Decitabine and Cedazuridine in Combination With Venetoclax for the Treatment of Patients Who Have Relapsed Acute Myeloid Leukemia After Donor Stem Cell Transplant

Eligibility Criteria

• * Age \>= 18 years at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF and meet all study requirements
• * History of morphologically confirmed AML (per World Health Organization \[WHO\] diagnostic criteria) with evidence of disease recurrence (\>= 5% blasts consistent with prior disease) that occurs after allogeneic hematopoietic cell transplantation (HCT). Patients transplanted for another indication (e.g., myelodysplastic syndrome/chronic myelomonocytic leukemia \[MDS/CMML\]) who relapse with AML are eligible to enroll
• * White blood cells (WBC) must be less than 25,000/ul for at least three days prior to cycle 1, day 1 (C1D1) (hydroxyurea allowed)
• * A bone marrow biopsy must be performed and tissue collected for entrance to the trial
• * Eastern Cooperative Oncology Group Performance Status of 0 - 2
• * Alanine transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) and/or aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) less than or equal to 3x upper limit of normal (ULN)
• * Total bilirubin \< 1.5 x ULN
• * Calculated creatinine clearance \>= 30 ml/min (per the Cockroft-Gault formula)
• * Willingness to abide by all study requirements, including contraception, maintenance of a pill diary, and acceptance of recommended supportive care medications
• * Prior relapse or progression while receiving venetoclax or other commercially available or investigational BCL-2 inhibitor
• * Anticancer therapy, including investigational agents =\< 2 weeks or =\< 5 half-lives of the drug, whichever is shorter, prior to C1D1. (Use of hydroxyurea is permitted)
• * Inadequate recovery from toxicity attributed to prior anti-cancer therapy to =\< Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] version \[v\]5.0), excluding alopecia or fatigue
• * History of allogeneic HCT, or other cellular therapy product, within 3 months of signing consent
• * Clinically active acute or chronic graft versus host disease (GVHD). Patients must be off calcineurin inhibitors for at least 4 weeks to be eligible
• * Radiation therapy or major surgery within 3 weeks of signing consent
• * Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Prophylaxis is acceptable
• * Inability to tolerate oral medication, presence of poorly controlled gastrointestinal disease, or dysfunction that could affect study drug absorption
• * Active documented central nervous system leukemia
• * Concurrent treatment with a non-permitted concomitant medication
• * Other malignancy IF currently being treated or likely to be treated in next 6 months except for basal or squamous cell carcinoma of the skin or cervical carcinoma in situ
• * Pregnancy or breastfeeding females
• * Known chronic alcohol or drug abuse
• * Clinically significant cardiovascular disease with major event or cardiac intervention within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented cardiac heart failure) as determined by the investigator
• * Any other condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents