Prashant Sharma1, Daniel A Pollyea2. 1. Division of Hematology, University of Colorado School of Medicine, 1665 Aurora Court, Mail Stop F754, Aurora, CO, 80045, USA. 2. Division of Hematology, University of Colorado School of Medicine, 1665 Aurora Court, Mail Stop F754, Aurora, CO, 80045, USA. daniel.pollyea@ucdenver.edu.
Abstract
PURPOSE OF REVIEW: Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax. RECENT FINDINGS: Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting. BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.
PURPOSE OF REVIEW: Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax. RECENT FINDINGS:Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting. BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.
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