Venetoclax-based therapies for acute myeloid leukemia

Abstract

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.

Keywords: Acute myeloid leukemia; Hypomethylating agents; Low-intensity chemotherapy; Venetoclax.

Conflict of interest statement

Disclosure of Conflicts of Interest:

The authors have no relevant conflicts of interest to disclose.

Copyright © 2019. Published by Elsevier Ltd.

Figures

Figure 1.

Mitochondrial pathways of apoptosis and venetoclax mechanism of action. In response to cellular stress, the pro-apoptotic proteins BAX and BAK are translocated to the mitochondria and induce the permeabilization of the outer mitochondrial membrane with release of cytochrome c (Cyt C) into the cytoplasm. The Cyt C/Apaf-1 complex activates caspase 9 and the caspase cascade, inducing apoptosis. The mitochondrial pathway is regulated by pro-apoptotic BH3-only proteins, which activate BAX and inhibit BCL-2 and MCL-1. BCL-2, MCL-1 and BCL-X regulate cell survival by inactivation of the pro-apoptotic proteins. Venetoclax triggers apoptosis by selective inhibition of BCL-2, leading to the release of Cyt C and cell death.