Acute Myeloid Leukemia Classification.pptx

Classification of AML

1. AML CLASSIFICATION

2. Leukemias Acute leukemias Chronic leukemias Lymphomas Hodgkin lymphoma Non-Hodgkin lymphoma Hematopoietic Malignancies Plasma cell disorders Multiple myeloma

3. Neoplastic proliferations of white blood cells - leukaemias and lymphomas, are the most important group of leucocyte disorders .

4. leukaemias classified - on the basis of cell types – myeloid and lymphoid -on the basis of natural history of the disease – acute and chronic

5. Acute Myeloid leukaemia Acute Lymphoid leukemia (AML and ALL) Chronic Myeloid leukaemia Chronic Lymphocytic leukaemias (CML and CLL)

6. Lymphomas which are malignant Hodgkin lymphoma or Hodgkin’s disease (HD) Non-Hodgkin’s lymphomas (NHL)

7. Myeloid neoplasms Myelodysplastic syndromes (MDS) Acute myeloid leukaemia (AML) Chronic myeloproliferative disorders

8. Lymphoid neoplasms Neoplasms of lymphoid lineage include leukaemias and lymphomas of B, T or NK cell origin. This group thus includes B cell neoplasms (including plasma cell disorders), T cell neoplasms , NK cell neoplasms and Hodgkin’s disease.

9. Classification of leukaemias FAB ( French,American &British) classification—morphology & cytochemical features REAL (Revised European-American classification of lymphoid neoplasms ) – immunophenotypic features WHO classification-cytogenetic and molecular features

10. AML Definition - Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by infiltration of malignant myeloid cells into the blood, bone marrow and other tissues.

11. Blasts/blast more than 20% in peripheral blood (PB) &/or bone marrow (BM) cells .

12. Myelopoiesis Myeloid Progenitor cell → Myeloblast → Promyelocyte → Myelocyte → Metamyelocyte → Band → Granulocyte Myeloid Progenitor cell → Myeloblast → Monoblast → Promonocyte → Monocyte Myeloid Progenitor cell → Proerythroblast Myeloid Progenitor cell → Megakaryoblast

13. Risk Factors: I. Constitutional Disorders Down syndrome: There is increased risk for AML (acute megakaryoblastic leukemia). II. Familial Predisposition Syndromes 1. Inherited bone marrow failure syndromes: i . Fanconi anemia (FA): There is increased risk of MDS/AML. ii. Dyskeratosis congenita . iii. Diamond- Blackfan anemia. iv. Shwachman -Diamond syndrome. 2. Familial AML with mutated CEBPA gene. 3. Familial AML with GATA2 mutations.

14. III. Environmental Exposures: 1. Ionizing radiation: Linked to the risk of secondary AML 2. Benzene exposure: - Strong dose-response relationship with the development ofAML 3. Cigarette smoking: -- Cigarette smoke contains benzene, which may be responsible for the increased risk 4. Pesticides/herbicides IV. Chemotherapy

15. V. Underlying Hematopoietic Neoplasm: • Myelodysplastic syndrome (MDS), Myeloproliferative neoplasm (MPN).

16. WHO classification: I. AML with genetic abnormalities AML with t(8;21)(q22;q22.);RUNX1/ETO fusion gene AML with inv(16)(p13.1q22) CBFB-MYH11 fusion gene AML with t(15;17)(q22;11-12) PML-RARA fusion gene AML with t(11q; q23.v); diverse MLL Fusion genes AML with normal cytogenetics and mutated NPM

17. II. AML with MDS like features With prior MDS AML with multilineage dysplasia AML with MDS like cytogenetic abnormalities III. Therapy-related myeloid neoplasms

18. IV. AML, NOS(Not otherwise specified) AML with minimal differentiation AML without maturation AML with myelocytic maturation AML with myelomonocytic maturation AML with monocytic maturation AML with erythroid maturation AML with megakaryocytic maturation

