Unmasking hidden high risk in RUNX1::RUNX1T1 pediatric AML: Development of a novel prognostic model.
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Although pediatric acute myeloid leukemia (pAML) harboring the RUNX1::RUNX1T1 fusion is generally classified as favorable risk, some patients experience poor outcomes. To address this heterogeneity, we developed and validated a prognostic model to refine risk stratification and guide individualized therapy. We analyzed 284 RR+ pAML cases from public datasets, randomized into training and internal validation cohorts, and assessed generalizability in an independent external cohort of 214 patients from multiple centers in China. The model integrates two readily accessible variables-minimal residual disease after induction (MRD1) and peripheral blood blast percentage at diagnosis-as core predictors. It consistently identified a >30% high-risk subgroup characterized by elevated relapse rates and mortality, who derived limited benefit from transplantation. Furthermore, KIT mutations, particularly in exon 17, delineated a very-high-risk subset with significantly inferior outcomes. In this group, dasatinib treatment was associated with improved overall and event-free survival, whereas no benefit was observed in low-risk patients. For high-risk patients lacking KIT mutations, transcriptional profiling and drug sensitivity analysis identified potential therapeutic candidates, including immune checkpoint modulators (e.g., targeting TLR3 and CD200) and small-molecule inhibitors. This stratification tool provides a simple framework for individualized risk assessment and offers actionable evidence to assist treatment decision-making for RR+ pAML patients.