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Review
. 2022 Jun 3;15(1):75.
doi: 10.1186/s13045-022-01295-3.

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination

Thomas E Lew  1   2 , John F Seymour  3   4
Affiliations
Review

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination

Thomas E Lew et al. J Hematol Oncol. .

Abstract

BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.

Keywords: Apoptosis; BCL2; Chronic lymphocytic leukemia; Lymphoma; Multiple myeloma; Navitoclax; Non-Hodgkin lymphoma; Programmed cell death; Venetoclax.

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Conflict of interest statement

T.E.L. is an employee of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax, is a recipient of a share in royalty payments paid to the Walter and Eliza Hall Institute of Medical Research and has received honoraria from AbbVie. J.F.S. has received research funding from AbbVie, Genentech, Celgene and Janssen and is an advisory board member for and has received honoraria from AbbVie, Acerta, Celgene, Genentech, Janssen, Roche, Sunesis and Takeda.

Figures

Fig. 1
Fig. 1
Mechanisms of venetoclax resistance in lymphoid malignancies
See this image and copyright information in PMC

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