Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome

Abstract

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 the start of the MTX infusion were associated with development of grade 4 and 5 toxicity.

Conclusion: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Fig 1.

Disposition of 100 patients who received glucarpidase, indicating pre-existence or absence of grade 4 toxicity before administration of glucarpidase; appropriate or inappropriate increase in leucovorin (LV) rescue within 3 days after the start of high-dose methotrexate (HDMTX); timing of administration of glucarpidase at ≤ 96 hours or more than 96 hours after starting HDMTX; presence of grade 4 toxicity after the administration of glucarpidase; and death directly attributed or not directly attributed to MTX toxicity.

Fig 2.

Plasma methotrexate (MTX) concentration/time profiles for 75 patients who had plasma MTX concentration determined by high-performance liquid chromatography. Lines are point to point, and symbols indicating individual measurements are not included. Glucarpidase administration was at hour 0. Plasma MTX concentration before administration of glucarpidase was determined at local institutions with commercially available assays.

Fig 3.

Maximum decrease and rebound increase in plasma methotrexate (MTX) concentration after administration of glucarpidase (CPDG₂) in 30 patients. The median peak rebound increase plasma MTX concentration was 3.3% (range, 0.8% to 13.7%) for 20 patients with plasma MTX concentration ≥ 10 μmol/L before glucarpidase and 20.1% (range, 3.7% to 30.8%) for 10 patients with plasma MTX concentration less than 10 μmol/L before glucarpidase.