Acute Myelogenous Leukemia by 9G8mBIy5

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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 Cancer Institute
                    OHSU
Blood Cell Formation
 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)
          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
        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
        Acute Leukemia:
     Clinical Manifestations
• Constitutional & Metabolic effects:

  – Weight loss
  – Fever
  – Hyperkalemia
  – Hyperuricemia
            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%)
        Acute Leukemia:
     Clinical Manifestations
• Marrow replacement, organ infiltration &
  metabolic effects

• Marrow replacement
  – Neutropenia: infection
  – Anemia: pallor, fatigue, dyspnea
  – Thrombocytopenia: abnormal bruising
    and bleeding
         Acute Leukemia:
      Clinical Manifestations
• Organ infiltration

  – Bone pain
  – Hepatosplenomegaly
  – Lymphadenopathy
  – Gingival hypertrophy
  – Leukemic meningitis
AML With Minimal Differentiation
          (M0/M1)
               Acute Leukemia
                  AML 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
             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
               AML
         FAB 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
  Acute Leukemia:
Blasts with Auer Rods
Auer rods = AML
          Acute Leukemia:
           AML vs. ALL
•   Cytochemistry         AML     ALL
•   Myeloperoxidase        +       -
•   Sudan black            +       -
•   Non-specific esterase + (M4,5) -
•   PAS                    + (M6)  +
•   Acid phosphatase       + (M6)  +
     FAB is Supplemented by
Cytogenetic and Molecular analysis
Flow Cytometry & FISH Analysis
Gingival Hyperplasia
      Chloroma
(Granulocytic Sarcoma)
Leukemia Cutis
             AML
Clinical 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
             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)
               AML
    Cytogenetics and Prognosis

•   Group          CR    5 year survival
•   Favorable      91%        65-75%
•   Intermediate   86%        40-50%
•   Adverse        63%        <15%
              AML
      Mutations & Prognosis
• Flt 3 (ITD)                - Adverse

• NPM-1 mutation & no Flt3   - Favorable

• MLL (PTD)                  - Adverse

• CEBPA                      - Favorable
         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
             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
            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)
         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
      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
         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
         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)
           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
    Current Risk Stratification
  OHSU Acute Leukemia Program
                      (modified NCCN Guidelines v.1.2009)




Risk Status      Cytogenetics                               Molecular
                                                            Mutations
Better-risk      Inv(16)1                                   Normal cytogenetics
                 t(8 ;21) 1                                 with isolated NPM1
                 t(16 ;16) 1                                mutation
Intermediate-risk Normal                                    c-KIT3 in patients
                  +8 only                                   with t(8;21) or
                  t(9 ;11)                                  Inv(16)
                  MK negative
Poor-risk        Complex (>3 abnormalities)                 Normal cytogenetics
                 -5, -7, 5q-, 7q-                           with isolated FLT3
                 MK positive                                mutations
              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
         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
             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
              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
          Acute Leukemia:
           AML vs. ALL
•   Cytochemistry         AML     ALL
•   Myeloperoxidase        +       -
•   Sudan black            +       -
•   Non-specific esterase + (M4,5) -
•   PAS                    + (M6)  + (c)
•   Acid phosphatase       + (M6)  + (T)
         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
AML-M3 (APL)
        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)
                  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
            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
               AML:
    Cytogenetics and Prognosis

•   Group          CR    5 year survival
•   favorable      91%        65%
•   intermediate   86%        41%
•   adverse        63%        14%
  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
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
        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
            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
      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
        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
         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?)
         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
         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
             AML:
      Disease Free Survival

       Chemo   Auto   Sib Allo   UD Allo


CR1    25-35% 50%     60%        40%


CR2    < 5%    38%    44%        37%
        AML Treatment:
     Risk adapted approach
         (Patients < 60 yrs of age)
• 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
           AML Treatment:
        Risk adapted approach
            (Patients > 60 yrs of age)
• Considerations include:

  – Fitness for conventional chemotherapy

  – Cytogenetics and molecular studies

  – Co-morbid conditions (transplant vs. observation)

  – Novel drugs eg, hypomethylating agents.
           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
  http://www.nccn.org/index.html
AML-M3 or APL
        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?
        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
       AML-M3 (APL)
Acute Promyelocytic leukemia
• t(15;17) fuses PML gene with retinoic
  acid receptor-a (RAR-a)
• PML/RAR-a protein represses RAR-a
  mediated gene activation and
  granulocyte differentiation
• ATRA (all trans retinoic acid) releases
  this repression and allows
  promyelocytes to differentiate
             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
           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-a gene
  that blocks normal granulocyte differentiation
      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
       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
      Ras Pathway Mutations are
          Common in AML
•   FLT3 internal tandem duplication             15-30%
•   FLT3 point mutation                          5-10%
•   FMS point mutation                           10-20%
•   Kit point mutation, deletion, insertion      <10%
•   Ras point mutations                          15-30%
•   At diagnosis 30-50% of AML have mutations in Ras
    pathway and 50% have abnormal phosphorylation of ERK,
    indicating aberrant pathway activation
         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
  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
   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
     Leukemia & the Hematopoietic
          Microenvironment
• How do we know there’s a significant biologic
  effect?
     Leukemia & the Hematopoietic
          Microenvironment
• How do we know there’s a significant biologic
  effect?

• Post transplant, donor derived leukemia
      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.
               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
     Complex Cytogenetics Revisited

• Complex cytogenetics considered unfavorable

• Criteria vary from > 3 to >5 cytogenetic abnormalities

• Favorable cytogenetics trump complex cytogentics?

• 1,975 AML patients aged 15-60 evaluated. Excluding
  normal cytogenetics and CBF, 733 patients evaluated

                                          Breems et al. JCO:2008
   Complex Cytogenetics Revisited
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%.
                                         Breems et al. JCO:2008
Complex Cytogenetics Revisited
    Complex Cytogenetics Revisited
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).

                                              Breems et al. JCO:2008
Complex Cytogenetic Revisited




                    Breems et al. JCO:2008
Elderly AML: The importance of reaching CR




                            Rowe Blood 103:479, 2005
                            Rowe Leukemia 19:1324, 2003
   Azacitidine and Decitabine are
Inhibitors of DNA Methyltransferase




            Goffin & Eisenhauer. Annals of Oncology 2002; 13:1699
Decitabine in Elderly Patients With AML

• Prospective, open-label, phase II   CR/Cri in 55 patients
  study in elderly patients with
  untreated AML (N = 55)
                                       AML De novo               7/31   23%
   – Treatment: decitabine 20
      mg/m2 on Days 1-5, every 4
      weeks                           Transformed MDS            5/19   26%
• Patient population
   – Median age: 74 years             Therapy related            2/4    50%
        • Range: 61-87
   – ECOG PS 2: 18%                   Poor risk cyto.            5/23   22%
   – Poor cytogenetics: 44%
                                      Inter. risk cyto.          7/29   24%
   – AML transformed from MDS:
      35%
                                      *Ongoing Phase III trial


                                      Cashen AF, et al. ASH 2008. Abstrac
       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/m2 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 2008. Abstract 2957.

								
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