The Scale of Problems Associated with High-Dose Methotrexate: A systematic review of Toxicity Patterns

Abstract

HDMTX is a cornerstone in the treatment of acute lymphoblastic leukaemia, osteosarcoma, and lymphoma, but its use is complicated by unpredictable toxicities. This systematic review synthesised evidence from 93 studies to identify consistent predictors of toxicity. Impaired elimination and elevated systemic exposure were the most consistent predictors of renal and downstream toxicities. Genetic variants, particularly in SLCO1B1, consistently predicted delayed clearance, while others, including MTHFR, showed weaker and less reliable associations. Demographic factors such as age and sex influenced risk mainly as modifiers rather than independent determinants once clearance was considered. Treatment-related factors, including high-dose intensity, interacting medications, and early biochemical changes, also shaped toxicity outcomes. Supportive care with hydration, alkalinisation, and leucovorin remains essential, while timely use of glucarpidase is the most effective intervention for severe delayed clearance or methotrexate-induced kidney injury. Overall, these findings support an exposure-driven model of HDMTX toxicity and highlight the importance of pharmacokinetic monitoring, careful management of drug-drug interactions, and prompt rescue strategies. Together, they provide a framework for safer and more individualised use of HDMTX in oncology.