Overview

The purpose of this study is to find out if azacitidine and venetoclax are an effective treatment approach to get rid of or lower measurable residual disease (MRD) in people with acute myeloid leukemia (AML) who have received standard chemotherapy and are planning to have an allogeneic hematopoietic stem cell transplant (HSCT). Allogeneic HSCT, sometimes called a bone marrow transplant, involves receiving healthy blood-forming cells (stem cells) from a donor in order to replace the patient's immune system and lower the chances of the disease returning (relapse).

Eligibility

Inclusion Criteria:

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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 other protocol requirements.
3. Patient has a confirmed diagnosis of de-novo AML (non-APL) as per World Health Organization (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 blasts seen by aspirate differential (or immunohistochemistry if no aspirate available) from bone marrow biopsy.
6. Patient and is either in CR, or CR with partial count recovery, either CRi/CRh\^1.

     1CR= BM with <5% blasts, absence of circulating blasts; absence of extramedullary
     disease, 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 = CR
     without 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 (MFC) or in molecular cases (NPM1 mutated or one of the
          CBF translocations) RT-qPCR at or above 0.01%, as described above (see section
          3.6). If RT-qPCR is not available, MFC will be allowed for determining
          eligibility for molecular patients (at or above 0.1%).
       8. Patient is eligible for intensive chemotherapy and immediate allogeneic
          transplant, with intention to proceed to transplant after trial intervention.
       9. Patient has an ECOG performance status of ≤3 10. Patient has adequate organ
          function defined as:
       1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
          x ULN
       2. Serum total bilirubin < 1.5 x ULN (or direct bilirubin normal in subjects with
          total bilirubin > 1.5 ULN). Except in cases of Gilbert's disease.
       3. Creatinine clearance greater than 30 mL/min based on the Cockroft-Gault
          glomerular filtration rate (GFR) estimation.
           11. Absence of active uncontrolled infection, heart failure or severe
               psychiatric or neurological disease.
           12. Females of childbearing potential may participate provided they have a
               negative serum pregnancy test at screening and a negative serum OR urine
               pregnancy test within two weeks of starting on treatment.
           13. Females of reproductive potential should use effective contraception
               during the study, and for 6 months after last dose of azacitidine. Males
               with female partners of reproductive potential should use effective
               contraception during treatment and for 3 months after.
          Exclusion Criteria:
            1. Patients with acute promyelocytic leukemia (APL) or relapsed/refractory
               AML 2. Blast crisis of chronic myeloid leukemia 3. Patient with 5% blasts
               or more by flow or bone marrow aspirate differential (or IHC if no
               aspirate available) 4. Patient has received previous therapy with a
               venetoclax containing regimen. 5. Patient has presence of any other
               condition that may increase the risk associated with study participation,
               and in the opinion of the investigator, would make the patient
               inappropriate for entry into the study.
            6. Patient has active uncontrolled systemic fungal, bacterial, or viral
               infection.
            7. Patient had recent, significant venous or arterial thrombotic event that
               would necessitate full anticoagulation or dual anti-platelet therapy,
               including PE within 30 days prior to start of treatment or insertion of
               drug eluting stent within 6 months prior to start of treatment. Chronic
               indications for anticoagulation such as atrial fibrillation, can be
               included if CHADS2 score below 4.
            8. Patient has mechanical heart valve. 9. Patient had recent significant
               hemorrhagic episode, at the discretion of investigator.
           10. Patient has significant active cardiac disease within 6 months prior to
               start of study treatment.
           11. Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or
               other conditions that limit the ingestion or gastrointestinal absorption
               of drugs administered orally.
           12. Female subject who is pregnant or lactating.