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Hematologic Malignancies CON 616, 2009 William H. Fleming, M.D., Ph.D. Division of Hematology & Medical Oncology Hematologic Malignancies Section Knight.

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Presentation on theme: "Hematologic Malignancies CON 616, 2009 William H. Fleming, M.D., Ph.D. Division of Hematology & Medical Oncology Hematologic Malignancies Section Knight."— Presentation transcript:

1 Hematologic Malignancies CON 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 Leukemia AML vs. ALL Cell Surface Markers by Flow cytometry AML CD13, CD33, glycophorin (M 6 ), platelet antigens (M 7 ) 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 AML FAB classification M 0,M 1, M 2 : Myeloblasts with no, little or some granulocytic maturation M 3 : Promyelocytic leukemia M 4 : Myelomonocytic or eosinophilic M 5 : Monocytic M 6 : Erythroleukemia M 7 : 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 CytochemistryAMLALL Myeloperoxidase + - Sudan black + - Non-specific esterase + (M 4,5 ) - PAS + (M 6 ) + Acid phosphatase + (M 6 ) +

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 AML Clinical Features & Prognosis Age – 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 AML Cytogenetics & 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 AML Cytogenetics and Prognosis GroupCR5 year survival Favorable91%65-75% Intermediate86%40-50% Adverse63%<15%

25 AML Mutations & 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 Treatment Autologous 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 ) Risk StatusCytogeneticsMolecular Mutations Better-riskInv(16) 1 t(8 ;21) 1 t(16 ;16) 1 Normal cytogenetics with isolated NPM 1 mutation Intermediate-riskNormal +8 only t(9 ;11) MK negative c-KIT 3 in patients with t(8;21) or Inv(16) Poor-riskComplex (>3 abnormalities) -5, -7, 5q-, 7q- MK positive Normal cytogenetics with isolated FLT3 mutations

35 AML: NCCN Guidelines National Comprehensive Cancer Network (NCCN) has issued guidelines for treatment of many cancers including AML (and other hematologic malignancies)

36

37 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

38 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

39 AML: FAB classification M 0,M 1, M 2 : Myeloblasts with no, little or some granulocytic maturation M 3 : Promyelocytic leukemia (APL) M 4 : Myelomonocytic or eosinophilic M 5 : Monocytic M 6 : Erythroleukemia M 7 : Megakaryoblastic

40 Acute Leukemia: AML vs. ALL CytochemistryAMLALL Myeloperoxidase + - Sudan black + - Non-specific esterase + (M 4,5 ) - PAS + (M 6 ) + (c) Acid phosphatase + (M 6 ) + (T)

41 Acute Leukemia: AML vs. ALL Immunologic markers / Flow cytometry AML: CD13, CD33, glycophorin (M 6 ), platelet antigens (M 7 ) ALL: –B lineage: CD19, CD22, CD10 (+/-), surface or cytoplasmic Ig, TdT (+/-) –T lineage: CD7, CD3, TdT

42 AML-M3 (APL)

43 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)

44 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

45 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

46 AML: Cytogenetics and Prognosis GroupCR5 year survival favorable91%65% intermediate86%41% adverse63%14%

47 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

48 AML Risk & Mutational Analysis Schlenk et al. N Eng J Med 358:2008 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

49 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

50 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

51 AML Treatment: Subsequent Consolidation Following induction into Complete Remission: (favorable & ?intermediate) 3-4 Cycles of high dose cytarabine (HiDAC) administered approximately every 5-6 weeks No subsequent therapy Follow for evidence of relapse

52 AML Treatment: Alternative Consolidation One or more cycles of consolidation chemotherapy (Intermediate or high risk) Allogeneic bone marrow transplantation after high dose chemotherapy Autologous stem cell transplant after high dose chemotherapy

53 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) translates into decreased rate of leukemic relapse. (How do we know?)

