Acute Myeloid Leukemia

Myeloid Neoplasms: - The common feature of this heterogeneous group of neoplasms is an origin from hematopoietic progenitor cells - primarily involve the marrow - include: 1- Acute myeloid leukemias 2- Myelodysplastic syndromes 3- Myeloproliferative disorders

Acute Myeloid Leukemia caused by acquired oncogenic mutations that impede differentiation accumulation of immature myeloid blasts in the marrow. produces marrow failure (anemia, thrombocytopenia, and neutropenia).

occurs at all ages peaking after 60 years of age.

Classification: WHO classification: 1- AML with genetic aberrations 2- AML arising after a myelodysplastic disorder (MDS) or with MDS-like features 3- Therapy-related AML 4- AML, Not Otherwise Specified ( classified according to earlier FAB classification, based on degree of differentiation and lineage of leukemic blasts)

genetic classification of AML is both inevitable and desirable. correlate with prognosis and guide therapy.

Pathogenesis: genetic aberrations seen in AML disrupt genes encoding transcription factors that are required for normal myeloid differentiation mutations that lead to activation of growth factor signaling pathways collaborate with transcription factor aberrations to produce AML

the two most common chromosomal rearrangements, t(8;21) and inv(16), disrupt the RUNX1 and CBFB genes, respectively. create chimeric genes encoding fusion proteins that interfere with the function of RUNX1/CBF1β transcription factor and block the maturation of myeloid cells

acute promyelocytic leukemia: Creates fusion gene encoding a chimeric protein consisting of the retinoic acid receptor-α (RARα) fused to a portion of a protein called PML (after the tumor). (RARα/PML) treatment with either all-trans retinoic acid or arsenic trioxide

younger adults: translocations, particularly t(8;21), inv(16), and t(15;17) older adults: is also more likely to be associated with “bad” aberrations, such as deletions of chromosomes 5q and 7q. MDS-like features and Therapy-related AML: Deletions or monosomies of chromosomes 5q and 7q.

MORPHOLOGY: The diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow.

Myeloblasts have delicate nuclear chromatin, two to four nucleoli, and more voluminous cytoplasm than lymphoblasts The cytoplasm often contains fine, peroxidase positive azurophilic granules Auer rods, distinctive needle-like azurophilic granules; they are particularly numerous in AML with the t(15;17)

Monoblasts have folded or lobulated nuclei, lack Auer rods, and are nonspecific esterase positive.

The number of leukemic cells in the blood is highly variable The number of leukemic cells in the blood is highly variable. Blasts may be more than 100,000/mm3, but are under 10,000/mm3 in about 50% of patients. Occasionally, blasts are entirely absent from the blood (aleukemic leukemia).

Clinical Features: anemia, neutropenia, and thrombocytopenia

Prognosis: AML is generally a difficult disease to treat; about 60% of patients achieve complete remission with chemotherapy, but only 15% to 30% remain free of disease for 5 years.

t(15;17): - all-trans retinoic acid and arsenic salts - curable in more than 80% of patients - best prognosis t(8;21) or inv(16): - conventional chemotherapy - good prognosis MDS-AML/therapy-AML/older adults: - BM transplantation - dismal prognosis