal, +8, +21, +22, del(7q), del(9q), • Adverse -5, -7, del(5q), abnormal 3q, complex karyotype (> 3 -5 abnormalities)

  24. AMLCytogenetics and Prognosis • Group CR 5 year survival • Favorable 91% 65-75% • Intermediate 86% 40-50% • Adverse 63% <15%

  25. AMLMutations & Prognosis • Flt 3 (ITD) - Adverse • NPM-1 mutation & no Flt3 - Favorable • MLL (PTD) - Adverse • CEBPA - Favorable

  26. AML Treatment:Induction Chemotherapy • Anthracycline (Idarubicin) for 3 days and Cytosine arabinoside (Ara-C) for 7 days (3+7, Younger/fit patients only) • Three to 5 weeks of pancytopenia • Supportive care red cell and platelet transfusions, prophylactic antibacterial, antifungals and antivirals

  27. AML:Response to Induction • Remission status determined by bone marrow at end of month following induction therapy (e.g. Day 14 & 28) • Complete remission: • Normal peripheral blood counts • Normocellular marrow with < 5% blasts and normal marrow cell maturation

  28. AML Treatment:Consolidation Following induction into Complete Remission • 3-4 cycles of high dose cytosine arabinoside (HiDAC) administered approximately every 5-6 weeks OR • Bone marrow (peripheral blood stem cell) transplant (Depends on degree of risk)

  29. AML Treatment:Alternative Consolidation One or more cycles of consolidation chemotherapy then either: Autologous stem cell transplant after high dose chemotherapy or Allogeneic bone marrow transplantation after high dose chemotherapy

  30. AML TreatmentAutologous Transplant Advantage Collection and subsequent infusion of patient’s stem cells allows administration of otherwise lethal doses of chemotherapy Disadvantages Despite CR, leukemic cells may persist in marrow, blood and stem cell product High dose therapy more toxic than standard consolidation

  31. AML Treatment:Allogeneic Transplant Advantages Stem cells from HLA-matched sibling or unrelated individual allow high dose therapy and are free of leukemia Immunologic graft versus leukemia effect (GVL). Results in decreased rate of leukemic relapse

  32. AML Treatment:Allogeneic Transplant Disadvantages • Immunologic graft versus host disease (GVHD) and immunosuppressive therapy result in significant morbidity and mortality • GVHD incidence and severity increases with increasing age. (Best results in Pediatrics) • Tolerability of high dose transplant limited by patient age. (Reduced dose being evaluated)

  33. AML Treatment:A risk adapted approach • Favorable Conventional chemotherapy followed by transplant only if relapse occurs • Intermediate Conventional chemotherapy alone or autologous or allogeneic transplant • Adverse Conventional chemotherapy followed by allogeneic transplant

  34. Current Risk Stratification OHSU Acute Leukemia Program (modified NCCN Guidelines v.1.2009)

  35. AML:NCCN Guidelines • National Comprehensive Cancer Network (NCCN) has issued guidelines for treatment of many cancers including AML (and other hematologic malignancies) http://www.nccn.org/index.html

  36. Acute Leukemia:AML versus ALL • Adults: 85% of acute leukemia is AML • Children: 85% of acute leukemia is ALL • Blast morphology • AML: cytoplasmic granules, Auer rods, more cytoplasm, 2-5 nucleoli • ALL: no cytoplasmic granules, minimal cytoplasm, 1-2 nucleoli

  37. AML:FAB classification • French American British classification based on the degree of blast differentiation along different cell lineages and extent of maturation • M0-M7 based on morphology, lineage-specific cytochemical and immunologic findings

  38. AML:FAB classification • M0,M1, M2: Myeloblasts with no, little or some granulocytic maturation • M3: Promyelocytic leukemia (APL) • M4: Myelomonocytic or eosinophilic • M5: Monocytic • M6: Erythroleukemia • M7: Megakaryoblastic

  39. Acute Leukemia:AML vs. ALL • Cytochemistry AML ALL • Myeloperoxidase + - • Sudan black + - • Non-specific esterase + (M4,5) - • PAS + (M6) + (c) • Acid phosphatase + (M6) + (T)

  40. Acute Leukemia:AML vs. ALL • Immunologic markers / Flow cytometry • AML: CD13, CD33, glycophorin (M6), platelet antigens (M7) • ALL: • B lineage: CD19, CD22, CD10 (+/-), surface or cytoplasmic Ig, TdT (+/-) • T lineage: CD7, CD3, TdT

  41. AML-M3 (APL)

  42. AML-M3 (APL)an important FAB subtype • Acute Promyelocytic Leukemia (M3) • Blasts and promyelocytes heavily granulated, Auer rods often abundant & disseminated intravascular coagulation (DIC) is common • Treatment differs from all other AML subtypes. (Differentiating agent therapy) • Favorable prognosis (>85% survival)

  43. AML:Prognosis • Age • < 60 years: 80% remission, 20-30% DFS • > 60 years: 50% remission, 5-15% DFS • Prior marrow disorder: MDS or secondary AML (prior chemo- or radio-therapy) • Cytogenetic analysis of blasts: specific chromosomal abnormalities dictate blast biology and have a major impact on outcome • Response to first round of therapy

  44. AML:Cytogenetics and Prognosis • Favorable • t(8;21), t(15;17), inv(16) • Intermediate • normal, +8, +21, +22, del(7q), del(9q), abnormal 11q23, others • Adverse Autosomal monosomy (-5, -7) abnormal 3q, complex cytogenetics

  45. AML:Cytogenetics and Prognosis • Group CR 5 year survival • favorable 91% 65% • intermediate 86% 41% • adverse 63% 14%

  46. AML Risk & Mutational Analysis Frequency of mutations in 872 adults < 60 yrs with normal cytogenetics • NPM1- 53% • FLT3 ITD - 31% and FLT3 TK mutations-11% • CEBPA -13% • MLL PTD- 7% and NRAS-13% Schlenk et al. N Eng J Med 358:2008

  47. AML Risk & Mutational Analysis Significantly associated with complete remission • NPM1 mutation without FLT3 ITD • Mutant CEBPA • Younger age Allogeneic transplant benefit in first CR was limited to patients with FLT3 ITD or wild type NPM1 and CEBPA Schlenk et al. N Eng J Med 358:2008

  48. AML Treatment:Induction Chemotherapy • Anthracycline (e.g. Idarubicin) for 3 days and Cytosine arabinoside (Ara-C) for 7 days • Several weeks of pancytopenia • Supportive care: anti-emetics, red cell and platelet transfusions, prophylactic and therapeutic antibacterial, antifungal and antiviral antibiotics

  49. AML:Response to Induction • Remission status determined by bone marrow at end of month following recovery from induction therapy ( Mean Day 28-35) • Complete remission: • Normal peripheral blood counts • Normocellular marrow with < 5% blasts and normal marrow cell maturation

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