Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms

• Diagnosis of acute myeloid leukemia (per the World Health Organization [WHO] 2016 classification) or high-grade myeloid neoplasm (>= 10% myeloid blasts in peripheral blood or marrow as assessed by morphology or multiparameter flow cytometry at initial presentation). Patients with biphenotypic or mixed phenotype acute leukemia are eligible.

• PHASE I:

  • Newly diagnosed patients presenting for trial entry must have adverse risk disease as per the European LeukemiaNet 2017 guidelines
  • Relapsed/refractory patients presenting for trial entry must require first or subsequent salvage therapy and have detectable blasts in peripheral blood or >= 5% blasts in bone marrow, as assessed by morphology or multiparameter flow cytometry; or extramedullary myeloid sarcoma, per European LeukemiaNet 2017 guidelines.
  • These patients are only allowed in the phase 1 portion of the trial
• PHASE II: Newly diagnosed patients presenting for trial entry must have adverse risk disease as per the European LeukemiaNet 2022 guidelines
• Age >= 18 years
• Aspartate transaminase (AST) and alanine transaminase (ALT) =\< 3.0 X upper limit of normal (ULN)
• Bilirubin =\< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
• Subject must have adequate renal function as demonstrated by a creatinine clearance >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
• Left ventricular ejection fraction (LVEF) >= 45%, assessed by multigated acquisition (MUGA) or echocardiogram (ECHO) within 3 months prior to study day 0 or after most recent anthracycline administration if appropriate and no clinical evidence of congestive heart failure
• Eastern Cooperative Oncology Group (ECOG) =\< 2
• Treatment-related mortality (TRM) score \< 13.1
• Female subjects of childbearing potential must have negative results for pregnancy test. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must agree to use an effective method of birth control from the time of signing the consent form until at least 3 months after the last dose of study drug
• Ability to understand and the willingness to sign a written informed consent document
• White blood cell count in peripheral blood must be \< 25,000/ul prior to initiation of study therapy (CLAG-M plus venetoclax). Cytoreduction with hydroxyurea and/or cytarabine (e.g., 500 mg/m\^2 per dose) is allowed to decrease the risk of tumor lysis syndrome

Exclusion Criteria:

• Acute promyelocytic leukemia or chronic myeloid leukemia in myeloid blast crisis
• Known active central nervous system (CNS) involvement with acute myeloid leukemia (AML)
• Concomitant illness associated with a likely survival of \< 1 year
• Active systemic infection, unless disease is under treatment with antimicrobials and considered controlled or stable; patients with fever thought to be likely secondary to leukemia are eligible. Patients with chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment would be excluded. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• Known hypersensitivity to any study drug
• Pregnancy or lactation because of the unknown risks of this combination
• Concurrent treatment with any other investigational agent
• Subject is known to be positive for human immunodeficiency virus (HIV)
• Subjects who cannot discontinue concomitant CYP3A inhibitors, except for voriconazole, prior to cycle 1 day 1 (C1D1)

• Treatment with any of the following within 7 days prior to the first dose of venetoclax

  • Steroid therapy for anti-neoplastic intent

• Administration or consumption of any of the following within 3 days prior to the first dose of venetoclax:

  • Grapefruit or grapefruit products
  • Seville oranges (including marmalade containing Seville oranges)
  • Star fruit