BCL-2 inhibition in acute myeloid leukemia: resistance and combinations.

IF 2.3 4区医学 Q2 HEMATOLOGY

Expert Review of Hematology Pub Date : 2024-11-18 DOI:10.1080/17474086.2024.2429604

Qi Zhang Tatarata, Zhe Wang, Marina Konopleva

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引用次数: 0

Abstract

Introduction: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response.

Areas covered: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge.

Expert opinion: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.

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急性髓性白血病中的 BCL-2 抑制剂：抗药性与联合用药。

简介venetoclax的问世彻底改变了急性髓性白血病的治疗格局，提供了新的治疗机会。然而，不同患者对venetoclax的临床反应差异很大，许多患者的反应持续时间有限：已确定的耐药机制包括VEN的内在耐药和获得性耐药。前者与细胞系和分化状态有关。后者包括对由遗传、表观遗传或翻译后机制、线粒体和代谢参与以及微环境介导的替代性 BCL-2 家族抗凋亡蛋白的依赖性。了解这些机制对于优化基于 Venetoclax 的疗法和提高急性髓性白血病患者的治疗效果至关重要。本综述旨在阐明venetoclax耐药的主要机制，并探讨克服这一挑战的现有治疗策略：对于venetoclax耐药的患者，替代选择包括根据细胞遗传学和既往治疗情况为个体病例量身定制的靶向联合疗法。其中许多疗法需要进一步的临床研究来验证其安全性和有效性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Expert Review of Hematology HEMATOLOGY-

CiteScore

4.70

自引率

3.60%

发文量

审稿时长

6-12 weeks

期刊介绍： Advanced molecular research techniques have transformed hematology in recent years. With improved understanding of hematologic diseases, we now have the opportunity to research and evaluate new biological therapies, new drugs and drug combinations, new treatment schedules and novel approaches including stem cell transplantation. We can also expect proteomics, molecular genetics and biomarker research to facilitate new diagnostic approaches and the identification of appropriate therapies. Further advances in our knowledge regarding the formation and function of blood cells and blood-forming tissues should ensue, and it will be a major challenge for hematologists to adopt these new paradigms and develop integrated strategies to define the best possible patient care. Expert Review of Hematology (1747-4086) puts these advances in context and explores how they will translate directly into clinical practice.