title: Amelioration of steroid-resistant chronic graft-versus-host-mediated liver disease via tacrolimus treatment.
abstract: Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), which are the standard therapy, give rather disappointing results, and toxicity is high. Tacrolimus (FK506) is a potent macrolide lactone immunosuppressant that is used in the prevention of solid organ rejection. This study evaluated the therapeutic role of FK506 in the treatment of severe cGVHD-mediated liver disease that did not respond to combined steroids and CSA therapy. Fifteen patients with various hematological disorders who underwent allogeneic stem cell transplantation were enrolled in the study. All patients had severe cholestatic liver disease disturbances and underwent liver biopsy, which was compatible with cGVHD-mediated liver disease. All the patients were negative for markers of chronic liver disease, including viral serology. They received FK506 orally (4-20 mg/day according to serum levels), and were evaluated biweekly by physical examination and liver function tests. Patients were followed for a median of 12 months (range 3-24 months). FK506 treatment ameliorated liver functions in 9 of 15 patients (60%), 5 of whom demonstrated complete normalization of liver enzymes (33%). In 5 patients, no major effect was observed, and 1 patient showed deterioration of his liver functions. Mean GGT levels decreased from 171.5 to 55.6 within 6 months of treatment. Median time to response was 3 months (range 1-11). Side effects were generally transient. Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associated liver disease, with manageable side effects. In view of these findings, FK506 may yet evolve into first line therapy for cGVHD induced liver toxicity.
authors.affiliation: Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.forename: Y
authors.initials: Y
authors.lastname: Menachem
authors.forename: Y
authors.initials: Y
authors.lastname: Ilan
mesh_terms: D000293:Adolescent; D000328:Adult; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D004341:Drug Evaluation; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000150:complications* / Q000188:drug therapy; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D011241:Prednisone / Q000494:pharmacology / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone; D016559:Tacrolimus; D008727:Methotrexate