Genotype- and Age-Specific Relapse Dynamics in Childhood Acute Lymphoblastic Leukemia: A Longitudinal Mechanistic Study

Background Despite advances in front-line therapy for pediatric acute lymphoblastic leukemia (ALL), relapse remains a leading cause of treatment failure and mortality. Building on prior virtual investigations of TEL-AML1–associated leukemogenesis, this study evaluates post-remission relapse risk across pediatric ALL genotypes using mechanistic simulation. Methods Seven clinically relevant pediatric ALL genotypes were modeled using aiHumanoid v11.0 simulations. Each cohort was simulated from remission (T0) through two post-remission intervals (T1 = 3 months; T2 = 6 months). Longitudinal change was assessed using the Hodges–Lehmann Estimator (HLE), Wilcoxon signed-rank test, and Cliff’s delta. Composite relapse metrics were derived from 12 relapse-related outcome domains. Results Early relapse signals were detected in high-risk genotypes, including TEL-AML1 + PAX5 deletion, TEL-AML1 + radiation exposure, and TEL-AML1 + Ikaros deletion, characterized by elevated HLE values and large effect sizes. Low-risk genotypes, including TEL-AML1 alone and TEL-AML1 + family history, showed minimal deviation from remission through 6 months. Conclusions HLE-based longitudinal analysis enables detection of genotype-specific relapse dynamics in pediatric ALL and supports individualized, time-aware post-remission surveillance strategies.