Delayed Elimination Concentrations of High-Dose Methotrexate in Adults With Hematological Malignancies: To...

High-dose methotrexate (HDMTX) is a cornerstone therapeutic regimen for hematological malignancies; however, delayed elimination remains a significant clinical challenge. Currently, no standardized definition for delayed elimination exists. This scoping review aims to identify and characterize methotrexate elimination threshold variability and its implication on clinical data interpretation.

A literature search was conducted using PubMed, Scopus, and the Cochrane database to identify studies published in English from the 1960s to February 2025. All study types reporting delayed elimination thresholds for high-dose methotrexate in adult patients with hematological malignancies were included.

Twenty-three studies meeting the inclusion criteria were charted and summarized. The most frequently reported thresholds were 10 µmol/L at 24 hours (42%), 1 µmol/L at 48 hours (44%), and 0.1 µmol/L at 72 hours (55%). The threshold values varied widely at 24, 48, and 72 hours by 750-, 100-, and 3-folds, respectively. For most of the studies (87%), time measurement was initiated at the start of infusion. Majority of studies (81%) used immunoassays to quantify methotrexate, whereas 19% used liquid chromatography, with no significant difference in concentration thresholds observed between assay types.

Significant variability exists in the thresholds used to define delayed HDMTX elimination, particularly at 48 hours, with the differences not explained by assay method. These inconsistencies affect clinical decisions, including toxicity predictions and rescue therapy implementation. Although standardization is needed to improve comparability, threshold definitions should also reflect population-specific pharmacokinetics and toxicity profiles to support more precise HDMTX monitoring and outcomes.