Venetoclax是一种高度选择性的B细胞淋巴瘤-2（BCL-2）抑制剂，与DNA低甲基化剂或低剂量的阿糖胞苷结合使用，可在急性髓系白血病（AML）患者中产生高初步反应率。然而，在大多数患者中，疾病仍会复发。对Venetoclax疗法的耐药机制包括TP53基因突变或p53蛋白失活，活化激酶突变如FLT3和RAS，以及其他BCL-2家族凋亡蛋白的上调。目前的临床试验正在探索各种策略，如双联或三联方案，包括p53激活剂，抗CD47抗体或其他新型药物，以靶向Venetoclax耐药所涉及的基因和蛋白质。进一步的研究应重点关注确定对Venetoclax疗法反应的预测性生物标志物并纳入免疫治疗方法，如检查点抑制剂，双特异性抗体，抗体-药物偶联物和CAR T细胞疗法，以改善AML患者的预后。版权所有©2022 Elsevier Ltd.保留所有权利。

Venetoclax is a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, which, combined with a DNA hypomethylating agent or low dose cytarabine, results in high rates of initial responses in patients with acute myeloid leukemia (AML). However, the disease relapses in most patients. Mechanisms of resistance to venetoclax-based therapy include TP53 gene mutations or inactivation of p53 protein, activating kinase mutations such as FLT3 and RAS, and upregulation of other BCL-2 family apoptotic proteins. Current clinical trials are exploring strategies such as doublet or triplet regimens incorporating a p53 activator, an anti-CD47 antibody, or other novel agents that target genes and proteins responsible for resistance to venetoclax. Further studies should focus on identifying predictive biomarkers of response to venetoclax-based therapy and incorporating immunotherapeutic approaches such as checkpoint inhibitors, bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy to improve outcomes for patients with AML.Copyright © 2022 Elsevier Ltd. All rights reserved.