ABSTRACT:
Nucleophosmin 1 (NPM1) mutations are commonly associated with a favorable prognosis in Acute Myeloid Leukemia (AML). However, this benefit may be substantially modified by concurrent FMS-like tyrosine kinase 3 (FLT3) mutations. The magnitude of survival loss attributable to FLT3 co-mutation in NPM1-mutated AML remains incompletely quantified in large genomic cohorts. This study aimed to quantify the survival penalty imposed by FLT3 co-mutation on overall survival (OS) in NPM1-mutated AML. We performed a retrospective survival analysis using AML cohort datasets, including the OHSU cohort, TCGA PanCancer Atlas, and GEO. Patients with complete mutational and survival data were stratified into three mutually exclusive groups: isolated NPM1 mutation, isolated FLT3 mutation, and co-mutated NPM1/FLT3. OS was analyzed using Kaplan–Meier methods and compared by log-rank testing. Analyses were conducted using R and Python. A highly significant and clinically decisive divergence in survival outcomes was observed among the three molecular subgroups (log-rank P = 0.0017). Patients harboring isolated NPM1 mutations demonstrated the most favorable prognosis, with a median OS of 56.38 months (95% CI: 20.45–NA). In contrast, the presence of concurrent FLT3 mutation resulted in a profound collapse of survival, with the co-mutated NPM1/FLT3 group exhibiting a median OS of only 13.15 months (95% CI: 10.39–19.56). This corresponds to an absolute survival penalty of 43.23 months (>3.5 years) attributable to FLT3 co-mutation. Notably, co-mutated patients experienced inferior survival even compared with those harboring isolated FLT3 mutations (median OS: 18.58 months), suggesting a synergistic adverse biological interaction rather than a simple additive effect. This multi-cohort genomic analysis demonstrates that FLT3 co-mutation completely negates the survival advantage conferred by NPM1 mutations in AML. The substantial survival penalty underscores the necessity of comprehensive molecular profiling and supports early implementation of FLT3-directed and intensified therapeutic strategies in this high-risk molecular subset.