Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia

Abstract

Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacologic mimic of the proteins that initiate apoptosis (a so-called BH3 mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells, which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a phase I study, including complete remissions in 20% of patients. Its use was approved by the FDA in April 2016 for patients with previously treated del(17p) CLL on the basis of a single-arm phase II trial demonstrating a 79% response rate and an estimated 1-year progression-free survival of 72% with 400 mg/day continuous therapy. This review focuses on venetoclax, its mechanism of action, pharmacology, and clinical trial data and seeks to place it in the context of rapid advances in therapy for patients with relapsed CLL, especially those with del(17p) CLL.

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression

“…4B). Importantly, the concentration used in these assays is clinically relevant based on steady state pharmacokinetics observed with venetoclax (25-27). Immunoprecipitation of BIM in NCI-H510A and DMS-53 whole cell lysates treated with 1 μM venetoclax revealed on-target activity of venetoclax as judged by the disassociation of BIM:BCL-2 complexes (Fig.…”

“…This translates to more potent BCL-2 inhibition, and venetoclax has proven effective against BCL-2-dependent CLL without inducing marked thrombocytopenia (27, 31). …”

“…Other studes using ABT-737 across a longer-scale treatment have found that tumors develop resistance (35, 37). Given the better tolerance for venetoclax due to a lack of thrombocytopenia development (27, 30, 31), it is also possible that this agent would be more efficacious in the treatment of SCLC. However, it remains unclear whether extended treatment times would lead to similar development of resistance using venetoclax.…”

The impact of non-genetic heterogeneity on cancer cell death

“…The role of BH3 family proteins in modulating apoptosis has prompted the development of BH3 mimetic therapeutics, compounds which mimic the effect of pro-apoptotic proteins at the mitochondrial outer membrane (Roberts et al 2017). Susceptibility to one such BH3 mimetic, WEHI-539, is heterogeneous among isogenic HCT116 colorectal cancer cells and correlated with expression of anti-apoptotic BCL2L1 at the single cell level (Pécot et al 2016).…”

Updates from the 2017 American Society of Hematology Annual Meeting: Practice-Changing Studies in Untreated Chronic Lymphocytic Leukemia

“…Idelalisib is also associated with important toxicities, including an increased risk of serious infections and immune complications, such that it is no longer recommended by Health Canada in the first-line setting 3,9 . Finally, the novel Bcl-2 protein inhibitor venetoclax has demonstrated promising response rates of approximately 79% in patients with relapsed or refractory disease, with no difference in outcome observed for those with del(17p) 10,11 . However, further data are needed to determine the efficacy of venetoclax in previously untreated cll.…”