Venetoclax + Azacitidine in Patients With Acute Myeloid Leukemia

Inclusion Criteria:

1. Patients must have confirmation of with acute myeloid leukemia (AML) with persistentmeasurable residual disease (MRD) or MRD reappearance after frontline intensivechemotherapy (including at least one cycle of cytarabine and anthracycline), andprior to allogeneic hematopoietic cell transplantation (allo-HCT).

2. In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used toestablish a molecular failure, defined as failure to achieve molecular responseafter consolidation therapy (NPM1mut/ABL1·100 > 0.01) or MRDreappearance after molecular response. All cases of molecular failure must beconfirmed with a second MRD assessment in 2 to 4 weeks.

3. In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 andCBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRDreduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100>0.1or CBFb-MYH11/ABL1·100>0.1), a log increase in MRD between two positivesamples or confirmed MRD reappearance after molecular response will beconsidered as molecular failures and could be included in the trial.

4. In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRDsurveillance. A cutoff of 0.1% will be used to define MRD positivity.

5. Age ≥18 years.

6. Without clinical signs of active central nervous system disease.

7. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance statusof ≤2 or Karnofsky performance status (KPS) equivalent.

8. Patients must have adequate renal function as demonstrated by a calculatedcreatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hourcreatinine clearance or by the Cockcroft Gault formula.

9. Patients must have adequate liver function as demonstrated by:

10. aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN)

11. alanine aminotransferase (ALT) ≤ 3.0 × ULN

12. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome

13. Non-sterile male patients must use contraceptive methods with partner(s) prior tobeginning study drug administration and continuing up to 3 months after the lastdose of study drug. Male patients must agree to refrain from sperm donation frominitial study drug administration until 3 months after the last dose of study drug.

14. WOCBP must agree to use two reliable forms of contraception simultaneously or topractice complete abstinence from heterosexual intercourse during the following timeperiods related to this study: 1) for at least 28 days before starting therapy; 2)throughout the entire duration of treatment; 3) during dose interruptions; and 4)for at least 6 months after discontinuation of therapy (last dose of study drug).

15. Patients must voluntarily sign and date an informed consent, approved by anInstitutional Review Board (IRB), prior to the initiation of any research directedscreening procedures.

Exclusion Criteria:

1. Patient has received other prior rescue treatment for MRD.

2. Patient is known to be positive for Human immunodeficiency virus (HIV). Note: HIVtesting is not required.

3. Patient is known to be positive for hepatitis B (HBV) or C (HCV) infection with theexception of those with an undetectable viral load. Note: Hepatitis B or C testing is not required and patients with serologic evidenceof prior vaccination to HBV (i.e., HBsAg-, anti-HBs+ and anti-HBc-) may participate.

4. Patient has known active central nervous system (CNS) involvement from AML.

5. Patient has received within 7 days prior to the first dose of study drug: steroidtherapy ≥ 20 mg/day (prednisone or equivalent) for antineoplastic intent; strong andmoderate CYP3A inhibitors; strong and moderate CYP3A inducers.

6. Patient has consumed grapefruit, grapefruit products, Seville oranges (includingmarmalade containing Seville oranges) or Star fruit within 3 days prior to theinitiation of study treatment.

7. Patient has any history of clinically significant condition(s) that in the opinionof the investigator would adversely affect his/her participating in this studyincluding, but not limited to:

8. New York Heart Association heart failure > class 2.

9. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic,hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.

10. Patient has a malabsorption syndrome or other condition that precludes the enteralroute of administration.

11. Patient exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).

12. Patient has a history of other malignancies within the prior year to study entry,except for:

13. Adequately treated in situ carcinoma of the breast or cervix uteri.

14. Basal cell carcinoma of the skin or localized squamous cell carcinoma of theskin.

15. Prostate cancer with no plans for therapy of any kind.

16. Previous malignancy confined and surgically resected (or treated with othermodalities) with curative intent.

17. Pregnant and breastfeeding females.