Materials and methods

We conducted a retrospective cohort study of children diagnosed with either precursor B-cell or T cell ALL, including infants, between 2011–2016 at Texas Children’s Cancer and Hematology Centers (TXCH), Houston, TX, USA. All patients diagnosed with ALL who received HDMTX dosed over 24 h (for patients aged< 1 year: 4 g/m 2; for patients aged≥ 1 year: 5 g/m 2) were evaluated. Due to significant variations in treatment modifications following the first dose of HDMTX based on clearance characteristics and toxicities experienced (eg increased concomitant intravenous fluids, increased doses of leucovorin, HDMTX dose reductions, etc.) only the first dose for each patient was considered. We abstracted age, sex, self-reported ethnicity using standard NIH categories (https://grants. nih. gov), disease data, methotrexate dosing, routine methotrexate administration monitoring, weight, height, body mass index (BMI) percentiles (https://www. cdc. gov/) and concurrent tyrosine kinase inhibitor (TKI) use. Race and/or ethnicity was defined as ‘unknown’if the patient actively declined to self-identify or if these demographics were not able to be collected from the patient. Routine methotrexate monitoring was performed in accordance with current Children’s Oncology Group study guidelines [Citation 1]. In addition, we collected patient-specific toxicity and renal function data. Toxicities were graded by the study team based on laboratory data and physician and nursing electronic medical record (EMR) documentation according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4. 03 (www. ctep. cancer. gov). Baseline creatinine was assumed to be the creatinine recorded on initial labs in the office prior to start of the hydration for the HDMTX infusion. Each patient was evaluated for a history of acute kidney injury (AKI), defined as positive if the patient had a rise in their creatinine above the upper limit of normal for age and sex at any point available in the electronic medical record prior to the initiation of the first HDMTX cycle. HDMTX-induced severe nephropathy was defined using Ponte di Legno Working Group criteria: increased creatinine of> 0.3 mg/dL and/or relative increase of 1.5 times greater than a baseline value (measured within 4 days prior to hydration preceding HDMTX)+ plasma methotrexate concentrations of> 20umol/L at 36 h,> 10umol/L at 42 h, and/or> 5umol/L at 48 h [Citation 8]. Once patients were identified to have severe nephrotoxicity, further chart review was performed to abstract length of hospitalization, complications of stay, and next steps for treatment. Full methods are described in the Supplementary material.