Ziftomenib for the Treatment of Patients With NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia Not Eligible for Standard Therapy

Inclusion Criteria: * Signed informed consent must be obtained prior to participation in the study * Morphologically confirmed diagnosis of the following based on 2022 World Health Organization (WHO) Classification: * Treatment-naïve acute myeloid leukemia * KMT2A rearrangement (defined as KMT2A translocations) OR NPM1 mutation (defined as NPM1 mutation resulting in cytoplasmic localization, or NPM1c) OR other mutations that have been shown to exhibit sensitivity to menin inhibition. Mutation status will be known from initial diagnosis using standard of care testing, which can be performed locally * Patients ineligible or unwilling to receive standard of care induction therapy, such as 7+3, hypomethylating agent, venetoclax, or other standard of care (SOC) regimens with ineligibility defined by the following: * ≥ 75 years of age with both of the following; * Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection * Subject must have adequate liver function as demonstrated by aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (unless considered due to leukemic organ involvement) OR * ≥ 18 to 74 years of age with at least one of the following co-morbidities: * Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3; * Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina; * Diffusion capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%; * Creatinine clearance ≥ 30 mL/min to \< 45 ml/min; * Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 x ULN; * Venous thromboembolism benefitting from prolonged anticoagulation or presence of prosthetic heart valve or any indication for therapeutic anticoagulation with a single agent * Prior history of severe infection requiring hospitalization with risk of recurrence with subsequent immunosuppression * Any other comorbidity that the physician judges to be incompatible with standard frontline therapy must be reviewed and approved by the study team before study enrollment * Peripheral white blood cell (WBC) counts ≤ 10,000/uL. Patients may receive hydroxyurea, cytarabine, or leukapheresis to control and maintain white blood cell count until the end of cycle 1 * Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 180 days after the last dose of study treatment * Non-sterile male patients must agree to use a highly effective method of contraception with partner(s) throughout the study and for at least 90 days after the last dose of study treatment Exclusion Criteria: * Diagnosis of acute promyelocytic leukemia * Diagnosis of chronic myelogenous leukemia in blast crisis * Clinically active central nervous system (CNS) leukemia * Prior treatment for AML except for hydroxyurea and/or cytarabine used for control of leukocytosis * Treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient * Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection. Patients with controlled disease will not be excluded from study enrollment * Pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML) * Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection * Mean Fridericia's formula-corrected QT interval (QTcF) \> 480 ms on triplicate electrocardiogram (ECG) * Any psychiatric illness that prevents patient from informed consent process * Women who are pregnant or lactating. All female patients with reproductive potential must have a negative serum pregnancy test within 72 hours prior to starting treatment * Participants requiring dual antiplatelet therapy