Intrahepatic arterial administration of low-dose methotrexate in patients with severe hepatic graft-versus-host disease: an open-label, uncontrolled trial.

Background: Hepatic grafr-versus-host disease (GVHD) is associated with significant morbidity and mortality. Standard therapy includes systemically administered immunosuppressive drugs. More recent reports have described catheter-directed intrahepatic arterial (IHA) delivery of low-dose methotrexate (MTX) and methylprednisolone in the treatment of corticosteroid-resistant severe hepatic GVHD.

Objective: This article reports on MTX toxicity and the variability in plasma drug concentrations after IHA administration of low-dose MTX in patients with severe hepatic GVHD.

Methods: In this open-label, uncontrolled pilot study, MTX and methylprednisolone were administered via the hepatic artery in patients with corticosteroid-resistant grade III or IV GVHD of the liver. Patients also received standard therapy. MTX concentrations were measured in the hepatic artery 5 and 10 minutes after injection and in peripheral venous blood at 1, 2, and 24 hours.

Results: Six patients (5 males [83.3%], I female [16.7%]; median age, 32 years; range, 8-42 years) were enrolled in the study. No hepatotoxicity was observed after IHA administration of MTX. In 5 patients with normal renal function, plasma drug concentrations 24 hours after administration of MTX ranged from 0.01 to 0.12 micromol/L (mean [SD], 0.043 [0.042] micromol/L). In 1 patient with renal failure, plasma MTX concentrations were 1.0 micromol/L 24 hours after administration and 0.07 micromol/L 5 days after administration. The severe hematologic and renal toxicity observed in this patient may have contributed to his death. Adverse events in patients with GVHD and normal renal function, who had normal plasma MTX concentrations, were comparable to those that have been reported after administration of an intravenous infusion.

Conclusions: In patients with GVHD and normal renal function, IHA administration of low-dose MTX was not associated with liver or bone marrow toxicity. Further study is needed to determine the optimal protocols for treating corticosteroid-resistant hepatic GVHD.