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Evaluating venetoclax and its potential in treatment-naïve acute myeloid leukemia

Authors Knight T, Edwards H, Taub JW, Ge Y

Received 10 January 2019

Accepted for publication 15 March 2019

Published 23 April 2019 Volume 2019:11 Pages 3197—3213

DOI https://doi.org/10.2147/CMAR.S180724

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 4

Editor who approved publication: Dr Beicheng Sun


Tristan Knight,1,2 Holly Edwards,3,4 Jeffrey W Taub,1–2,4 Yubin Ge2–4

1Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA; 2Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; 3Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; 4Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

Abstract: Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML) in adult patients aged 75 years or older, or otherwise unable to tolerate intensive induction chemotherapy, in combination with either hypomethylating agents or low-dose cytarabine. In this review article, we discuss venetoclax’s mechanism of action, in relation to both the BCL-2 protein family in general and BH3-mimetic activity in particular. We then outline the pharmacological advances that preceded and facilitated its development, as well as providing an overview of key preclinical and clinical studies which lead to its use first in chronic lymphoid leukemia (CLL), then in small lymphocytic leukemia (SLL), and subsequently in AML. Finally, we seek to offer an overview of the challenges and opportunities encountered as venetoclax moves into more widespread use, including its use and activity against leukemia initiating cells and oxidative phosphorylation.

Keywords: ABT-199, acute myeloid leukemia, apoptosis, BCL-2 inhibitor, BH3-mimetic, venetoclax

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