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

Voravit Ratanatharathorn, Richard A. Nash, Donna Przepiorka, