Amelioration of steroid-resistant chronic graft-versus-host-mediated liverdisease via tacrolimus treatment

Liver disease associated with chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity. Steroids and cyclosporin (CSA), w hich are the standard therapy, give rather disappointing results, and toxic ity is high. Tacrolimus (FK506) is a potent macrolide lactone immunosuppres sant that is used in the prevention of solid organ rejection. This study ev aluated the therapeutic role of FK506 in the treatment of severe cGVHD-medi ated liver disease that did not respond to combined steroids and CSA therap y. Fifteen patients with various hematological disorders who underwent allo geneic stem cell transplantation were enrolled in the study. All patients h ad 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 serolog y. They received FK506 orally (4-20 mg/day according to serum levels), and were evaluated biweekly by physical examination and liver function tests. P atients 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 liv er 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 effec ts were generally transient. Treatment with FK506 was found to be effective in the majority of patients with steroid and CSA-resistant cGVHD-associate d liver disease, with manageable side effects. In view of these findings, F K506 may yet evolve into first line therapy for cGVHD induced liver toxicit y.