19. FAB Classification of AML M0 undifferentiated acute myeloblastic leukemia (5%) M1 AML with minimal maturation (20%) M2 AML with maturation (30%) – t(8;21) M3 Acute promyelocytic leukemia (5%) t(15;17) M4 Acute myelomonocytic leukemia (20%) M4 eos Acute myelomonocytic leukemia with eosinophilia (5%) inv (16) M5 Acute monocytic leukemia (10%) t(9;11) M6 Acute erythroid leukemia (3%) M7 Acute megakaryoblastic leukemia (3%)

20. FAB Morphology,cytochemistry,immunophenotyping,cytogenetics,molecular genetics

21. DUE TO BONE MARROW FAILURE Anaemia Bleeding manifestations due to thrombocytopenia causing spontaneous bruises, petechiae , bleeding from gums and other bleeding tendencies. Infections Fever

22. DUE TO ORGAN INFILTRATION. Pain and tenderness of bones (e.g. sternal tenderness) Lymphadenopathy Splenomegaly Hepatomegaly Leukaemic infiltration of the kidney may be present and complications such as haemorrhage or blockage of ureter supervene. Gum hypertrophy due to leukaemic infiltration of the gingivae is a frequent finding in myelomonocytic (M4) and monocytic (M5) leukaemias .

23. Gingival Infiltration in Monocytic (AML M4 eos ) Variant of AML

24. AML mimics a lymphoma by manifesting as a discrete tissue mass (a so-called granulocytic sarcoma)

25. Clinical symptoms/Physical Findings Extramedullary disease ( ie , myeloid sarcoma/chloroma) Can also have involvement of lymph nodes, intestine, mediastinum , ovaries, uterus

26. Pathogenesis Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation t(8;21),inv(16)-RUNX1 and CBFB genes Epigenetic alterations -DNA methylation -posttranslational modifications of histones

27. BLAST Larger High N/C ratio Nucleus is large, open chromatin,1-5 nucleoli Thin rim to moderate amount of cytoplasm

28. Myeloblast 4Ms More in size More nucleoli Moderate cytoplasm Myeloperoxidase Auer rod

29. Myeloblasts (precursors of granulocytes) have delicate nuclear chromatin, three to five nucleoli, and fine azurophilic cytoplasmic granules Auer rods, distinctive red-staining rod like structures(azurophilic granules), may be present in myeloblasts or more differentiated cells; they are particularly numerous in acute promyelocytic leukemia

30. Myeloblasts - AML Auer rod

31. Clinical features: -Young adults. - Myeloid sarcomas (tissue infiltration – chloromas ). CBC/Blood morphology: -Anemia. - neutropenia -Thrombocytopenia. -Circulating blasts; possibly with Auer rods. - Generally leukocytosis dominated by blasts. - Evidence of neutrophilic maturation. -

32. BMA: Increased myeloid blasts. Some cases less than the required 20% ( low blast count AML ). Large blasts, abundant basophilic cytoplasm, numerous azurophilic granules . Characteristic Auer rods : Thin with tapered ends and usually single within a cell. They are seen in cytoplasm of blasts and maturing/mature granulocytes. Abnormal neutrophilic precursors. .

33. 1)AML with Minimal Differentiation: - FAB type: AML-M0. - Large, Agranular , lineage- indeterminant blasts predominate.intended nuclei - Lineage of blasts not apparent by morphology or cytochemistry . - Flow cytometric,immunophenotyping is required for delineation of myeloid lineage. - There are no recurrent cytogenetic abnormalities. - Prognosis is poor.

34. 2. AML without Maturation: - FAB type: AML-M1. -Blasts myeloblast by morphology ( azurophilic granules, Auer rods)and/ or cytochemistry (MPO+). The blast percentage exceeds 90% in PS, and there is no significant maturation of these leukemia cells (maturation < 10%) in BM .

35. 3. AML with Maturation: - FAB type: AML-M2. - ≥ 20% blast threshold .myeloblasts - ≥ 10% of cells are promyelocytes , myelocytes , metamyelocytes , or neutrophils . - Monocytic component < 20%.

