MINI REVIEW article
Front. Oncol.
Sec. Hematologic Malignancies
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1577908
This article is part of the Research TopicBCL-2 Family Inhibitors in Hematologic MalignanciesView all 10 articles
Factors affecting response and resistance to venetoclax in acute myeloid leukemia
Provisionally accepted
- Thalassemia and Sickle Cell Disease Unit, Department of Hematology, General Hospital of Larissa, Larissa, Greece
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The use of the BCL2 inhibitor venetoclax in combination with hypomethylating agents (HMA) is a revolution for the treatment of frail and elderly acute myeloid leukemia (AML) patients. This effective treatment strategy is increasingly more and more applicable for other subsets of AML patients and is currently being tested in numerous clinical trials in combination with other drugs in all treatment lines. In particular, venetoclax combinations can also serve as a definitive therapy or as an effective bridge to allogeneic hematopoietic stem cell transplantation (HSCT). However, the factors affecting response to venetoclax in the abovementioned AML patients are not completely clear and understood until today. The aim of this review is to describe the molecular and clinical patterns of response and durable remission of venetoclax-based combinations in AML patients. Hence, mutations in IDH1, IDH2, ASXL1, NPM1, DDX41, chromatin-cohesin complex and splicing-factor genes predict superior response to venetoclax, while inferior response to the drug has been observed for FLT3-ITD, KRAS, NRAS and TP53 gene mutations. Intriguingly, the achievement of measurable residual disease (MRD) negativity in the first four cycles of venetoclax administration characterizes a subgroup of NPM1-mutated AML patients with a more favorable outcome. Even though focus will be given on factors influencing response to the drug in this review, the main mechanisms of resistance to venetoclax in AML patients will also be discussed.
Keywords: Mini-Review Acute myeloid leukemia (AML), response, Resistance, Venetoclax (VEN), BCL2 (B-cell lymphoma 2) inhibition, Azacitidine (AZA), Hypomethylating agents (HMAs), MCL1 (Myeloid cell leukemia sequence 1) overexpression
Received: 16 Feb 2025; Accepted: 29 Aug 2025.
Copyright: © 2025 Diamantidis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Michael D. Diamantidis, Thalassemia and Sickle Cell Disease Unit, Department of Hematology, General Hospital of Larissa, Larissa, Greece
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