Venetoclax and ASTX727 for the Treatment of Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia

This phase II trial studies the possible benefits of venetoclax and ASTX727 in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory), or elderly patients with newly diagnosed acute myeloid leukemia who are not candidates for intensive chemotherapy. Venetoclax may help block the formation of growths that may become cancer. ASTX727 is the combination of a fixed dose of 2 drugs, cedazuridine and decitabine. Cedazuridine may slow down how fast decitabine is broken down by the body, and decitabine may block abnormal cells or cancer cells from growing. Giving venetoclax and ASTX727 may help to control the disease.

Inclusion Criteria: * Patients with AML by the World Health Organization (WHO) classification who have failed prior therapy, refractory to it or relapsed after prior response. Patients with isolated extramedullary AML are eligible (cohort 1) * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * For cohort 2 (frontline elderly or unfit AML AML), the following inclusion criteria: * Confirmed newly diagnosed AML * Ineligible for induction therapy defined as * Either age \>= 75 years * Or 18-74 years of age with at least one comorbidity (chronic heart failure \[CHF\] requiring therapy or eject fraction \[EF\] =\< 50%, carbon monoxide diffusing capability \[DLCO\] =\< 65% or forced expiratory volume in 1 second \[FEV1\] =\< 65%, or ECOG 2 or 3) * Creatinine clearance ≥30 mL/min to \1.5 to ≤3.0 × upper limit of normal (ULN) * Creatinine clearance ≥ 45 ml/min unless related to the disease (e.g. infiltration) * Total bilirubin \< 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement * Alanine aminotransferase (ALT) \< 3 x ULN unless considered due to leukemic involvement (by biopsy or imaging) * Able to give written informed consent * Oral hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and hydroxyurea while the patient is on active study treatment through cycle 1, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted * Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment * Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment Exclusion Criteria: * Acute promyelocytic leukemia * Prior therapy with a BCL2 inhibitor * Symptomatic or uncontrolled CNS leukemia * Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician * Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator * Pregnant or breastfeeding