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

<b>Background:</b> While <i>NPM1</i>-mutated AML in the absence of <i>FLT3</i>-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. <b>Results:</b> The median overall survival (OS) was significantly better in <i>NPM1</i>^MT compared to <i>NPM1</i>^WT patients [20.86 vs. 17 mo., <i>p</i> = 0.003]. When stratified by age, <i>NPM1</i>^MT patients had higher OS than <i>NPM1</i>^WT patients in the 55-65-year age group (28.62 vs. 16.3 mo., <i>p</i> ≤ 0.0001). This OS benefit was heterogenous and prevailed most strikingly in the 55-60 (68.3 vs. 15.6 mo., <i>p</i> = 0.002), and up to the 60-65-year group (mOS not estimable vs. 20 mo., <i>p</i> = 0.007), but not beyond 65 y. Notably, the ≤65 cohort was more enriched with dominant <i>NPM1</i> (21% vs. 15%, <i>p</i> ≤ 0.001), while the >65 cohort was enriched with abnormal karyotype (20% in >65 years vs. 16% in ≤65 years, <i>p</i> = 0.001), and co-occurring <i>SRSF2</i> and <i>ASXL1</i> mutations (18.7% vs. 7.5%, <i>p</i> ≤ 0.0001 and 13.5% vs. 4.1%, <i>p</i> ≤ 0.0001 resp.). <b>Conclusions:</b> We demonstrate that in a real-world setting, the prognostic benefit of <i>NPM1</i> 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 <i>NPM1</i>^MT AML and inform therapeutic decision making.