Impact of secondary-type mutations on the prognosis of AML patients with NPM1 mutation: a systematic review and meta-analysis.

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.