Comprehensive Age-Stratified Impact of NPM1 Mutation in Acute Myeloid Leukemia: A Real-World Experience

Background: While NPM1-mutated AML in the absence of FLT3-ITD generally carries a favorable prognosis, large registry studies suggest the positive prognostic benefit may not extend to patients > 65 years of age. We examined this preferential, age-dependent prognostic impact through a real-world analysis of 2811 adult AML patients. Results: The median overall survival (OS) was significantly better in NPM1^MT compared to NPM1^WT patients [20.86 vs. 17 mo., p = 0.003]. When stratified by age, NPM1^MT patients had higher OS than NPM1^WT patients in the 55-65-year age group (28.62 vs. 16.3 mo., p ≤ 0.0001). This OS benefit was heterogenous and prevailed most strikingly in the 55-60 (68.3 vs. 15.6 mo., p = 0.002), and up to the 60-65-year group (mOS not estimable vs. 20 mo., p = 0.007), but not beyond 65 y. Notably, the ≤65 cohort was more enriched with dominant NPM1 (21% vs. 15%, p ≤ 0.001), while the >65 cohort was enriched with abnormal karyotype (20% in >65 years vs. 16% in ≤65 years, p = 0.001), and co-occurring SRSF2 and ASXL1 mutations (18.7% vs. 7.5%, p ≤ 0.0001 and 13.5% vs. 4.1%, p ≤ 0.0001 resp.). Conclusions: We demonstrate that in a real-world setting, the prognostic benefit of NPM1 does not extend beyond age 65, underscoring the need for age-adapted risk stratification models. This granular approach could prevent the potential overestimation of prognosis in older patients with NPM1^MT AML and inform therapeutic decision making.