This study is being done to determine if treatment with azacitidine and venetoclax is effective treatment for elderly patients with acute myeloid leukemia (AML) who have not received previous treatment. Azacitidine and venetoclax will be given as induction treatment followed by venetoclax maintenance treatment for patients who respond to the induction treatment.

This is a phase 2 study for elderly patients who have not received previous treatment for acute myeloid leukemia (AML). Up to 42 patients will be enrolled. All patients will be treated with azacitidine and venetoclax until a minimal residual disease (MRD) negative response is achieved. Once patients achieve a MRD negative composite response, azacitidine will be discontinued and venetoclax dose will be decreased to "maintenance" dose.

Inclusion Criteria:

1. Subject must have confirmation of non-APL AML by WHO criteria and be ineligible or unwilling to undergo treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidities or other factors

2. Subject must have received no prior treatment for AML; hydroxyurea is not considered a treatment and is allowed

3. Subject must be ≥ 60 years of age

4. Subject must have a projected life expectancy of at least 12 weeks

5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2

6. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula

7. Subject must have adequate liver function as demonstrated by:

   • aspartate aminotransferase (AST) ≤ 3.0 × ULN*

   • alanine aminotransferase (ALT) ≤ 3.0 × ULN*

   • bilirubin ≤ 3.0 × ULN, unless due to Gilbert's syndrome*

     • Unless considered due to leukemic organ involvement

8. Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.

9. Female subjects must be either:

   • Postmenopausal; defined as Age > 55 years with no menses for 12 or more months without an alternative medical cause; OR
   • Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

10. Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

1. Subject has received treatment with a hypomethylating agent and/or other chemotherapeutic agent either conventional or experimental for myelodysplastic syndrome (MDS) or AML

2. Subject has acute promyelocytic leukemia

3. Subject has known active CNS involvement from AML

4. Subject is known to be positive for HIV. HIV testing is not required

5. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag, anti-HBs+ and anti-HBc-) may participate

6. Subject has received anticancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents within 5 half-lives prior to first dose of study drug

7. Subject has received biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent within 30 days prior to first dose of study drug

8. Subject has received the following within 7 days prior to the first dose of the study drug:

   • Steroid therapy for anti-neoplastic intent;
   • Strong and Moderate CYP3A inhibitors (see Appendix A for examples)
   • Strong and Moderate CYP3A inducers (see Appendix A for examples)

9. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment

10. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

    • New York Heart Association heart failure > class 2
    • Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia

11. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration

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

13. Subject has a history of other malignancies prior to study entry, with the exception of:

    • Adequately treated in situ carcinoma of the breast or cervix uteri
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
    • Prostate cancer with no plans for therapy of any kind
    • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent

14. Subject has a white blood cell count > 25 × 109/L. Note: hydroxyurea is permitted to meet this criteria

15. Any subject who is a candidate for intensive induction therapy and agrees to receive this therapy

From the time the patient receives the first dose of study drug until 30 days after last study treatment, an average of 60 days.

Single-arm design without a comparator limits causal inference. Outcomes are based on a relatively small, older AML cohort at a single center and may not generalize broadly. Duration estimates are subject to censoring; missing data were not imputed.