Part 4 Acute Myeloid Leukemia

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Part 4 Acute Myeloid Leukemia

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

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