Decitabine/Cedazuridine and Venetoclax in Combination With Ivosidenib or Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Inclusion criteria

• Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML); OR
• Patients (\> 60 year old) with newly diagnosed AML not eligible for intensive chemotherapy are also eligible
• To be considered not eligible for intensive chemotherapy, participants must be defined by the following: Age 75 years or older, or Age 18 to 74 years with at least one of the following comorbidities:
• Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
• Severe pulmonary disorder (eg, 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 × upper limit of normal (ULN)
• ECOG performance status of 2 or 3
• Age \>= 18 years
• Subjects must have documented IDH1 or IDH2 gene mutation
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Adequate renal function including creatinine \< 2 unless related to the disease
• Direct bilirubin \< 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \< 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT \< 5 x ULN will be considered eligible)
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy agent(s). Oral hydroxyurea and/or cytarabine (up to 2 g/m\^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principle investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
• Male subjects who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 90 days after last dose of study drug
• Willing and able to provide informed consent

Exclusion criteria

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML)
• Patients with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment
• Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Corrected QT (QTc) interval using Fridericia's formula (QTcF) \>= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI
• Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection
• Subject has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea is permitted to meet this criterion)
• Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception
• Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)