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Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond

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Abstract

Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology over the past decade. Recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies. The discovery of drugs that promote apoptosis in leukemic cells has translated to encouraging activity in clinical trials. B-cell lymphoma (BCL)-2 inhibition has been at the center of drug development efforts to target apoptosis in AML. Remarkable clinical success with venetoclax has revolutionized the ways we treat hematological malignancies. Several landmark trials have demonstrated the potent antitumor activity of venetoclax, and it is now frequently combined with traditional cytotoxic agents to treat AML. However, resistance to BCL-2 inhibition is emerging, and alternative strategies to address resistance mechanisms have become an important focus of research. A number of clinical trials are now underway to investigate a plurality of novel agents that were shown to overcome resistance to BCL-2 inhibition in preclinical models. Some of the most promising data come from studies on drugs that downregulate myeloid cell leukemia (MCL)-1, such as cyclin-dependent kinases (CDK) inhibitors. Furthermore, innovative approaches to target apoptosis via extrinsic pathways and p53 regulation have added new cytotoxic agents to the arsenal, including drugs that inhibit inhibitor of apoptosis protein (IAP) family proteins and murine double minute 2 (MDM2). This review provides a perspective on past and current treatment strategies harnessing various mechanisms of apoptosis to target AML and highlights some important promising treatment combinations in development.

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  1. Division of Hematology and Medical Oncology, New York University School of Medicine and Perlmutter Comprehensive Cancer Center, New York University Langone Health, New York, NY, USA

    Jun H. Choi & Raoul Tibes

  2. Mayo Clinic, Scottsdale, AZ, USA

    James M. Bogenberger

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Jun H. Choi has no conflicts of interest that might be relevant to the contents of this manuscript. Raoul Tibes and James M Bogenberger received writing support from Ashfield Healthcare Communications for an unrelated review article and have no conflicts of interest that are directly relevant to the content of this article. Raoul Tibes has received honorarium and travel support from Abbvie. James M Bogenberger has research funding pending from Tolero Pharmaceuticals for the preclinical investigation of alvocidib/TP-1287 in solid tumor models. Raoul Tibes and James M Bogenberger have published work on alvocidib in AML that is being used by pharmaceutical companies designing clinical trials; neither have received any personal or research compensation for this work.

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Choi, J.H., Bogenberger, J.M. & Tibes, R. Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond. Targ Oncol 15, 147–162 (2020). https://doi.org/10.1007/s11523-020-00711-3

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