Cai Yiming, Rui Jingwen, Ding Zhengwen, Xie Judan, Jin Zhou, Xiao Jinyan, Xu Yang
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, P. R. China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, P. R. China.
Cancer Med. 2025 Jul;14(14):e71037. doi: 10.1002/cam4.71037.
ASXL1 is one of the most frequently mutated genes in acute myeloid leukemia (AML) and retains adverse-risk status in intensively treated cohorts according to 2022 European Leukemia Net (ELN) risk criteria. The therapeutic and prognostic impacts of hypomethylating agents (HMAs) and venetoclax in young adults with ASXL1-mutated AML is unclear.
Eighty-one patients with ASXL1-mutated AML ≤ 60 years old were retrospectively analyzed. The effects of HMAs plus venetoclax on treatment response and its prognostic value were compared with intensive chemotherapy (IC) and HMAs combined with low-intensity chemotherapy.
Intensive chemotherapy independently predicted a worse treatment response (IC vs. HMA + venetoclax, OR = 0.183, 95% CI 0.048-0.693, p = 0.012) and inferior overall survival (OS) (IC vs. HMA + venetoclax, HR = 3.316, 95% CI 1.332-8.255, p = 0.010). After 15 patients with favorable cytogenetics or mutations were excluded, the HMA + venetoclax combination still outweighed IC with respect to treatment response (IC vs. HMA + venetoclax, OR = 0.063, 95% CI 0.012-0.332, p = 0.001) and OS (IC vs. HMA + venetoclax, HR = 3.072, 95% CI 1.216-7.758 p = 0.018) in patients with an adverse risk according to 2022 European Leukemia Net guidelines. Allogeneic hematopoietic stem cell transplantation independently predicted superior OS (HR = 0.234, 95% CI 0.088-0.626, p = 0.004). Additionally, in patients receiving HMAs combined with venetoclax, the G646fs variant of the ASXL1 mutation was associated with a lower complete remission or with an incomplete hematological recovery rate (4/7 vs. 2/19, 42.9% vs. 10.5%, p = 0.026) and worse event-free survival (median, 14.0 months vs. not reach, p = 0.045).
HMAs and venetoclax could benefit newly diagnosed younger patients with ASXL1-mutated AML.
ASXL1是急性髓系白血病（AML）中最常发生突变的基因之一，根据2022年欧洲白血病网络（ELN）风险标准，在接受强化治疗的队列中仍处于不良风险状态。低甲基化药物（HMAs）和维奈克拉对ASXL1突变的年轻成人AML患者的治疗和预后影响尚不清楚。
回顾性分析81例年龄≤60岁的ASXL1突变AML患者。将HMAs联合维奈克拉对治疗反应的影响及其预后价值与强化化疗（IC）以及HMAs联合低强度化疗进行比较。
强化化疗独立预测较差的治疗反应（IC组与HMA + 维奈克拉组，OR = 0.183，95%CI 0.048 - 0.693，p = 0.012）和较差的总生存期（OS）（IC组与HMA + 维奈克拉组，HR = 3.316，95%CI 1.332 - 8.255，p = 0.010）。在排除15例具有良好细胞遗传学或突变的患者后，对于根据2022年欧洲白血病网络指南处于不良风险的患者，HMA + 维奈克拉联合方案在治疗反应（IC组与HMA + 维奈克拉组，OR = 0.063，95%CI 0.012 - 0.332，p = 0.001）和OS（IC组与HMA + 维奈克拉组，HR = 3.072，95%CI 1.216 - 7.758，p = 0.018）方面仍优于IC组。异基因造血干细胞移植独立预测较好的OS（HR = 0.234，95%CI 0.088 - 0.626，p = 0.004）。此外，在接受HMAs联合维奈克拉治疗的患者中，ASXL1突变的G646fs变体与较低的完全缓解率或血液学不完全恢复率相关（4/7 vs. 2/19，42.9% vs.
