Venetoclax With Combination Chemotherapy in Treating Patients With Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria:

• Diagnosis of AML by World Health Organization (WHO) criteria. Patients with highrisk myelodysplastic syndrome (MDS) as defined by the presence of >= 10% blasts arealso eligible at the discretion of the principal investigator

• Patients older than 65 who are deemed fit to receive intensive chemotherapy by thetreating physician will be eligible after discussion with the principal investigator (PI).

• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

• Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation

• Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due toGilbert's disease or leukemic involvement

• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULNunless considered due to leukemic involvement

• Ability to understand and provide signed informed consent

• Male subjects must agree to refrain from unprotected sex and sperm donation frominitial study drug administration until 90 days after the last dose of study drug

• Only patients who are relapsed, refractory, or intolerant of standard AML therapywill be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)

Exclusion Criteria:

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)

• Patients having received any prior BCL2 inhibitor therapy

• Subject has known active central nervous system (CNS) involvement with AML

• Patients with New York Heart Association (NYHA) class III or IV congestive heartfailure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram ormulti-gated acquisition (MUGA) scan

• Patients with a history of myocardial infarction within the last 6 months orunstable / uncontrolled angina pectoris or history of severe and/or uncontrolledventricular arrhythmias

• Patients with known infection with human immunodeficiency virus (HIV) or activehepatitis B or C

• Patients with known dysphagia, short-gut syndrome, or other conditions that wouldaffect the ingestion or gastrointestinal absorption of drugs administered orally

• Subject has any other significant medical or psychiatric history that in the opinionof the investigator would adversely affect participation in this study

• Subject has a white blood cell count > 25 x 10{9}/L. (Note: hydroxyurea is permittedto meet this criterion)

• Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancytest, or women of childbearing potential who are not willing to maintain adequatecontraception (a) appropriate method(s) of contraception include oral or injectablehormonal birth control, intrauterine device (IUD), and double barrier methods (forexample a condom in combination with a spermicide)