A Study of Azacitidine and Venetoclax in People With Acute Myeloid Leukemia (AML)

Inclusion Criteria:

1. Adult patient ≥18 years of age at the time of signing the informed consent form (ICF). Legal Authorized Representatives (LAR) are permitted.

2. Patient is willing and able to adhere to the study visit schedule and otherprotocol requirements.

3. Patient has a confirmed diagnosis of de-novo AML (non-APL) as per World HealthOrganization (2022) guidelines. All (non-APL) subtypes of AML are permitted,irrespective of ELN risk category or mutational status.

4. Patient has received 2 cycles of intensive chemotherapy (either induction +consolidation or 2 induction cycles).

5. Patient is in a morphologic remission, defined as less than 5% percent blastsseen by aspirate differential (or immunohistochemistry if no aspirateavailable) from bone marrow biopsy.

6. Patient and is either in CR, or CR with partial count recovery, eitherCRi/CRh^1.

1CR= BM with <5% blasts, absence of circulating blasts; absence of extramedullarydisease, absolute neutrophil count (ANC) ≥ 1000 cells/µL and platelet (PLT) count ≥ 100,000/µL. CRh = CR with ANC 500-1000 cells/µL and PLT 50,000-100,000 /µL. CRi = CRwithout meeting CRh criteria (residual neutropenia or thrombocytopenia).

7. Patient has positive measurable residual disease (MRD) at or above a level of 0.1%, by flow cytometry or in molecular cases (NPM1 mutated or one of the CBFtranslocations) RT-qPCR reported at or above 0.01%, as described above (seesection 3.6).

8. Patient is eligible for intensive chemotherapy and immediate allogeneictransplant, with intention to proceed to transplant after trial intervention.

9. Patient has an ECOG performance status of ≤3 10. Patient has adequate organfunction defined as:

10. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN

11. Serum total bilirubin < 1.5 x ULN (or direct bilirubin normal in subjects withtotal bilirubin > 1.5 ULN). Except in cases of Gilbert's disease.

12. Creatinine clearance greater than 30 mL/min based on the Cockroft-Gaultglomerular filtration rate (GFR) estimation.

13. Absence of active uncontrolled infection, heart failure or severepsychiatric or neurological disease.

14. Females of childbearing potential may participate provided they have anegative serum pregnancy test at screening and a negative serum OR urinepregnancy test within two weeks of starting on treatment.

15. Females of reproductive potential should use effective contraceptionduring the study, and for 6 months after last dose of azacitidine. Maleswith female partners of reproductive potential should use effectivecontraception during treatment and for 3 months after.

Exclusion Criteria:

1. Patients with acute promyelocytic leukemia (APL) or relapsed/refractoryAML 2. Blast crisis of chronic myeloid leukemia 3. Patient with 5% blastsor more by flow or bone marrow aspirate differential (or IHC if noaspirate available) 4. Patient without count recovery (CBC less than CRh)
2. Patient has received previous therapy with a venetoclax containingregimen. 6. Patient has presence of any other condition that may increasethe risk associated with study participation, and in the opinion of theinvestigator, would make the patient inappropriate for entry into thestudy.
3. Patient has active uncontrolled systemic fungal, bacterial, or viralinfection.
4. Patient had recent, significant venous or arterial thrombotic event thatwould necessitate full anticoagulation or dual anti-platelet therapy,including PE within 30 days prior to start of treatment or insertion ofdrug eluting stent within 6 months prior to start of treatment. Chronicindications for anticoagulation such as atrial fibrillation, can beincluded if CHADS2 score below 4.
5. Patient has mechanical heart valve. 10. Patient had recent significanthemorrhagic episode, at the discretion of investigator.
6. Patient has significant active cardiac disease within 6 months prior tostart of study treatment.
7. Patient is known to have dysphagia, short-gut syndrome, gastroparesis, orother conditions that limit the ingestion or gastrointestinal absorptionof drugs administered orally.
8. Female subject who is pregnant or lactating.