title: Intrahepatic arterial administration of low-dose methotrexate in patients with severe hepatic graft-versus-host disease: an open-label, uncontrolled trial.
abstract: 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.
authors.affiliation: Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Bloom
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Shapira
authors.forename: Reuven
authors.initials: R
authors.lastname: Or
authors.forename: Talia
authors.initials: T
authors.lastname: Sasson
authors.forename: Igor B
authors.initials: IB
authors.lastname: Resnick
authors.forename: Irena
authors.initials: I
authors.lastname: Zilberman
authors.forename: Anthony
authors.initials: A
authors.lastname: Verstandig
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004351:Drug Resistance; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006499:Hepatic Artery; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007261:Infusions, Intra-Arterial; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008775:Methylprednisolone / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000503:physiopathology
chemical_list: D007166:Immunosuppressive Agents; D008775:Methylprednisolone; D008727:Methotrexate