Effect of high-dose methotrexate infusion duration on 48-hour drug levels and toxicity in children with acute lymphoblastic leukaemia: a quality-of-care study.

BACKGROUND

High‑dose methotrexate (HD‑MTX) is a cornerstone of pediatric acute lymphoblastic leukaemia (ALL) therapy. However, deviations from protocol-mandated infusion durations need regular monitoring as part of standard quality care. Hence, an observational quality assessment study was planned with a secondary objective to evaluate the acute toxicity in patients who did not receive the infusion within the recommended time period.

METHODS

This study enrolled 42 children (75 cycles) who received HD-MTX (3-5 g/m2 over 24 h) according to the ICiCLe ALL-14 protocol. The actual infusion duration was recorded, and 48-h MTX levels were measured using an enzyme-multiplied immunoassay technique. Toxicity was graded via CTCAE v5.0.

RESULTS

Only 35% of cycles were completed within the targeted 24-h window [Median (IQR): 23.75 h (21.25, 25.33)]. Prolonged infusions (> 25 h) resulted in significantly higher 48-h MTX levels compared to shortened infusions (median 0.475 vs 0.270 µmol/L; p = 0.015). Multivariable analysis identified male sex (OR, 12.24), T-ALL immunophenotype (OR, 8.36), and the infusion duration (OR, 1.50 per hour) as independent predictors of delayed clearance. A 48-h level > 0.315 µmol/L predicted development of toxicity (AUC 0.686), though no life-threatening event or mortality was recorded in any cycle. Additionally, MTX levels did not differ significantly across the four HD-MTX cycles that each patient received, and elevated levels in one cycle did not predict delayed clearance in subsequent cycles.

CONCLUSIONS

Deviations in infusion duration were high and independently drive pharmacokinetic variability and toxicity. Ensuring timely drug delivery is as critical as dose precision.