Successful re-exposure to high-dose methotrexate after severely delayed methotrexate elimination and renal toxicity in children with acute lymphoblastic leukemia

High-dose methotrexate (HDMTX) is a cornerstone of contemporary treatment protocols for both pediatric and adult acute lymphoblastic leukemia (ALL); however, up to 4% of children and 15% of adults develop renal toxicity with severely delayed MTX elimination (DME). Evidencebased guidance on re-exposure after DME is lacking, and omission of further HDMTX may compromise anti-leukemic efficacy and potentially increase the risk of relapse. This study, conducted within the Ponte di Legno international toxicity working group, aimed to evaluate the safety of HDMTX re-challenge in pediatric patients after DME. National investigators from 12 countries provided case-level data on initial DME events and subsequent HDMTX re-exposures via structured questionnaires. Data from 189 patients treated for ALL who experienced DME were analyzed, of whom 143 were subsequently re-exposed to HDMTX. Clinical toxicities after the initial DME included gastrointestinal complications (vomiting, diarrhea, mucositis), infections, and neurological events (encephalopathy, seizures, MTX stroke-like syndrome). Laboratory toxicities comprised cytopenias and hepatic abnormalities. Two patients transiently required dialysis. DME led to chemotherapy modifications in 73% of the patients. After reexposure, toxicities were similar in spectrum, self-limited, and non-fatal. Twenty children (14%) developed recurrent DME, including three with two additional episodes. Recurrent DME could not be predicted by clinical, pharmacokinetic, or demographic variables, nor by uniform MTX dose reduction during re-exposure. In conclusion, re-exposure to HDMTX following DME is feasible and generally well tolerated, although the risk of recurrence is increased. Re-challenge should be considered once renal function has normalized, with careful monitoring and individualized dose adjustment.