Glucarpidase, Leucovorin, and Thymidine for High-Dose Methotrexate-Induced Renal Dysfunction: Clinical and Pharmacologic Factors Affecting Outcome

作者：Brigitte C. Widemann, Frank M. Balis, AeRang Kim, Matthew Boron, Nalini Jayaprakash, Aiman M. Shalabi, Michelle O'Brien, Michelle Eby, Diane E. Cole, Robert F. Murphy, Elizabeth Fox, Percy S. Ivy, Peter C. Adamson · 发表于：Journal of Clinical Oncology · 年份：2010 · DOI：10.1200/jco.2009.25.4540 · 被引用次数：173 · 研究领域：Acute Lymphoblastic Leukemia research、Chemotherapy-induced organ toxicity mitigation、Chronic Lymphocytic Leukemia Research

PURPOSE: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. METHODS: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. RESULTS: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after...