Venetoclax for AML: changing the treatment paradigm

Abstract

Venetoclax is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignancies, the survival of which depends on dysregulation of this pathway. Preclinical data, using various model systems including cell lines and patient samples, suggested targeting BCL-2 could be a successful therapeutic strategy in patients with acute myeloid leukemia (AML). As predicted by this work, the use of venetoclax in the clinical setting has resulted in promising outcomes for patients with this disease. Although venetoclax showed limited activity as a single agent in the relapsed disease setting, recent studies have shown that when combined with a backbone therapy of a hypomethylating agent or low-dose cytarabine, high response rates with encouraging remission durations for older patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy were observed. Furthermore, venetoclax-based therapies allowed for rapid responses and were able to effectively target the leukemia stem cell population. Here we review the preclinical data that supported the development of venetoclax in AML, as well as the results of the promising clinical trials.

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. M.Y.K. received research funding/clinical trial support from AbbVie, Genentech, F. Hoffman-La Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and AstraZeneca; served on advisory boards for AbbVie, Genentech, F. Hoffman-La Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji; and holds stock options and received royalties from Reata Pharmaceutical. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Figure 1.

Intrinsic apoptosis pathway and BH3 profiling. (A) Proapoptotic mitochondrial proteins with BH3-domain only include NOXA (sensitizer), BIM, and PUMA (activators); proapoptotic mitochondrial proteins with multiple domains include BAX and BAK (effectors). Sensitizers and activators suppress (and are suppressed by) antiapoptotic proteins, including BCL-2, BCL-XL, BCL-W, BCL2-A1, and MCL-1. Antiapoptotic proteins also suppress effectors. (B) BH3 profiling exploits the selective binding of BH3 peptides to specific antiapoptotic proteins (adapted from Certo et al).

Figure 2.

OS of elderly patients treated with venetoclax combined with decitabine or azacitidine. Kaplan-Meier curve showing OS survival of patients in the dose escalation as well as dose expansion phases of the trial. OS is divided into the 3 different doses of venetoclax used in this trial. This figure was adapted from DiNardo et al.