To investigate the impact of nucleophosmin 1-mutated (NPM1m) subtypes, variant allele frequency (VAF) and co-mutations on the survival outcomes of patients with acute myeloid leukemia (AML).

Clinical data, mutation status, and outcomes of 86 NPM1m-AML patients admitted in Department of Hematology, First Hospital of Lanzhou University between June 2017 and September 2024 were collected and retrospectively analyzed. Spearman correlation analysis, Kaplan-Meier curve analysis, Log-rank test, and Cox regression analysis was applied for correlation analysis, survival analysis, and factors affecting survival.

The overall survival (OS) was significantly shorter in the Rares subtype of NPM1m than the ABD subtype (median OS: 164 d vs 416 d, P=0.043). The VAF of NPM1mwas positively correlated with the initial peripheral blood white blood cell count and lactate dehydrogenase (LDH) level (P<0.05). OS was reduced when VAF was ≥0.37 (median OS: 164 d vs 730 d, P=0.003). The presence of myelodysplasia-related gene (MR) mutations was associated with a poorer prognosis when compared to the MR wild-type (median OS: 45 d vs 395 d, P<0.001). The triple mutation of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and DNMT3A also indicated a worse prognosis than the non-triple mutation (median OS: 173 d vs 483 d, P=0.007). The presence of PTPN11 mutations was associated with improved OS (median OS: 395 d vs 240 d, P=0.027), while the patients with coexistence of N/KRAS mutations trended toward better prognosis than the wild-type patients (median OS: 662 d vs 189 d) though no statistical significance (P=0.070). Multivariate analysis revealed that LDH (HR=1.002, 95%CI: 1.000~1.003, P=0.005), NPM1m VAF (HR=2.415, 95%CI: 1.208~4.829, P=0.013), Rares subtype (HR=3.037, 95%CI: 1.134~8.136, P=0.027), and MR mutations (HR=5.283, 95%CI: 1.991~14.017, P<0.001) were independent risk factors associated with OS in the patients.

Molecular heterogeneity of NPM1m should be taken into account in prognostic stratification of NPM1m-AML. Factors including the Rares subtype, VAF≥0.37, coexistence of FLT3-ITD and DNMT3A mutations, and MR mutations are associated with poor prognosis of NPM1m-AML. The presence of PTPN11 mutations improves the prognosis, while the presence of N/KRAS mutations shows a trend toward better prognosis. LDH, NPM1m VAF, Rares subtype, and MR mutations are independent risk factors affecting OS of patients with NPM1m-AML.