Glaviano Antonino, Weisberg Ellen, Lam Hiu Y, Tan Donavan J J, Innes Andrew J, Ge Yubin, Lai Catherine E, Stock Wendy, Glytsou Christina, Smit Linda, Yoshida Tatsushi, Zhang Tian Y, Kennedy Vanessa E, Smith B Douglas, Mercher Thomas, de Botton Stéphane, Diana Patrizia, Konopleva Marina, Mauro Michael J, Griffin James D, DiNardo Courtney D, Kumar Alan P
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Rev Clin Oncol. 2025 Sep 1. doi: 10.1038/s41571-025-01068-0.
Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML.
急性髓系白血病（AML）仍然是一种具有挑战性的血液系统恶性肿瘤，大多数患者会对标准治疗（SOC）产生耐药性。这种耐药性通常归因于抗凋亡BCL-2家族蛋白的过度表达，这些蛋白通过抑制促凋亡效应蛋白（如BAX和BAK）来调节内源性凋亡途径。AML细胞利用这种失衡来逃避凋亡并维持生存，因此需要开发新的治疗策略。BH3模拟物是靶向促生存BCL-2家族蛋白的小分子抑制剂，已成为无法接受高强度诱导化疗的AML患者的有前景的药物。与BCL-2特异性抑制剂维奈托克和各种SOC疗法联合治疗已被证明是有效的，目前有几种联合疗法已被美国食品药品监督管理局批准用于年龄≥75岁和/或不符合强化诱导化疗条件的成年AML患者，与之前的SOC相比，其缓解率和生存结果有所改善。在本综述中，我们强调了BH3模拟物在AML治疗中的变革潜力，包括正在进行的研究新型联合方案以及进一步优化治疗策略的努力，最终目标是改善AML患者的预后。
