Wang Tao, Zhao Lei, Ma Hongbing
Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
Ann Hematol. 2025 May 28. doi: 10.1007/s00277-025-06431-w.
Nucleophosmin 1 (NPM1) mutation is commonly associated with a favorable prognosis in acute myeloid leukemia (AML). Conversely, secondary mutations such as those in ASXL1, RUNX1, EZH2, and SRSF2 are generally linked to poor outcomes. The combined prognostic impact of NPM1 and secondary mutations in AML patients remains unclear. This meta-analysis aimed to evaluate the prognostic significance of secondary mutations in AML patients harboring NPM1 mutation. A systematic literature search was conducted following PRISMA guidelines, identifying studies published up to June 2024 from databases such as PubMed, Web of Science, and the Cochrane Library. The inclusion criteria included adult AML patients with confirmed NPM1 mutation, detailed reporting of secondary mutations, and comparative prognostic outcomes. Fourteen high-quality studies from twelve publications were included, encompassing 4,022 patients who all carried NPM1 mutations; among these, 618 also harbored secondary mutations. Data extraction and quality assessment were performed independently by two researchers via the Newcastle-Ottawa Scale (NOS). Statistical analyses involved fixed-effects models due to low heterogeneity (I²=0% for OS and I²=35% for EFS/RFS). Publication bias and sensitivity analyses confirmed the robustness of the findings. Secondary mutations were not significantly associated with OS (HR = 1.16, 95% CI: 0.99-1.35, p = 0.07) or EFS/RFS (HR = 1.15, 95% CI: 0.96-1.38, p = 0.14) in the overall NPM1-mutated AML population. However, within the European LeukemiaNet (ELN) favorable prognosis group, the presence of secondary mutations was significantly associated with reduced OS (HR = 1.95, 95% CI: 1.39-2.73, p < 0.01). Subgroup analyses based on median age, geographical region, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) rates did not reveal significant modifiers of the prognostic impact of secondary mutations. Secondary mutations do not significantly adversely affect OS or EFS/RFS in the general population of AML patients with NPM1 mutation. Notably, within the ELN favorable prognosis group, secondary mutations are associated with markedly poorer OS, highlighting the need for careful prognostic assessment and potential treatment strategy adjustments in this subset of patients.
核磷蛋白1（NPM1）突变通常与急性髓系白血病（AML）的良好预后相关。相反，ASXL1、RUNX1、EZH2和SRSF2等二次突变通常与不良预后相关。NPM1和二次突变对AML患者的联合预后影响仍不清楚。这项荟萃分析旨在评估携带NPM1突变的AML患者中二次突变的预后意义。按照PRISMA指南进行了系统的文献检索，从PubMed、Web of Science和Cochrane图书馆等数据库中识别截至2024年6月发表的研究。纳入标准包括确诊为NPM1突变的成年AML患者、二次突变的详细报告以及比较性预后结果。纳入了来自12篇出版物的14项高质量研究，涵盖4022例均携带NPM1突变的患者；其中618例还存在二次突变。两名研究人员通过纽卡斯尔-渥太华量表（NOS）独立进行数据提取和质量评估。由于异质性较低（总生存期I² = 0%，无事件生存期/无复发生存期I² = 35%），统计分析采用固定效应模型。发表偏倚和敏感性分析证实了研究结果的稳健性。在总体携带NPM1突变的AML人群中，二次突变与总生存期（HR = 1.16，95%CI：0.99 - 1.35，p = 0.07）或无事件生存期/无复发生存期（HR = 1.15，95%CI：0.96 - 1.38，p = 0.14）无显著关联。然而，在欧洲白血病网络（ELN）的良好预后组中，二次突变的存在与总生存期缩短显著相关（HR = 1.95，95%CI：1.39 - 2.73，p < 0.01）。基于中位年龄、地理区域和异基因造血干细胞移植（allo - HSCT）率的亚组分析未发现二次突变预后影响的显著修饰因素。二次突变在携带NPM1突变的AML患者总体人群中对总生存期或无事件生存期/无复发生存期无显著不利影响。值得注意的是，在ELN良好预后组中，二次突变与明显更差的总生存期相关，突出了对这部分患者进行仔细预后评估和潜在治疗策略调整的必要性。
