Azacitidine or Decitabine With Venetoclax for Acute Myeloid Leukemia With Prior Hypomethylating Agent Failure

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent

• Diagnosis of AML by World Health Organization (WHO) 2016 criteria (Arber 2016)

• Age >= 18 years

• Treatment naïve and eligible for venetoclax plus HMA: * Age >= 75 OR * Age >= 18-74with at least one of the following co-morbidities: ** Eastern Cooperative OncologyGroup (ECOG) performance status of 2 or 3 ** Cardiac history of chronic heartfailure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) =< 50% or chronic unstable angina ** Carbon monoxide diffusing capability (DLCO) =< 65%or forced expiratory volume in 1 second (FEV1) =< 65% ** Creatinine clearance >= 30mL/min to =< 45 mL/min ** Moderate hepatic impairment with total bilirubin > 1.5 to =< 3 x upper limit of normal (ULN) ** Any other situation that the investigatorjudges to be incompatible with intensive chemotherapy must be reviewed with thestudy chair before study enrollment

• Patient experienced HMA failure for an antecedent hematologic disorder (e.g.myelodysplastic syndrome) prior to study entry (Santini 2019), defined as: * Diseaseprogression or stable disease as best response to >= 4 cycles of HMA or >= 2 cyclesof HMA combination therapy (primary resistance) OR * Relapse or progression afterprior response to HMA (secondary resistance)

• Prior decitabine and/or azacitidine, including oral formulations, for antecedenthematologic disorder is required. The patient should be treatment naïve for the AMLdiagnosis

• Prior allogeneic hematopoietic transplant for antecedent hematologic disorder isallowed if done at least 3 months prior to enrollment and there is no evidence ofactive graft versus host disease (GVHD) or requirement for systemic immunesuppression

• ECOG performance status of: * 0 to 2 for subjects >= 75 years of age OR * 0 to 3 forsubjects >= 18-74 years of age

• Whole blood cell (WBC) >= 25,000/mm^3 at the start of study therapy (leukapheresisand hydroxyurea areallowed to meet this criteria)

• Total bilirubin =, 1.5 x institution's ULN unless related to AML or Gilbert'ssyndrome (subjects who are >= 18-74 may have a total bilirubin of =< 3 xinstitution's ULN)

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) andalanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SPGT) =< 3 xinstitutional ULN unless related to AML

• Creatinine clearance >= 30 mL/min (calculated by the Cockcroft Gault formula ormeasured by 24-hours urine collection)

• Women of child-bearing potential and men with partners of child-bearing potentialmust agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry, for the duration of study participation,and for 90 days following completion of therapy. Should a woman become pregnant orsuspect she is pregnant while participating in this study, she should inform hertreating physician immediately. * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remainingcelibate by choice) who meets the following criteria: ** Has not undergone ahysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausalfor at least 12 consecutive months (i.e., has had menses at any time in thepreceding 12 consecutive months)

• Women of child-bearing potential has negative pregnancy test prior to initiatingstudy drug dosing

• Able to swallow and retain oral medication

Exclusion Criteria:

• Current or anticipated use of other investigational agents within 14 days or 5half-lives (whichever is shorter) prior to the first dose and throughout venetoclaxadministration

• Diagnosis of acute promyelocytic leukemia

• Active central nervous system involvement by AML

• Anticancer therapies, including investigational therapy, chemotherapy, targetedsmall molecule agents, or radiotherapy within 14 days or 5 half-lives (whichever isshorter) prior to the first dose and throughout venetoclax administration. Biologicagents (e.g. monoclonal antibodies) given for anti-neoplastic intent within 30 daysprior to the first dose and throughout venetoclax administration

• Prior therapy with venetoclax

• Known diagnosis of human immunodeficiency virus (HIV) infection or known activehepatitis A, B or C infection with the exception of those with an undetectable viralload and CD4+ T-cell (CD4+) counts >= 350 cells/μL within 3 months of starting studytreatment. Should have no titers within 28d of day 1. Patients with hepatitis Cvirus (HCV) infection should have completed curative antiviral treatment

• Known strong and/or moderate CYP3A inducers within 7 days prior to the initiation ofstudy treatment

• Subject has consumed grapefruit, grapefruit products, Seville oranges or starfruitwithin 3 days prior to the initiation of study treatment

• Severe or uncontrolled medical disorder that would, in the investigator's opinion,impair ability to receive study treatment (i.e., uncontrolled diabetes, chronicrenal disease, chronic pulmonary disease or active, uncontrolled infection,psychiatric illness/social situations that would limit compliance with studyrequirements)

• History of other malignancies, except for malignancy treated with curative intentwith no known active disease present for >= 1 year; treated non-melanoma skincancer; and localized, cured prostate and cervical cancer

• Evidence of uncontrolled active systemic infection requiring therapy (viral,bacterial, or fungal). Fever of unknown origin is not an exclusion criterion, asthis may be disease related

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to agents used in study

• Subject has a malabsorption syndrome of other condition that precludes enteral routeof administration

• Subjects with a cardiovascular disability status of New York Heart Association classgreater than 2

• Pregnant or nursing. There is a potential for congenital abnormalities and for thisregimen to harm nursing infants