Comparing New Treatments for People With Newly Diagnosed Acute Myeloid Leukemia That Has an IDH2 Gene Change (A MyeloMATCH Treatment Trial)

PRIMARY OBJECTIVES: I. To evaluate the safety of decitabine and cedazuridine (ASTX727) + venetoclax + enasidenib (Arm 2) before initiating randomization. II. To compare the rate of measurable residual disease (MRD) negative complete remission with or without partial hematologic recovery (complete remission \[CR\] or complete remission with partial hematologic recovery \[CRh\]) based on multiparameter flow cytometry (MFC) after two cycles of treatment in older adults (or unfit adults age 18 or older) with IDH2 mutated acute myeloid leukemia (AML) who receive ASTX727, venetoclax, and enasidenib versus ASTX727 and venetoclax alone. III. If the rate of measurable residual disease (MRD) negative CR+CRh is significantly higher on the ASTX727, venetoclax, and enasidenib arm compared to the ASTX727 and venetoclax arm, to hierarchically evaluate whether the measurable residual disease (MRD) negative CR rate is different between the randomized arms. SECONDARY OBJECTIVES: I. To estimate the rate of composite remission (CR + complete remission with incomplete count recovery \[CRi\] + complete remission with partial hematologic recovery \[CRh\]), relapse-free survival (RFS), event-free survival (EFS), duration of response (DOR), and overall survival (OS) of participants by treatment arm. II. To estimate IDH2 mutated variant allele frequency, flow cytometry MRD, and molecular MRD after two cycles of therapy in participants' bone marrow aspirates and blood by treatment arm. III. To estimate remission rates (CR with and without MRD \[MFC and molecular MRD\], CRh and CRi), and to estimate the rates of hematologic improvement by treatment arm. IV. To estimate the frequency and severity of adverse events by treatment arm. V. To evaluate the association between MFC and molecular MRD after two cycles of protocol treatment with the outcomes RFS and OS (landmarked by date of MRD measurement) by treatment arm. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. All patients undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. After completion of study treatment, patients are followed up every month for the first year, every 2 months for the second year, every 3 months for the third year, and every 6 months until 5 years after registration or death.