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

Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Azacitidine / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Cohort Studies
  • Decitabine / administration & dosage
  • Female
  • Follow-Up Studies
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Maximum Tolerated Dose
  • Prognosis
  • Sulfonamides / administration & dosage
  • Survival Rate

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Sulfonamides
  • Decitabine
  • Azacitidine
  • venetoclax

Associated data

  • ClinicalTrials.gov/NCT02203773