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

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

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

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