54 AML Treatment: Allogeneic Transplant Disadvantages –Toxicity of high dose chemotherapy –Immunologic graft versus host disease (GVHD) and immunosuppressive therapy result in significant morbidity and mortality –GVHD incidence and severity increases with increasing age –Tolerability of standard transplant limited by patient age

55 AML Treatment: Autologous 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

56 AML: Disease Free Survival ChemoAutoSib AlloUD Allo CR125-35%50%60%40% CR2< 5%38%44%37%

57 AML Treatment: 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 ( Patients < 60 yrs of age)

58 AML Treatment: Risk adapted approach Considerations include: –Fitness for conventional chemotherapy –Cytogenetics and molecular studies –Co-morbid conditions (transplant vs. observation) –Novel drugs eg, hypomethylating agents. ( Patients > 60 yrs of age)

59 AML: NCCN Treatment Guidelines National Comprehensive Cancer Network (NCCN) has issued guidelines for treatment of many cancers including AML (and other hematologic malignancies) Details can be found at

60 AML-M3 or APL

61 AML-M3 (APL) Acute Promyelocytic leukemia HL-60, a human AML cell line (M3) And primary human APL differentiates in vitro following treatment retinoic acid. Initial clinical trials of retinoic acid failed. Why?

62 AML-M3 (APL) Acute Promyelocytic leukemia HL-60, a human AML cell line (M3) And primary human APL differentiates in vitro following treatment retinoic acid. Initial clinical trials of retinoic acid failed. Why? Lab studies & initial clinical trials done with cis- retinoic acid. (Chemical grade cis-retinoic acid is ~5% trans. The trans isomer is active.) Dr. Zhu Chen, Shanghi Institute of Hematology first published the all trans-retinoic acid results

63 AML-M3 (APL) Acute Promyelocytic leukemia t(15;17) fuses PML gene with retinoic acid receptor-  (RAR-  ) PML/RAR-  protein represses RAR-  mediated gene activation and granulocyte differentiation ATRA (all trans retinoic acid) releases this repression and allows promyelocytes to differentiate

64 AML-M3 or APL Acute Promyelocytic Leukemia (APL M3) Blasts and promyelocytes heavily granulated, Auer rods often abundant Disseminated intravascular coagulation (DIC) common Treatment differs from all other AML subtypes once had the worst prognosis now the best prognosis

65 AML-M3 or APL Treated with a derivative of Vitamin A (all trans retinoic acid or ATRA) Favorable prognosis if diagnosed just prior to starting chemotherapy (>80% cured) Has chromosomal translocation, t(15;17) involving the retinoic acid receptor-  gene that blocks normal granulocyte differentiation

66 Core Binding Factor in AML CBF is an alpha/beta heterodimeric transcription factor Disruption of alpha and beta subunits of CBF results in a favorable prognosis (>70% cured) t(8;21) fusion of the AML1 gene from chromosome 21q22 with the ETO gene on chromosome 8q22 Inv(16) fusion of the CBFbeta gene from chromosome 16q22 with the MYH11 gene from chromosome 16p13

67 Ras Signaling in AML Ras proteins function as a hub of signal transduction pathways that promote cell cycling and proliferation and prevent apoptosis Receptor tyrosine kinases (RTK) (e.g. FLT3 PDGF, FMS, c-KIT,) bind ligand and transmit signal to activate Ras Ras and RTKs play a role in AML

68 Ras Pathway Mutations are Common in AML FLT3 internal tandem duplication15-30% FLT3 point mutation5-10% FMS point mutation10-20% Kitpoint mutation, deletion, insertion<10% Raspoint mutations15-30% At diagnosis 30-50% of AML have mutations in Ras pathway and 50% have abnormal phosphorylation of ERK, indicating aberrant pathway activation

69 FLT3-ITD mutation Mutant FLT3 receptors spontaneously dimerize leading to autophosphorylation due to constitutive activation of the tyrosine kinase Allow autonomous, cytokine-independent growth in culture

70 FLT3-ITD mutation and AML Associated with leukocytosis and increased marrow blast percentage Associated with a poor prognosis due to increased relapse rate Can be detected by PCR assay

