Frontline Venetoclax Shows Promise in Elderly AML Patients

Venetoclax (Venclexta) in combination with a hypomethylating agent induced complete remissions in 61% of patients aged 65 years or older with previously untreated acute myeloid leukemia.

Courtney D. DiNardo, MD

Venetoclax (Venclexta) in combination with a hypomethylating agent induced complete remissions in 61% of patients aged 65 years or older with previously untreated acute myeloid leukemia (AML), according to phase Ib study data published in The Lancet Oncology.1

Overall, 63% (36 of 57) of patients achieved a response, which included complete remission (CR) or CR with incomplete marrow recovery (CRi) in 61% (95% CI, 47.6-74.0).

“Venetoclax in combination with hypomethylating agents seems to be a well-tolerated regimen with low early mortality and promising antileukemic activity in elderly, treatment-naive patients with acute myeloid leukemia,” first author Courtney D. DiNardo, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, and colleagues wrote.

The dose-escalation phase separated patients into 3 groups: groups A (n = 23) and B (n = 22) were enrolled from November 2014 to December 2015, and group C (n = 12) was enrolled from June 2015 to January 2016.

Group A was assigned to venetoclax and intravenous decitabine at 20 mg/m2 on days 1 to 5 of each 28-day cycle. Group B received venetoclax and 75 mg/m2 of subcutaneous or intravenous azacitidine 75 mg/m2 on the first 7 days of each 28-day cycle.

In group C, patients were assigned to venetoclax and decitabine with the oral CYP3A inhibitor posaconazole. Posaconazole was assigned at 300 mg twice on day 21 of cycle 1 and at 300 mg once daily on days 22 to 28 of cycle 1 to assess its effect on venetoclax pharmacokinetics.

Dose escalation followed a standard 3 + 3 design with at least 3 evaluable patients enrolled per cohort. Daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C.

Maximum-tolerated dose was not reached. The recommended phase II dose was 400 mg once per day or 800 mg with an interrupted dosing schedule. The expansion phase is ongoing but is closed to accrual.

In groups A and B (n = 45), 60% (95% CI, 44.3-74.3) of patients reached CR or CRi.

“Further evaluation of the 400 mg and 800 mg doses of venetoclax in an expansion phase of this study is ongoing and will provide additional insight into the safety and efficacy of these combinations,” DiNardo et al wrote.

As of the June 15, 2016, data cutoff, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (47%) with 9 incidents in group A, 13 in group B, and 5 in group C; febrile neutropenia (42%), with 11 in group A, 10 in group B, and 3 in group C; and neutropenia (40%) with 12 in group A, 8 in group B, and 3 in group C. Febrile neutropenia was the most common serious TEAE in groups A (30%) and B (32%), compared with lung infection in group C (33%).

Overall, 86% of patients had TEAEs. The most common events in groups A and B included nausea (52% vs 32%, respectively), fatigue (26% vs 32%, respectively), and decreased neutrophil count (26% vs 27%, respectively). The most common events in group C were nausea (58%), leucopenia (50%), vomiting (42%), and decreased platelet count (42%).

Writing in an accompanying editorial, Carsten Müller-Tidow, MD, and Richard F. Schlenk, MD, of Heidelberg University Hospital called the findings “remarkable,” especially in this hard-to-treat patient population.2 They noted that that the CR rate is double that of monotherapy with hypomethylating drugs in a similar patient population and toxicity appeared manageable.

“What do these results mean for the treatment of acute myeloid leukemia? Initially, more patients should be treated with the hypomethylating agent—venetoclax combination, and these trials are ongoing,” wrote Müller-Tidow and Schlenk. “The preliminary data provided by DiNardo and colleagues suggests that the combination of hypomethylating drugs and venetoclax is effective in acute myeloid leukemia therapy. The magnitude of the benefit should be assessed in further clinical trials, but venetoclax is emerging as a novel and important drug in treatment of this disease.”


  1. DiNardo CD, Pratz KW, Letai A, et a. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study [published online January 12, 2018]. Lancet Oncol. 2018; 19:216-228. doi: 10.1016/S1470-2045(18)30010-X.
  2. Müller-Tidow C, Schlenk RF. A new option for remission induction in acute myeloid leukaemia [published online January 12, 2018]. Lancet Oncol. 2018; 19:156-157. doi: 10.1016/S1470-2045(18)30012-3.