Contemporary treatment approach for transplant-ineligible patients with AML. The initial evaluation should consist of a comprehensive history and physical exam to ascertain the patient's fitness and ability to undergo leukemia-directed therapy, followed by a bone marrow examination with special attention to cytogenetic and molecular abnormalities that can inform treatment selection and prognosis. Risk-stratification using either the 4-gene prognostic risk signature or Mayo Clinic risk-prognostication model (after initiation of therapy) may provide important prognostic information. For patients with IDH1-mutated AML, AZA-IVO may be preferred over HMA-VEN. For patients with TP53-mutated AML, a clinical trial option is preferred over HMA-VEN if available. Ongoing clinical trials (highlighted in yellow boxes) are actively investigating targeted therapies in combination with HMA-VEN in molecularly informed patient subgroups.