Pharmacogenomics of treatment toxicities in pediatric B-Cell ALL: toward safer precision therapy

Pharmacogenomics (PGx) has emerged as a key strategy to predict and prevent drug hypersensitivity reactions and treatment-related toxicities, thereby improving therapeutic adherence and survival in cancer care. Despite major advances in survival outcomes for pediatric B-Acute Lymphoblastic Leukemia (B-ALL), treatment-related toxicities remain a significant clinical challenge. Notably, treatment de-escalation strategies for low-risk leukemia are currently being explored in several clinical trials to reduce therapy-related toxicities. This review focuses on the mechanisms of drug-induced toxicity and their association with pharmacogenetic determinants in B-ALL therapy. Among the pharmacogenetic factors influencing toxicity of commonly used B-ALL treatments, variants in the TPMT and NUDT15 genes, both involved in the metabolism of 6-mercaptopurine, represent the most robust and clinically validated predictors. Emerging evidence also links additional genetic variants to toxicities associated with other key agents used in ALL treatment regimens, including variants in SLCO1B1 associated with methotrexate-related gastrointestinal toxicity and variants in CEP72 associated with vincristine-induced neuropathy. The integration of pharmacogenomic biomarkers into clinical protocols, enabling genotype-guided dose adjustment, may represent a valuable strategy to avoid toxicity and improve overall cancer outcomes. However, further studies and innovative approaches are required to validate emerging biomarkers and facilitate their translation into routine clinical practice.