AbstractObjectiveWe aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next‐generation sequencing (NGS) data in adult patients withNPM1‐mutated (NPM1mut) acute myeloid leukemia (AML) induced with standard‐dose (SD, 100–200 mg/m2) and intermediate‐dose (ID, 1000–2000 mg/m2) cytarabine arabinose (Ara‐C).MethodsIn the entire cohort andFLT3‐ITD subgroups, multivariate Logistic and Cox regression analyses were used to analyze the comprehensive complete remission (cCR) rate after one or two induction cycles, event‐free survival (EFS), and overall survival (OS).ResultsAmong a total of 203NPM1mutpatients evaluable for clinical outcome, 144 (70.9%) received a first SD‐Ara‐C induction and 59 (29.1%) received ID‐Ara‐C induction. Early death was recorded in seven (3.4%) after one or two cycles of induction. Focusing analysis on theNPM1mut/FLT3‐ITD(−)subgroup, independent factors showing inferior outcome were presence ofTET2mutation [cCR rate, OR = 12.82 (95%CI 1.93–85.28),p= 0.008; EFS, HR = 2.92 (95%CI 1.46–5.86),p= 0.003], increasing age [EFS, HR = 1.49 (95%CI 1.10–2.02),p= 0.012 by every 10‐years elevation], white blood cell count ≥60 × 109/L [EFS, HR = 3.30 (95%CI 1.63–6.70),p= 0.001], and ≥4 mutated genes at initial diagnosis [OS, HR = 5.54 (95%CI 1.77–17.33),p= 0.003]. In contrast, when focusing on theNPM1mut/FLT3‐ITD(+)subgroup, factors showing superior outcome were ID‐Ara‐C induction [cCR rate, OR = 0.20 (95%CI 0.05–0.81),p= 0.025; EFS, HR = 0.27 (95%CI 0.13–0.60),p= 0.001] and allo‐transplantation [OS, HR = 0.45 (95%CI 0.21–0.94),p= 0.033]. Factors showing inferior outcome included CD34(+)[cCR rate, OR = 6.22 (95%CI 1.86–20.77),p= 0.003; EFS, HR = 2.01 (95%CI 1.12–3.61),p= 0.020] and ≥5 mutated genes [OS, HR = 2.85 (95%CI 1.33–6.10),p= 0.007].ConclusionWe conclude thatTET2(+), age, and white blood cell count convey an outcome risk modulation for AML withNPM1mut/FLT3‐ITD(−), as does CD34 and ID‐Ara‐C induction forNPM1mut/FLT3‐ITD(+). The findings permit re‐stratification ofNPM1mutAML into distinct prognostic subsets to guide risk‐adapted individualized treatment.