Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: 1)Higher doses of venetoclax are tolerable and more effective, and 2)Azacitidine can be discontinued after deep remissions. Forty-two newly-diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine + Venetoclax (HiDDAV) Study. Patients received 1-3 “induction” cycles of venetoclax 600mg daily with azacitidine. Responders received MRD-positive or negative “maintenance” arms: azacitidine with 400mg venetoclax or 400mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD-negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital PCR. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD-negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.
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