Toxicity-Tailored Thresholds of Delayed Methotrexate Elimination in Non-Hodgkin Lymphoma: A Population-Based Approach...

High-dose methotrexate (HDMTX) is an essential agent in hematological malignancies, the use of which is complicated by toxicities related to delayed elimination. Existing thresholds to define delayed elimination vary widely, creating inconsistencies in clinical practice.

This multicenter retrospective study evaluated adult non-Hodgkin Lymphoma patients from Malaysia to establish a locally relevant delayed elimination threshold and identify factors influencing it.

Patients who received HDMTX ≥ 500 mg/m² were included. Data extracted from medical records were HDMTX regimen, supportive therapy, renal and liver function, full blood count, MTX concentrations, and MTX-related toxicities. MTX thresholds at 48 h were assessed based on their association with post-treatment clinical outcomes. The selected threshold was subsequently used to categorize patients into delayed and nondelayed elimination groups, and factors associated with delayed elimination were evaluated using logistic regression.

A toxicity-based receiver operating characteristic (ROC) approach identified ≥ 0.2 µmol/L at 48 h as the concentration at which lymphocyte count and alanine aminotransferase (ALT) worsened by 50% and mucositis risk increased nearly threefold. Logistic regression showed increased baseline serum creatinine, decreased baseline albumin, and 24 h infusion duration as factors associated with delayed elimination, while Chinese ethnicity was associated with reduced odd of delayed elimination.

These findings support a population-tailored threshold to better guide supportive management and highlight key predictors that can inform future pharmacokinetic modeling for optimized HDMTX therapy.