Venetoclax: a primer

Venetoclax is a BH3-mimetic small molecule drug that directly and selectively inhibits BCL-2. BCL-2 is highly expressed in many hematologic malignancies and is the predominant prosurvival protein in diseases such as chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. In preclinical animal models and in vitro assays of primary cells from patients, venetoclax induces apoptosis rapidly in the majority of CLL cells and BCL-2–overexpressing lymphoma cell lines, and in subsets of cell lines and primary samples of myeloma and acute myeloid leukemia (AML). Venetoclax kills cells independently of TP53. Venetoclax is an oral medication, taken daily with food. As a single agent, it is most effective in patients with relapsed CLL and mantle cell lymphoma, where response rates are ∼80% and complete remission rates of 20% are observed. Responses are typically achieved rapidly, but the depth of response often continues to deepen with ongoing therapy for >1 year. The drug is generally well tolerated, but mild gastrointestinal side effects are common, as is neutropenia in CLL patients. Venetoclax 400 mg per day is approved for previously treated patients with deletion 17p CLL in the United States, Canada, and Europe. Single-agent response rates are more modest in follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma (predominantly t[11;14]-bearing disease), and AML. Preliminary clinical data combining venetoclax with monoclonal antibodies, tyrosine kinase inhibitors, hypomethylating agents, and DNA-damaging chemotherapy suggest incremental efficacy across a spectrum of blood cancers. Randomized trials of combination therapy are underway in all these diseases.

Correspondence: Andrew W. Roberts, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia; e-mail: roberts@wehi.edu.au.