Clinical Outcomes in Patients with High-Dose Methotrexate Toxicity Treated with Vs. without Glucarpidase

Background. High-dose methotrexate (HDMTX) is a cornerstone of treatment for lymphoma and leukemia involving the central nervous system, but can cause significant toxicity, which manifests predominantly as acute kidney injury (AKI) as well as bone marrow suppression and hepatotoxicity. Glucarpidase is a recombinant bacterial enzyme that cleaves 99% of circulating MTX to inactive metabolites within 15 minutes of its administration. It is approved for use in the setting of supratherapeutic MTX levels to mitigate renal and extrarenal toxicity. Despite its potent biochemical effects, no study has rigorously examined whether glucarpidase improves clinical outcomes in patients with HDMTX toxicity compared to controls not treated with glucarpidase. This key evidence gap has led to wide variation in the use of glucarpidase across institutions. Methods. We examined the clinical outcomes of patients with HDMTX-associated AKI (HDMTX-AKI) treated with and without glucarpidase across a large multicenter cohort of 684 adults from 26 major cancer centers across the US from 2000 to 2022. HDMTX-AKI was defined as a ≥1.5-fold increase in serum creatinine (SCr) within 4 days following treatment with HDMTX. We collected data on demographics, comorbidities, medications, laboratory values, and outcomes. The primary outcome was renal recovery, defined as a return of SCr to