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Saliba et al. Cancer Drug Resist 2021;4:125-42 Cancer
DOI: 10.20517/cdr.2020.95 Drug Resistance

Review Open Access

Resistance to venetoclax and hypomethylating
agents in acute myeloid leukemia

Antoine N. Saliba , August J. John , Scott H. Kaufmann 1,2,3
2
1
1 Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
2 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
3 Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Correspondence to: Dr. Antoine N. Saliba and Scott H. Kaufmann, Division of Oncology Research, Gonda 19-212, Mayo Clinic,
200 First St., S.W., Rochster, MN 55905, USA. E-mails: Saliba.Antoine@mayo.edu; Kaufmann.Scott@mayo.edu
How to cite this article: Saliba AN, John AJ, Kaufmann SH. Resistance to venetoclax and hypomethylating agents in acute
myeloid leukemia. Cancer Drug Resist 2021;4:125-42. http://dx.doi.org/10.20517/cdr.2020.95
Received: 18 Oct 2020 First Decision: 6 Nov 2020 Revised: 12 Nov 2020 Accepted: 16 Nov 2020 Available online: 19 Mar 2021

Academic Editor: Robert C. A. M. van Waardenburg Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Despite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or
azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML),
resistance - primary or secondary - still constitutes a significant roadblock in the quest to prolong the duration of
response. Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy, HMA
monotherapy, and the doublet of venetoclax and HMA for the treatment of AML. We approach the mechanisms of
resistance to HMAs and venetoclax in the light of the agents’ mechanisms of action. We briefly describe potential
therapeutic strategies to circumvent resistance to this promising combination, including alternative scheduling or
the addition of other agents to the HMA and venetoclax backbone. Understanding the mechanisms of action and
evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations,
identify new therapeutic targets, define potential prognostic markers, and avoid treatment failure.

Keywords: Venetoclax, hypomethylating agents, resistance, acute myeloid leukemia, azacitidine, decitabine

INTRODUCTION
Acute myeloid leukemia (AML) is a heterogeneous disease with diverse molecular profiles, clinical
outcomes, and disease-specific mortality. In 2020, there will be an estimated 20,000 new cases of AML and
[1]
11,200 deaths due to the disease in the U.S. . For decades, the cornerstone of treatment for primary AML

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
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and indicate if changes were made.

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