71 What to do about AML with FLT3 mutation ? More intensive therapy (e.g. Transplant) Targeted therapy (in clinical trials): - FLT3 kinase inhibitors Farnesyl transferase inhibitors (block transport of Flt3 to the membrane) -Novel agents

72 Leukemia & the Hematopoietic Microenvironment How do we know there’s a significant biologic effect?

73 Leukemia & the Hematopoietic Microenvironment How do we know there’s a significant biologic effect? Post transplant, donor derived leukemia

74 Leukemia & the Hematopoietic Microenvironment How do we know there’s a significant biologic effect? Post transplant, donor derived leukemia Resistance to imatinib (TK inhibitor for CML) occurs in some patients but the in vitro sensitivity to imatinib is unchanged.

75 AML Summary AML is a heterogeneous group of diseases Age is one of the most important prognostic factors State of the art cytogenetic and mutational analysis is critical to determine prognosis and to guide therapy Novel therapeutic agents may be effective in traditional unfavorable risk patients

76 Complex Cytogenetics Revisited Breems et al. JCO:2008 Complex cytogenetics considered unfavorable Criteria vary from > 3 to >5 cytogenetic abnormalities Favorable cytogenetics trump complex cytogentics? 1,975 AML patients aged evaluated. Excluding normal cytogenetics and CBF, 733 patients evaluated

77 Complex Cytogenetics Revisited Breems et al. JCO:2008 Of 733 patients with cytogenetic abnormalities: Loss of a single chromosome was associated with poor OS (12% at 4 yr). Monosomy 7 most common but other monosomies with same OS. Structural abnormalities influenced outcome only if associated with a single autosomal monosomy. >2 monosomal abnormalities very poor prognosis OS of 3%.

78 Complex Cytogenetics Revisited

79 Breems et al. JCO:2008 New definition of monosomal karyotype (MK) proposed After excluding normal cytogentics and CBF subsets MK negative (MK-) Poor Prognosis: Structural abnormality but no autosomy. ( OS is 26% at 4 yr). MK positive (MK+) Very poor prognosis: > 2 autosomal monosomies or 1 autosomal monosomy and at least one structural abnormality. ~25% of non-CN non-CBF AML ( OS 4% at 4 yr).

80 Complex Cytogenetic Revisited Breems et al. JCO:2008

81 Elderly AML: The importance of reaching CR Rowe Blood 103:479, 2005 Rowe Leukemia 19:1324, 2003

82 Goffin & Eisenhauer. Annals of Oncology 2002; 13:1699 Azacitidine and Decitabine are Inhibitors of DNA Methyltransferase

83 Decitabine in Elderly Patients With AML Prospective, open-label, phase II study in elderly patients with untreated AML (N = 55) –Treatment: decitabine 20 mg/m 2 on Days 1-5, every 4 weeks Patient population –Median age: 74 years Range: –ECOG PS 2: 18% –Poor cytogenetics: 44% –AML transformed from MDS: 35% CR/Cri in 55 patients AML De novo7/31 23% Transformed MDS 5/1926% Therapy related 2/4 50% Poor risk cyto. 5/23 22% Inter. risk cyto. 7/29 24% *Ongoing Phase III trial Cashen AF, et al. ASH Abstract 560.

84 Low-Dose Decitabine in Elderly Patients With AML Preliminary results from phase II study of decitabine in elderly untreated AML patients (15 with secondary AML): N = 33 –Median age: 74 years (range: 60-83) –Risk factors > 70 years of age, AHD, poor cytogenetics, ECOG PS 2 ≥ 3 (n = 16); 2 (n = 15); 1 (n = 2) –Treatment: decitabine 20 mg/m 2 IV daily x 10 days/month → consolidation for 3- 5 days/month Median cycles: ≥ 3 Median cycles to CR: 1 –CR: 11/22 (50%) –Induction mortality: 4 (infections) Blum W, et al. ASH Abstract 2957.


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