Relapse and resistance in acute myeloid leukemia post venetoclax: improving second lines therapy and combinations.

IF 2.3 4区医学 Q2 HEMATOLOGY

Expert Review of Hematology Pub Date : 2024-10-01 Epub Date: 2024-09-13 DOI:10.1080/17474086.2024.2402283

Rabia Shahswar, Arnold Ganser

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引用次数: 0

Abstract

Introduction: The combined use of the BCL-2 inhibitor venetoclax with azacitidine now is the standard of care for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy with outcomes exceeding those achieved with hypomethylating agents alone. Venetoclax in combination with intensive chemotherapy is also increasingly used both as frontline as well as salvage therapy. However, resistance to and relapse after venetoclax-based therapies are of major concern and outcomes after treatment failure remain poor.

Areas covered: A comprehensive search was performed using PubMed database (up to April 2024). Studies evaluating venetoclax-based combination treatments in AML and studies assessing markers of response and resistance to venetoclax were investigated. We summarize the status of venetoclax-based therapies in the frontline and relapsed/refractory setting with focus on the main mechanisms of resistance to BCL-2 inhibition. Further, strategies to overcome resistance including combinatorial regimens of hypomethylating agent (HMA) + venetoclax + inhibitors targeting actionable mutations like IDH1/2 or FLT3-ITD and the introduction of novel agents like menin-inhibitors are addressed.

Expert opinion: Although venetoclax is reshaping the treatment of unfit and fit AML patients, prognosis of patients after HMA/VEN failure remains dismal, and strategies to abrogate primary and secondary resistance are an unmet clinical need.

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venetoclax治疗后急性髓性白血病的复发和耐药性：改进二线疗法和联合疗法。

简介对于不适合接受强化化疗的急性髓性白血病（AML）患者，BCL-2抑制剂Venetoclax与阿扎胞苷的联合使用现已成为标准治疗方法，其疗效超过了单独使用低甲基化药物的疗效。Venetoclax 联合强化化疗也越来越多地被用作前线治疗和挽救治疗。然而，以 Venetoclax 为基础的疗法的耐药性和复发是令人关注的主要问题，治疗失败后的疗效仍然不佳：使用 PubMed 数据库进行了全面检索（截至 2024 年 4 月）。我们调查了评估以venetoclax为基础的急性髓细胞白血病联合疗法的研究，以及评估对venetoclax的反应和耐药性标志物的研究。我们总结了一线治疗和复发/难治性治疗中基于 Venetoclax 的疗法的现状，重点关注 BCL-2 抑制的主要耐药机制。此外，还探讨了克服耐药性的策略，包括低甲基化药物（HMA）+ venetoclax+针对可作用突变（如IDH1/2或FLT3-ITD）的抑制剂的组合方案，以及新型药物（如menin抑制剂）的引入：尽管venetoclax正在重塑不适合和适合急性髓细胞性白血病患者的治疗，但HMA/VEN失败后患者的预后仍然不容乐观，消除原发性和继发性耐药的策略是一项尚未满足的临床需求。

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.