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ETIOLOGY AND EPIDEMIOLOGY

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Acute myeloid leukemia (AML) is an aggressive and frequently lethal hematologic malignancy, with a median age of presentation beyond the sixth decade. Approximately 12,000 new cases of AML are diagnosed in the United States each year, and most cases are idiopathic. However, AML is increasingly seen in survivors of other cancers who were previously exposed to chemotherapy and radiotherapy. Alkylating agents, such as melphalan and chlorambucil, can give rise to therapy-related AML, with a median time of onset of 5–10 years, and associated abnormalities in chromosomes 5 and 7. Inhibitors of topoisomerase, such as etoposide and anthracyclines, can also cause a therapy-related AML, with a median time of onset of 2–3 years. These cases of AML are often associated with balanced chromosomal translocations at 11q23 and involve alterations of the mixed lineage leukemia (MLL) protein. Myelodysplastic syndrome and myeloproliferative disorders, such as polycythemia vera and myelofibrosis, can also progress to AML. The "secondary" leukemias that derive from previous therapy or other myeloid diseases have significantly worse outcomes than the "de novo" cases of AML. Of note, the risk of leukemia is 20-fold higher in patients with Down's syndrome (1). Common mutations with prognostic value in AML include the FLT3-internal tandem duplication (ITD) mutation and the NPM1 (nucleophosmin) mutation. The FLT3-ITD mutation, identified in approximately a quarter of patients, leads to the production of an abnormal, constitutively active FLT3 receptor tyrosine kinase on the surface of leukemic cells. This in turn leads to uncontrolled proliferation of undifferentiated blasts and a higher propensity for relapse and poor outcomes (2, 3). The NPM1 mutation, on the other hand, is associated with a better prognosis if present as an isolated lesion, and affects a larger proportion of patients with AML. This mutation leads to the aberrant sequestration of altered nucleophosmin proteins in the cytoplasm, and disruption of regulated cell cycling in malignant cells (4, 5).

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  • Most cases of AML are idiopathic.

  • AML may arise secondary to prior chemotherapy or radiotherapy, or from underlying myelodysplastic/myeloproliferative processes.

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PATHOPHYSIOLOGY

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Acute leukemia is a clonal disease derived from leukemic stem cells. DNA mutations render myeloid precursor cells incapable of normal differentiation and maturation and promote unchecked proliferation, leading to the acute leukemic phenotype. The myeloblasts proliferate in the bone marrow compartments, resulting in hematopoietic insufficiency and progressive cytopenias. When myeloblasts expand outside of the bone marrow, severe peripheral leukocytosis may result, leading to additional sequelae, such as leukostasis and significant tumor lysis. Rarely extravascular solid tumors, known as chloromas or granulocytic sarcomas, may arise in tissue.

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DIAGNOSIS

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AML can be subtle in its presentation with some patients presenting with days to weeks of nonspecific symptoms, such as fatigue, shortness of breath, and bleeding. A complete blood count, examination of the peripheral blood smear, and bone marrow aspirate and biopsy are ...

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