Impact of FLT3^ITD-L and age in NPM1-mutated AML on OS and relapse-free survival in ELN 2017 favorable-risk patients. (A) In the AMLSG cohort, there was a significant difference in survival between NPM1^mutFLT3^wt patients vs NPM1^mutFLT3^ITD-L patients (AR < 0.5). This difference is not seen in the TCGA and TARGET cohorts. The AMLSG (B) and TCGA (C) cohorts were stratified by age. Younger (<60 years) patients with NPM1^mutFLT3^ITD-L had outcomes inferior to NPM1^mutFLT3^wt patients in both cohorts. In older (≥60 years) patients in both cohorts, NPM1^mutFLT3^wt appeared to lose its favorable influence, with both groups having similarly poor outcomes. (D) Comparison of ELN 2017 favorable NPM1^mut FLT3^ITD-L patients with other ELN 2017 risk groups in the AMLSG cohorts. NPM1^mutFLT3^ITD-L patients <60 years showed an increased risk of death compared with other favorably classified patients (P = 8.7 × 10⁻⁸; HR, 2.5; 95% CI, 1.8-3.5), whereas there was no difference compared with the intermediate risk group (P = .76). NPM1^mutFLT3^wt patients showed no difference from other favorably classified patients (P = .07), but a significantly decreased risk compared with the intermediate risk group (P = 8.8 × 10⁻⁵; HR, 0.6; 95% CI, .4-.8). In patients ≥60 years, no statistical difference was observed between favorable, intermediate, NPM1^mutFLT3^wt, and NPM1^mutFLT3^ITD subgroups. (E) Similar trends were observed for the TCGA cohort in patients <60 years, with NPM1^mutFLT3^ITD-L patients having a significantly poorer survival compared with the favorable (P = .004; HR = 6.9; 95% CI, 1.9-25.7) and intermediate groups (P = .03; HR, 2.8; 95% CI, 1.1-7). In this cohort, survival of NPM1^mutFLT3^wt patients was not statistically different to favorable (P = .3) or intermediate risk groups (P = .8). In patients ≥60 years, there were also no significant differences between the favorable, intermediate, and NPM1^mutFLT3^wt and NPM1^mutFLT3^ITD-L subgroups. (F) Conversely, in the TARGET pediatric cohort, NPM1^mutFLT3^wt (P = .98) and NPM1^mutFLT3^ITD-L (P = .87) patients had similar survival to other favorably classified patients. Although the NPM1^mutFLT3^wt group had a significantly decreased risk of death compared with intermediate-classified patients (P = .006; HR, 0.37; 95% CI, 0.28-0.5), the difference between the intermediate and NPM1^mutFLT3^ITD-L groups did not reach significance (P = .06). All P values displayed in the graphs are the result of a log rank test statistic to assess the global statistical significance of the model.