Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia

Haematologica. 2023 Oct 1;108(10):2616-2625. doi: 10.3324/haematol.2023.282681.


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: i) higher doses of venetoclax are tolerable and more effective, and ii) 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 (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg 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 polymerase chain recation. 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 >400 mg 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Azacitidine*
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Humans
  • Leukemia, Myeloid, Acute* / diagnosis
  • Leukemia, Myeloid, Acute* / drug therapy
  • Neoplasm, Residual / drug therapy


  • Azacitidine
  • Bridged Bicyclo Compounds, Heterocyclic
  • venetoclax

Grants and funding

Funding: This research was supported by the Leukemia and Lymphoma Society’s Scholar in Clinical Research Program, the Robert H. Allen MD Chair in Hematology Research and AbbVie.