36. M0 M2

37. FAB - M3 Acute Promyelocytic Leukemia Hypergranular promyelocytes Increased Auer rods 15;17 chromosomal translocation (retinoic acid receptor gene) RAR- Ch17 PML-Ch 15

38. Acute promyelocytic leukemia - AML M3

39. AML M3 (Promyelocytic) Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

40. AML M3 (Promyelocytic) Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

41. M3

42. 4. Acute Myelomonocytic Leukemia (AMML): - FAB type:AML-M4. - Blasts and blast equivalents ( promonocytes ) ≥ 20% in blood or bonemarrow . - ≥ 20% maturing granulocytic lineage cells. ≥ 20% monocytic lineage cells. neutrophils - Blood picture may closely resemble CMML. Therefore, blast enumeration is very important. -

43. 5. Acute Monocytic Leukemias : - FAB type: AML-M5. - Immature monocytic cells predominate in this AML, NOS type. - ≥ 80% monocytic lineage cells. - ≤ 20% neutrophilic lineage cells. • If monoblasts predominate, termed acute monoblastic leukemia. • If promonocytes predominate, termed acute monocytic leukemia .

44. M4-M5 AMML Normal “classic” monocyte

45. 6. Pure erythroid leukemia: - FAB type: AML-M6. - > 80% of the bone marrow cells are erythroid , with ≥ 30% proerythroblasts ), with no evidence of a significant myeloblastic component . - Cases previously classified as erythroleukemia ( erythroid /myeloid type) on the basis of counting myeloblasts as a percentage of non- erythroid cells when erythroid precursor cells constituted ≥ 50% of the marrow cells are now classified on the basis of the total bone marrow or peripheral blood blast cell count:

46. 7. Acute Megakaryoblastic Leukemia: - ≥ 20% blasts in blood and / or BM. - > 50% of blasts are megakaryoblasts . - Clumps ( pseudometastasis ). - Variable cytological features. - Pure megakaryoblastic vs multilineage . - Fibrosis is common and it can preclude aspiration for morphology and flow cytometric immunophenotyping . Acute megakaryoblastic leukemia is more common in children than adults .

47. M6-M7 ERYTHROLEUKEMIA MEGAKARYOCYTIC LEUKEMIA

48. Lab findings in Acute leukaemia Cytochemistry Myeloperoxidase + ve in myeloid Sudanblack + ve in AML Periodic acid –Schiff (PAS) + ve in lymphoid and AML M6 Non-specific-esterase (NSE) + ve in AML M4 &M5 Acid phosphatase Focal + in ALL and diffuse + in M4 & M5

49. Lab findings in Acute leukaemia Immunophenotyping CD13 and CD33 in AML cells CD41 and CD 42 in AML M7

50. CHRONIC MYELOID LEUKEMIA

51. Chronic Myeloproliferative Disorders Chronic myeloid leukemia Polycythemia vera Essential thrombocythemia Chronic myelofibrosis Proliferation of one or more myeloid lineages

52. Chronic Leukemia

53. Chronic Myeloid Leukemia

54. Normal chromosomes Chromosomes in CML

55. t(9;22)(q34;q11.2) BCR-ABL Fusion-activation of tyrosine kinase-RAS/JAK/STAT/AKT pathway-cell division, Inhibition of apoptosis ABL-Abelson murine leukemia virus BCR-breakpoint cluster region

56. Clinical features Anemia Bleeding Massive splenomegaly lymphadenopathy

57. Chronic Myeloid Leukemia Chronic phase -Stable counts -Blasts less than 10% -3-4 years Accelerated phase -unstable counts -Blasts10-19% -Striking basophilia(20 % or more) -fatal within months Blast crisis -lots of blasts more than 20% -fatal within weeks

58. Polycythemia Vera (PV) JAK 2 point Mutations Bone marrow-hypercellular of all elements mainly erythroid

59. Polycythemia vera

60. ESSENTIAL THROMBOCYTOPENIA JAK 2 MUTATION Megakaryocytic lineage

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