Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.
Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.
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DOI：
10.20517/cdr.2020.95
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kaufmann SH
中科院分区：
文献类型：
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作者：
Saliba AN;John AJ;Kaufmann SH
尽管维奈托克与低甲基化药物（HMA）地西他滨或阿扎胞苷联合治疗在老年、既往未经治疗的急性髓性白血病（AML）患者中诱导缓解取得了成功，但原发性或继发性耐药仍然是寻求延长缓解持续时间的重要障碍。在这里，我们回顾了建议和证明耐药机制维奈托克单药治疗，HMA单药治疗，和维奈托克和HMA的双重治疗AML。我们根据药物的作用机制探讨了对HMAs和维奈托克的耐药机制。我们简要描述了潜在的治疗策略，以规避耐药性这一有前途的组合，包括替代调度或添加其他代理人的HMA和维奈托克骨干。了解AML的作用机制和耐药性的演变仍然是一个优先事项，以最大限度地提高新药和联合用药的获益，确定新的治疗靶点，确定潜在的预后标志物，并避免治疗失败。
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.