Pharmacogenomic impact and genetic architecture of toxicity in pediatric acute lymphoblastic leukemia induction therapy: an exploratory modeling approach.

Induction chemotherapy for pediatric Acute Lymphoblastic Leukemia (ALL) is highly curative but accompanied by a severe toxicity profile. Evaluating the genetic susceptibility to these adverse events could inform hypothesis-generating risk stratification. In this exploratory retrospective cohort study (N = 178), we investigated the influence of 14 candidate pharmacogenetic variants on the development of prevalent Adverse Drug Reactions (ADRs, ≥ 10 events). Multiple logistic regression, adjusted for basic demographic and anthropometric covariates (age and body surface area), was utilized across comprehensive inheritance architectures (additive, dominant, recessive, and co-dominant). For clinical translation hypothesis generation, we applied LASSO-penalized logistic regression (α = 1), 10-fold cross-validation to derive parsimonious Pharmacogenetic Risk Scores (PGRS). Model performance was evaluated using the optimism-corrected Area Under the Receiver Operating Characteristic Curve (AUC) via 1000-iteration bootstrap resampling, and calibration was assessed via the Brier score. We observed several complex interactions, notably suggesting an increased risk of severe neutropenia in patients carrying a homozygous variant