Acute toxicity due to delayed elimination of methotrexate in cancer therapy: A case report

Abstract

High-dose methotrexate (HD-MTX) is widely administered in cancer therapy, and generally includes doses of 500 mg/m 2 or higher. Administration of such high doses of methotrexate is followed by leucovorin rescue therapy. The leucovorin rescue is intended to minimize damage to healthy cells; otherwise, Delayed elimination of methotrexate can lead to serious adverse events and even death, despite of the preventive measures. We report herein a case of a 25-year-old woman having Acute Lymphoblastic Leukemia (ALL) who showed delayed elimination of MTX associated with functional kidney failure, spinal cord aplasia, persistent ulcers of the oral cavity and liver damage. This patient received a cumulative dose of 906 mg/m 2 (1.315 g) over 43 hours followed by Leucovorin (Folinic Acid) rescue at 4H after the end of MTX infusion. The monitoring of MTX plasma levels showed a high concentration at 72 H (2.45 μmol/L) and at 96H (2.23 μmol/L). In fact, MTX levels remained above 0.2 μmol/L until H144. Elevation of creatinine and transaminases has been reported in the first 24 H post-infusion and reaching their maximum (Creat = 337 μmol/L, ASAT = 85UI/L, ALAT = 155IU/L) at 72 H leading to the readjustement of the Leucovorin rescue to 800 mg/D at 96H. Once the MTX levels are below the cytotoxic threshold (0.01 μmol/L), the folinic acid rescue was stopped and the outcome was favorable with a decrease of creatinine and transaminases levels. This case clearly demonstrates the role of therapeutic drug monitoring, particularly in long period infusions, where the toxicity of HD-MTX may be more prominent causing kidney damage which can lead to delayed elimination and liver damage responsible of the elevation of MTX levels, a condition which requires precise dosage of folinic acid because conventional doses are no longer covering the real needs to limit MTX toxicity.