Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations inFLT3-ITD,NRAS/KRAS,TP53, andBAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody–drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.
急性髓系白血病（AML）传统上预后较差，尤其对于不适合强化化疗的老年患者。维奈托克作为一种强效口服BH3模拟物，靶向抗凋亡蛋白BCL2，其问世显著推动了AML治疗进展。该药物与去甲基化药物阿扎胞苷的联合方案（AZA/VEN）已成为这类AML患者的标准治疗方案，总体缓解率达65%，中位总生存期为14.7个月，而阿扎胞苷单药治疗的对应数据分别为22%和8个月。然而，耐药与复发仍十分常见，构成重大临床挑战。近期研究已明确FLT3-ITD、NRAS/KRAS、TP53及BAX基因突变等分子改变是耐药的主要驱动因素。此外，代谢改变、抗凋亡蛋白表达水平以及单核细胞或红系/巨核细胞分化状态等因素也导致治疗失败。当前临床试验正在探索克服维奈托克耐药的策略，包括针对IDH和FLT3突变的双联或三联疗法、新型表观遗传学方法、menin/XPO1/MDM2抑制剂，以及单克隆抗体和抗体-药物偶联物等免疫疗法。通过单细胞分析深入理解耐药分子机制，将为未来治疗策略的开发提供关键依据。
肿瘤(癌症)患者之家