Prognostication refinement in NPM1‐mutated acute myeloid leukemia stratified by FLT3‐ITD status with different induction doses of cytarabine

Objective We aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next‐generation sequencing (NGS) data in adult patients with NPM1‐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). Methods In the entire cohort and FLT3‐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). Results Among a total of 203 NPM1mut patients 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 the NPM1mut/FLT3‐ITD(−) subgroup, independent factors showing inferior outcome were presence of TET2 mutation [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 the NPM1mut/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]. Conclusion We conclude that TET2(+), age, and white blood cell count convey an outcome risk modulation for AML with NPM1mut/FLT3‐ITD(−), as does CD34 and ID‐Ara‐C induction for NPM1mut/FLT3‐ITD(+). The findings permit re‐stratification of NPM1mut AML into distinct prognostic subsets to guide risk‐adapted individualized treatment. NPM1mut/FLT3‐ITD(−)/TET2(+) is identified as an unfavorable prognostic subset in NPM1mut/FLT3‐ITD(−) patients. Induction containing intermediate‐dose cytosine arabinoside improves outcome in NPM1mut/FLT3‐ITD(+) patients. Clinicopathologic parameters, including age and white blood cell count, convey an outcome