Successful re-exposure to high-dose methotrexate after severely delayed methotrexate elimination and renal toxicity in children with acute lymphoblastic leukemia
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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). Evidence-based 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 re-exposure, 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 neither 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.
Source: Haematologica
Authors: Shlomit Barzilai-Birenboim, Nira Arad-Cohen, Edit Bardi, Jesper Heldrup, Gábor Kovács, Marion Mateos, Anja Moericke, Natanja Oosterom, Saskia Sonnenberg, Freya Steinhauer, Goda E. Vaitkevičienė, Inge M. Van der Sluis, Sigal M. Weinreb, Ester Zapotocka, David Zucker, Kjeld Schmiegelow, Torben Stamm Mikkelsen
Institutions: Tel Aviv University, Schneider Children's Medical Center, Technion – Israel Institute of Technology, Rambam Health Care Campus, Johannes Kepler University of Linz, St Anna Children's Hospital, St. Anna Children's Cancer Research Institute, Medical University of Vienna, Skåne University Hospital, Semmelweis University, UNSW Sydney, Sydney Children's Hospital, University Hospital Schleswig-Holstein, University Medical Center Utrecht, University of Groningen, Vilnius University, Vilnius University Hospital Santariskiu Klinikos, Princess Máxima Center, Hadassah Medical Center, Charles University, University Hospital in Motol, Hebrew University of Jerusalem, Copenhagen University Hospital, Rigshospitalet, Aarhus University Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,157
Award: G1460529261
OpenAlex ID: W7127956195