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/m 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.