PHASE-III STUDY COMPARING METHOTREXATE AND TACROLIMUS (PROGRAF, FK506) WITH METHOTREXATE AND CYCLOSPORINE FOR GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS AFTER HLA-IDENTICAL SIBLING BONE-MARROW TRANSPLANTATION

We report the results of a phase III open-label, randomized, multicent er trial comparing tacrolimus/methotrexate to cyclosporine/methotrexat e for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignanc y. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives wer e to compare the relapse rate, disease-free survival, overall survival , and the incidence of chronic GVHD. Patients were stratified accordin g to age (< 40 v greater than or equal to 40) and for male recipients of a marrow graft from an alloimmunized female. There was a significan tly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = .02). The incidence of grade Ii-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). T he incidence of grade Ill-IV acute GVHD was similar, 17.1% in cyclospo rine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclos porine group (55.9% and 49.4%, respectively; P = .8). However, there w as a significantly higher proportion of patients in the cyclosporine g roup who had clinical extensive chronic GVHD (P = .03). The relapse ra tes of the two groups were similar. The patients in the cyclosporine a rm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the re sult of the patients with advanced disease, 24.8% with tacrolimus vers us 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher fr equency of deaths from regimen-related toxicity in patients with advan ced disease who received tacrolimus. There was no difference in the di sease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyc losporine/methotrexate in the prevention of grade Ii-IV acute GVHD wit h no difference in disease-free or overall survival in patients with n onadvanced disease. The survival disadvantage in advanced disease pati ents receiving tacrolimus warrants further investigation. (C) 1998 by The American Society of Hematology.