Genomic Determinants of Induction Failure and Persistent Prognostic Risk of FLT3-ITD in Pediatric Acute Myeloid Leukemia.
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BACKGROUND: Induction failure (IF) after standard induction chemotherapy is associated with poor outcomes in pediatric acute myeloid leukemia (pAML); however, whether established molecular markers such as FLT3-ITD retain prognostic significance across induction response states remains incompletely understood. We characterized the genomic landscape of IF and evaluated the prognostic significance of FLT3-ITD according to induction response. METHODS: This multi-cohort study integrated a TARGET discovery cohort (n = 1979) and an independent cohort from the Children's Hospital of Chongqing Medical University (CHCMU; n = 98). Clinical characteristics, somatic mutations, fusion profiles, and gene-gene interaction patterns were compared between patients with and without IF. Multivariable logistic regression identified genomic factors associated with IF, and survival analyses evaluated the prognostic impact of FLT3-ITD according to induction response. RESULTS: IF was associated with inferior OS (overall survival) (pooled HR = 3.24, 95% CI: 2.66-3.95). FLT3 mutations were consistently enriched in IF patients, whereas KIT mutations and favorable core-binding factor fusions were more frequent among non-IF patients. NUP98-NSD1 fusion was strongly enriched in IF patients in the TARGET cohort. Gene interaction analyses revealed reduced recurrent co-mutation patterns among IF patients. FLT3 mutation independently and reproducibly associated with IF. Among patients achieving induction remission, FLT3-ITD remained associated with inferior OS (HR = 1.34, 95% CI: 1.06-1.69, p = 0.014), whereas no statistically significant additional prognostic effect was detected among patients with IF. CONCLUSIONS: This study characterizes the genomic landscape of IF in pAML and identifies FLT3 mutation as a reproducible marker of induction resistance. Achieving induction remission does not eliminate the adverse prognostic significance of FLT3-ITD, supporting the integration of molecular risk and treatment response in subsequent risk stratification.