Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia

Abstract

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a "real-world" scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy.

Conflict of interest statement

Conflict-of-interest disclosure: D.A.P. receives research funding from AbbVie and serves on advisory boards for AbbVie, Pfizer, Gilead, Astellas, Agios, and Daiichi Sankyo. L.L. has served on advisory boards for Agios, Celgene, Incyte Corporation, Novartis, Takeda Oncology, and Pfizer. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Outcomes for clinical trial vs off-label patients. (A) Median response duration for off-trial venetoclax patients (blue) compared with clinical trial patients (red). (B) Median OS for off-trial venetoclax patients (blue) compared with clinical trial patients (red).

Figure 2.

Best MRD outcome in 14 responding patients treated off-trial with venetoclax plus azacitidine using the ddPCR technique. Between 1 and 3 mutations identified on diagnostic NGS were monitored throughout therapy for patients who achieved a morphologic remission with venetoclax plus azacitidine, had baseline mutations or mutations that could be followed with ddPCR, and had available follow-up bone marrow samples (N = 14). The maximal decrease in VAF (normalized percentage of decrease in VAF from baseline) is shown on the y-axis; individual mutations for each patient are shown on the x-axis. Four patients (green bars) had MRD negativity and remain in remission. Five patients (red bars) were MRD+ and relapsed. Six patients (blue bars) were MRD+ but have not relapsed at the time of data censoring. *Individual mutations that were undetectable at best response (<0.01% VAF).