Carboxypeptidase-G(2), thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction

Purpose: Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypeptidase-G(2) (CPDG(2)) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG(2) in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG(2) rescue administered with thymidine and leucovorin in 20 patients is presented here. Methods: Patients with high-dose methotrexote-induced renal dysfunction received one to three doses of CPDG(2), 50 U/kg body weight intravenously (IV), thymidine 8 g/m(2)/d by continuous IV infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N-10-methylpteroic acid (DAMPA) were measured before and after CPDG(2) using high-pressure liquid chromatography (HPLC). Tolerance of CPDG(2) and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored. Results: Twenty patients who received high-dose methotrexate for osteosarcoma (n=11), lymphoid cancers (n=8), and gastric cancer (n=1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mu mol/L at hour 46). CPDG(2) and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days. Conclusion: CPDG(2), thymidine,and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion. (C) 1997 by American Society of Clinical Oncology.