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Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

Courtney D. DiNardo, Keith Pratz, Vinod Pullarkat, Brian A. Jonas, Martha Arellano, Pamela S. Becker, Olga Frankfurt, Marina Konopleva, Andrew H. Wei, Hagop M. Kantarjian, Tu Xu, Wan-Jen Hong, Brenda Chyla, Jalaja Potluri, Daniel A. Pollyea and Anthony Letai

Key Points

  • Venetoclax plus decitabine or azacitidine showed tolerable safety and favorable overall response rate (CR + CRi rate: 67%) in elderly patients with AML.

  • This novel combination regimen produced favorable responses in high-risk groups, such as age 75 or older, poor cytogenetics, and secondary AML.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

  • Submitted August 14, 2018.
  • Accepted October 12, 2018.
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