Acute Myeloid Leukemia Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

Overview Originate from transformed hematopoietic progenitors …due to acquired oncogenic mutations that impede differentiation …leading to: Accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis The replacement of the marrow with blasts produces marrow failure and complications related to anemia, thrombocytopenia, and neutropenia

Overview, cont’d Occurs at all ages, but the incidence rises throughout life, peaking after 60 years of age The current WHO classification subdivides AML into four categories …see next slide

Pathogenesis Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation …defective maturation of early myeloid cells resulting in the accumulation of myeloid precursors (blasts) in the marrow Of particular interest is the (15;17) translocation in acute promyelocytic leukemia …results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 and the PML gene on chromosome 15 …the chimeric gene produces a PML/RARα fusion protein that blocks myeloid differentiation at the promyelocytic stage …probably in part by inhibiting the function of normal retinoic acid receptors …Pharmacologic doses of all-trans retinoic acid (ATRA), an analogue of vitamin A can be used…also its combination with arsenic trioxide (a salt that induces the degradation of the PML/RARA fusion protein) can cure 80% of patients

Pathogenesis, cont’d Some of the other mutations implicated in AML have no effect on differentiation but instead enhance cellular proliferation and survival …examples: - FLT3, a receptor tyrosine kinase - RAS

Morphology By definition, in AML myeloid blasts or promyelocytes make up more than 20% of the bone marrow cellular component Myeloblasts (precursors of granulocytes) -delicate nuclear chromatin -three to five nucleoli -fine azurophilic cytoplasmic granules -Auer rods, distinctive red-staining rod-like structures..may be present in myeloblasts or more differentiated cells …they are particularly numerous in acute promyelocytic leukemia …Auer rods are specific for neoplastic myeloblasts and thus a helpful diagnostic clue when present In other subtypes of AML, monoblasts, erythroblasts, or megakaryoblasts predominate

Morphology, cont’d

Clinical notes Splenomegaly and lymphadenopathy generally are less prominent than in ALL On rare occasions AML mimics a lymphoma by manifesting as a discrete tissue mass (a so-called granulocytic sarcoma)

Clinical notes, cont’d The overall survival in all patients is only 15% to 30% with conventional chemotherapy t(8,21) and inv16 are good Hematopoietic stem cell transplantation…sometimes used

Diagnosis The diagnosis and classification of AML are based on: -morphologic -histochemical -immunophenotypic -karyotypic findings Of these, the karyotype (to detect translocations) is most predictive of outcome

Immunohistochemistry (Immunophenotype of tumor cells) myeloid-associated antigens: …CD13, CD14, CD15, CD64, CD117 (cKIT), or CD33

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