The role of pharmacogenetics in the therapy regimen of acute lymphoblastic leukemia in children: recent discoveries and future perspectives

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. Although survival rates have improved in recent decades, relapse and therapy-related toxicities remain major challenges in pediatric ALL. Pharmacogenetics is an approach with the potential to refine precision medicine in pediatric ALL. This review synthesizes current knowledge on pharmacogenetic markers of drug efficacy, toxicity, and adverse effects for drugs used in childhood ALL, including glucocorticosteroids, vincristine, asparaginase, anthracyclines, 6-mercaptopurine, and methotrexate. Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are the only pharmacogenetic markers with established clinical guidelines that inform thiopurine and methotrexate dosing. Insufficient and inconsistent evidence has limited the translation of most other pharmacogenetic findings into clinical practice. While most studies centered on coding variants, we also point to new approaches focusing on noncoding regions and epigenetic variation that hold promise for expanding the scope of clinically relevant biomarkers in the near future. Finally, we propose future research avenues, that could support the development of more individualized treatment strategies for children with ALL.