Venetoclax (Venclexta™) is a selective, small-molecule inhibitor of the pro-survival B-cell lymphoma 2 (BCL-2) proteins. Thereby, venetoclax triggers mitochondrial outer membrane permeabilisation and activates caspases. These mechanisms restore the apoptotic ability of malignant cells.

Currently, venetoclax is not yet approved in Europe, but it received orphan designation in February 2016 for the treatment of acute myeloid leukaemia patients, who are older than 65 years and who cannot receive standard treatment. In April 2016, the Food and Drug Administration (FDA) licensed venetoclax for the treatment of chronic lymphocytic leukaemia (CLL) patients with del(17p), as determined by a FDA-approved test (Vysis CLL FISH probe kit) and who have received at least one prior therapy. This approval was based on the interim analysis of a single-arm, phase II study (M13-982). In this trial, 107 CLL patients were enrolled to receive a 400 mg daily dose of venetoclax with a priori weekly dose ramp-up schedule over 4–5 weeks. The primary outcome of the study was the proportion of patients achieving an overall response (OR), assessed by an independent review committee. 85 (79.4%, CI 70.5–86.6) patients of the per-protocol population achieved an OR; of whom 8 (8%) patients showed a complete remission (CR) or a CR with incomplete blood recovery of blood counts. Median overall survival (OS), median progression-free survival (PFS) as well as the median duration of overall response (DOR) had not been reached at the time of interim analysis. In regard to safety outcomes, 65% of the per-protocol population experienced treatment-related grade 3–4 AEs (most frequent: neutropenia, infection, anaemia, and thrombocytopenia), another 11% of patients had grade 5 AEs and 17% of patients had died in the study.

Venetoclax might be a treatment option for relapsed or refractory CLL patients with del(17p) as it has not been agreed upon any standard care for this indication. Nevertheless, a randomised controlled trial (RCT) will be necessary to compare safety and efficacy outcomes in order to enable the interpretation of the actual treatment effect. In addition, mature data is needed to evaluate the efficacy and safety of venetoclax, also in regard with long-term effects and potential resistant mechanisms.