Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative.

• Age: >= 18 years.

• Eastern Cooperative Oncology Group (ECOG) =< 2.

• Life expectancy > 3 months.

• Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with relapsed/refractory disease.

• Patients must have any one of the following treatment history criteria:

  • Relapsed AML

    • Failed at least 1 line of salvage therapy or
    • Untreated relapse and are not candidates for allogeneic hematopoietic stem cell transplantation (alloHCT)

  • De novo AML

    • have not achieved complete response (CR) after 2 lines of therapy or
    • refractory to frontline therapy and not eligible for alloHCT

  • AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agents (HMA) or induction chemotherapy

  • Patients who have relapsed after allo-HCT are eligible if they are at least 3 months after HCT, do not have active graft versus host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less).

• Male subjects must agree to not donate sperm while taking protocol therapy through at least 90 days after the last dose.

• White blood cell (WBC) =< 25 x 10^9/L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required.

• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease).

• Aspartate aminotransferase (AST) =< 2.5 x ULN.

• Alanine aminotransferase (ALT) =< 2.5 x ULN.

• Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula.

• QTc =< 480 ms.

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months (females) and 3 months (males) after the last dose of protocol therapy.

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria:

• Current or planned use of other investigational agents, antineoplastic, biological, chemotherapy, or radiation therapy during the study treatment period, or within 2 weeks prior to day 1 of protocol therapy, with the following exception:

  • Hydroxyurea which may be continued through cycle 1.

• Expected to undergo HCT within 120 days of enrollment.

• Current or planned use of agents that prolong or suspected to prolong QTc.

• Received strong or moderate CYP3A inducers or St. John's Wort within 7 days prior to day 1 of protocol therapy.

• Received strong or moderate CYP3A inhibitors, or consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to day 1 of protocol therapy.

• P-glycoprotein (P-gp) inhibitors within 7 days prior to day 1 of protocol therapy.

• Narrow therapeutic index P-gp substrates within 7 days prior to day 1 of protocol therapy.

• Acute promyelocytic leukemia.

• Active central nervous system (CNS) leukemia.

• Active fungal infection or bacterial sepsis.

• Class III/IV cardiovascular disability according to the New York Heart Association classification.

• Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of enrollment. Subjects with controlled, asymptomatic atrial fibrillation can enroll.

• History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment.

• History of unexplained syncope, significant histories of CAD (requiring revascularization by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), cardiomyopathy (ejection fraction [EF] < 50%).

• Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).

• Unable to swallow capsules, has a partial or small bowel obstruction, or has a gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel resection with malabsorption).

• Active peptic ulcer disease.

• Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ.

• Females only: Pregnant or breastfeeding.

• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.

• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).