Methods

This retrospective chart review evaluated pediatric patients with mature B/T-cell NHL who received intravenous HD-MTX (3 g/m2/dose intravenously over 3 hours) from October 1, 2010 through June 30, 2020 at Texas Children’s Hospital. Patients were excluded from data analysis if they received an empiric methotrexate dose reduction. All data were abstracted from the electronic health record, including diagnosis, race/ethnicity, age, height and weight at diagnosis; dose and timing of HD-MTX administration; relevant laboratory details (i.e., serum creatinine, methotrexate levels, urine pH and specific gravity); select supportive care interventions (i.e., leucovorin, hydration, alkalization, glucarpidase, concomitant medications); tumor lysis syndrome; and vital status. Body surface area and body mass index were calculated from extracted variables. The primary outcome was delayed methotrexate clearance, defined by a methotrexate level above the protocol-defined clearance threshold at hour 48. Secondary outcomes included the time to clearance, frequency of serum creatinine elevations (i.e., an increase ≥25% after start of methotrexate), and incidence of Common Terminology Criteria for Adverse Events (version 5.0) grade ≥3 mucositis. Planned exploratory analysis included evaluation of risk factors associated with delayed clearance of methotrexate, serum creatinine elevations, and mucositis.
The frequency of each methotrexate-associated toxicity was summarized by the number of methotrexate doses resulting in each toxicity and number of patients who experienced the toxicity following any HD-MTX. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between clinical characteristics and the development of each outcome (delayed clearance, creatinine elevations, and mucositis) were calculated using multivariable mixed-effects logistic regression to account for repeated measures following each methotrexate infusion within each patient. A mixed-effects linear regression model was constructed to evaluate associations with time to methotrexate clearance. A step-wise selection process was used to identify a parsimonious model including age, race/ethnicity, and other clinical features associated (p-value<0.2) with one or more of the outcomes in unadjusted models. All analyses were conducted using Stata SE version 15.1 (College Station, TX) at a two-sided significance level of 0.05. This study was approved by Institutional Review Board at Baylor College of Medicine.