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Review
. 2017 Feb;12(1):11-19.
doi: 10.1007/s11899-017-0359-0.

The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Benjamin L Lampson  1 , Matthew S Davids  2
Affiliations
Review

The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Benjamin L Lampson et al. Curr Hematol Malig Rep. 2017 Feb.

Abstract

The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.

Keywords: BCL-2 inhibitors; Chronic lymphocytic leukemia; Clinical trials; Venetoclax.

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Figures

Figure 1
Figure 1. Mechanism of action of venetoclax
At baseline, BCL-2 and BIM exist in equilibrium on the outer mitochondrial membrane. Venetoclax selectively antagonizes the interaction between the anti-apoptotic protein BCL-2 and the pro-apoptotic protein BIM, leading to BIM displacement from BCL-2 and recruitment of BAX/BAK in active conformation to the mitochondrial membrane. BAX/BAK homo-oligmerization lead to mitochondrial outer membrane permeabilization, cytochrome c release, and induction of caspase-mediated apoptosis.
See this image and copyright information in PMC

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