Pill combo could replace harsh chemo for High-Risk leukemia

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Subjects must be between 18-65 years of age at the time of signing the Informed Consent Form (ICF) and must be able to meet all study requirements. AML patients under the age of 18 are excluded as is being studied in patients under 18 years of age in different venues * Morphologically confirmed diagnosis of AML in accordance with World Health Organization (WHO) diagnostic criteria * Adverse risk AML per 2017 European LeukemiaNet (ELN) recommendations * Subjects must be either treatment naive defined by =\< 1 cycle of deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) therapy, no history of cytotoxic chemotherapy for their AML; prior treatment with lenalidomide, hydroxyurea or erythropoiesis-stimulating agents (ESAs) is allowed (prior treatment for myelodysplastic syndrome \[MDS\] with \> 1 cycle of DNMTi is not allowed) * A bone marrow aspirate and biopsy must be performed, and tissue collected for entrance to the trial * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%) * Recovery to =\< grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia * White blood cell count (WBC) \< 25,000 (may be reduced with leukapheresis or hydroxyurea prior to study start) * Direct bilirubin =\< 2 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN * Creatinine clearance \>= 30 mL/min (per the Cockcroft-Gault formula) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment or have received treatment, they are eligible if they have an undetectable HCV viral load * Tumor lysis present prior to therapy must be treated accordingly prior to start of therapy * The effects of venetoclax and ASTX727 on the developing human fetus are unknown. For this reason and because BCL2 inhibitor and DNMTi agents as well as other therapeutic agents used in this trial (cytarabine and daunorubicin) are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal method of birth control or abstinence) prior to study entry and for the duration of study participation, and for 6 months following completion of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception (latex or synthetic condom or abstinence) prior to the study, for the duration of study participation, and 3 months after completion of venetoclax and ASTX727 administration * Ability to understand and the willingness to sign a written informed consent document * Adequate cardiac systolic function as measured by ejection fraction (EF) \>= 50% Exclusion Criteria: * Favorable or intermediate risk AML as defined by 2017 ELN criteria * Presence of FLT3 TKD or FLT-ITD mutations * Inability to tolerate oral medication or keep a pill diary * Active documented central nervous system (CNS) leukemia * Concurrent treatment with a non-permitted concomitant medication * Concurrent anticancer treatment, major surgery, or use of any investigational drug within 28 days before the start of trial treatment * Other malignancy currently being treated or likely to be treated in next 6 months with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ and patients receiving hormonal therapy for prevention of hormone-sensitive cancers * History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax, ASTX727, or other agents used in study * Patient must not have received known moderate or strong CYP3A inducers within 7 days of enrollment. Patient must not have known medical conditions requiring chronic therapy of moderate CYP3A inducers. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product * Patients with uncontrolled intercurrent illness * Patients with psychiatric illness/social situations (including substance abuse) that would limit compliance with study requirements * Pregnant women are excluded from this study because venetoclax and ASTX727 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, breastfeeding should be discontinued if the mother is treated with venetoclax. These potential risks may also apply to other agents used in this study * Previous exposure to either venetoclax or \> 1 cycle of DNMTi (e.g. azacitidine, decitabine, ASTX727, CC486) * Active, uncontrolled infection as determined by the investigator. Patients with infection under active treatment and controlled with antibiotics are eligible * Any condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents