Part 4 Acute Myeloid Leukemia

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  • 1. Myeloid Neoplasm
    MALIGNANT NEOPLASM OF HEMATOPOIETIC STEM CELLS
    ARISE
    PRIMARILY IN BONE MARROW
    ALSO SPLEEN, LIVER, LN - To a Lesser Extent
    FLOOD THE CIRCULATING BLOOD & OTHER ORGANS
  • 2. 3 Broad Categories of Myeloid Neoplasm
    1. Acute Myelogenous
    Immature progenitor cells accumulate in BM
    2. Myelodysplastic Syndromes
    Ineffective Hematopoiesis
    Peripheral Cytopenias
  • 3. 3 Broad Categories of Myeloid Neoplasm
    3. Chronic Myeloproliferative D/O
    Increased production
    1 or more terminally differentiated myeloid elements
    GRANULOCYTES
    Leads to elevated peripheral blood counts
    TYPES:
    CML, Polycthemiavera, Essential thrombocytosis, primary myelofibrosis
  • 4. ACUTE MYELOID LEUKEMIA
  • 5. Features
    Affects primarily Adults
    15 – 39 y/o peak incidence
    Acute Onset of symptoms R/T
    Anemia
    Neutropenia - Infections
    Spontaneous mucosal & cutaneous Bleeding
    Bleeding diasthesis is most striking feature
  • 6. Features
    Enlargement of liver, spleen
    LN enlargement is not pronounced
    If untreated, course is rapidly progressive
  • 7.
  • 8. PATHOPHYSIOLOGY
    1. MOSTLY with Acquired genetic alterations
     INHIBITION OF TERMINAL MYELOID DIFFERENTIATION
    Proliferation of Relatively Undifferentiated Myeloblast
    REPLACED NORMAL MARROW ELEMENTS
    Its replication rate is LOWER than normal myeloid cells
    INDICATING :
    1. BLOCKED MATURATION
    2. INCREASED SURVIVAL
  • 9. PATHOPHYSIOLOGY
    2. Chromosomal Abnormalities- AML t(8;21) , inv(16) , t(15,17)
    De Novo cases
    Associated with Myelodysplastic syndromes
    Radiation therapy
  • 10. PATHOPHYSIOLOGY
    Recurrent Chromosomal Aberrations
    Translocation  Disrupt genes encoding for Factors needed for NORMAL MYELOID DIFFERENTIATION
    Eg. t(8,21) AND inv(16) Chimeric gene  New Protein  Dominant Negative activity  Daughter cells exhibit partial or complete block in terminal differentiation
  • 11. Additional Collaborative Aberration present
    Promyelocytic Leukemia (AML-M3)
    T(15,17) producing fusion gene RARaand PML
    Suppress the function of RARa Becomes a Repressor of Transcription  Turns off genes needed for full and complete myeloid differentiation
    Point mutation in FLT3  constitutive activation of tyrosine kinase  promote cellular proliferation & survival
  • 12. Diagnosis:
    Dxrequires at least 30% of ANC are Myeloblast(ANC- all nucleated cells )
    WHO criteria
    Been lowered to 20%
    With elimination of of MDS
    Refractory anemia w/ excess blast Blastin Transformation
    Helpful in the dx is (+) Auer rods in myeloblast cells
  • 13. Myeloblast
  • 14. SBB
    Myeloperoxidase
    Esterase
  • 15. AUER RODS
    Linear or Spindle
    Red- Purple Inclusions
    In Myeloblast/myelocyte
    Derivatives of Azurophilic granules
    Stain (+) SBB, MPO, ACP
    Especially associated w/ M1 to M3
  • 16. Revised Classification of AML
  • 17.
  • 18.
  • 19. M6 Erythroleukemia
    Erythroid precursor predominates
    Blast are also Increased
    Dx when > 50% of BM cells are erythroid precursors and Myeloblast represent > 30% of Non-Erythroidcells
    M7
    Megakaryoblast are identified by Ab against
    Platelet-associated Antigens
  • 20.
  • 21. TREATMENT / PROGNOSIS
    With ChemoTx
    60% Complete remission
    15-30% remain free from disease for 5 years
    t(8;21) , inv(16)
    Relative good response to chemoTx
    Allogenic BM therapy
    High risk forms AML
    Develop from myelodysplastic syndrome
    Relapse AML
  • 22. Vit A derivative
    Overcome the block in differentiation r/t t(15,17) and presence of RAR PML fusion protein
    Ultimately relapses when used alone
    Fail to prevent self-renewal of neoplastic progenitor cells
    TREATMENT / PROGNOSIS
  • 23. Difference of AML & ALL
  • 24. AML-M1
    M1- Blast cells are minimally differentiated
    Express CD 34 (marker of multipotent stem cells )
    Negative for CD 64 ( marker of mature myeloid cells )
    (+) CD33 ( marker for immature myeloid cells
    Subset (+) CD 15 ( marker for more mature myeloid cell
  • 25. Acute Myeloblastic Leukemia w/ Maturation M2
    Myeloblast represent 20% (WHO) to 89% of total marrow cells
    > 10% of NEC are promyelocyte to neutrophils
    Auer rods are usually present –mulitple
  • 26. ACUTE PROMYELOCYTIC LEUKEMIA M3(35-40y/o)
    Promyelocytes
    predominate
    Azurophilic granules
    abundant & stain intenselyHypergranularpromyelocytes
    Auer rods almost always (+) , multiple or clusters
    Hemorrhagic complications frequent due to DIC
    Initiated by PROCOAGULANT materials from Leukemic cell Granules
  • 27. ACUTE MONOCYTIC LEUKEMIA M5
    Promyelocytes and Blast
    Gum Infiltrates
    2 types
    Poorly Differentiated M5A
    LARGE BLAST >80% OF MARROW MONOCYTIC CELLS
    Differentiated M5B
    FEWER MONOBLAST
    < 80% OF MARROW MONOCYTIC CELLS
    MORE PROMONOCYTES & MONOCYTES
  • 28. ERYTHROLEUKEMIA M6
    Erythroblast predominates
    Myeloblast are also Increased
    > 50% NC of BM are Erythroblast
    >20% (WHO) of NEC are Myeloblast
  • 29. MEGAKARYOCYTIC M7
    Undifferentiated Blast
    Megakaryoblast identified by Ab against Platelet associated antigens
    Marrow Fibrosis