Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients

Abstract

Background: High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. The authors retrospectively reviewed glucarpidase use in pediatric cancer patients at their institution and evaluated whether subsequent resumption of HDMTX was tolerated.

Methods: Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed.

Results: Of 1141 patients who received 4909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dose was 51.6 U/kg (range, 13-65.6 U/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 μM (range, 1.3-590.6 μM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244-763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66-268 hours) for the next HDMTX course, and 72 hours (range, 42-116 hours) for subsequent courses. The median peak serum creatinine level during these HDMTX courses was 2.2 mg/dL (range, 0.8-9.6 mg/dL), 0.8 mg/dL (range, 0.4-1.6 mg/dL), and 0.6 mg/dL (range, 0.4-0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients, and no patient died as a result of methotrexate toxicity.

Conclusions: The current results indicated that it is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury.

Figure 1. Plasma levels of methotrexate and DAMPA after glucarpidase

Plasma methotrexate and DAMPA concentration vs. time after glucarpidase treatment. Methotrexate (MTX) was measured by fluorescence polymerization immunoassay (●) and HPLC (○), and DAMPA was measured by HPLC (△), in the six patients who had assays by both methods. The arrow indicates the time of glucarpidase administration.

Figure 2. High-dose methotrexate rechallenge

Disposition of 20 patients who received glucarpidase, whether they were rechallenged with high-dose methotrexate (HDMTX) following glucarpidase use, whether they received the full recommended HDMTX dose or a reduced dose for the course immediately after glucarpidase, and whether the full recommended dose was ever given. * HDMTX doses for ALL and lymphoblastic lymphoma patients were targeted to a steady state concentration of 65 µM based on the clearance of the previous HDMTX course. Full dose was defined as the administration of the recommended targeted dose.

Figure 3. Range of MTX plasma concentrations for patients during the HDMTX course in which glucarpidase was given, the first HDMTX course after glucarpidase, and the expected range for dose

Methotrexate (MTX) plasma concentrations (µM) vs. time during the HDMTX courses during which glucarpidase was given (red), the next HDMTX course (green), and the expected range (blue). Colored regions represent the range of methotrexate concentrations for (a) patients who received a 24-hour infusion of 5 g/m² of MTX or a dose targeted to a MTX steady-state concentration of 65 µM and (b) patients who received a 4-hour infusion of 8 – 12 g/m² of MTX. MTX doses may have been reduced for the first course after glucarpidase. Each set of two panels shows data for a 96-hour and a 700-hour time period, respectively. The expected ranges for dose were obtained from the pharmacokinetic data for previous cohorts of St. Jude patients with acute lymphoblastic leukemia and osteosarcoma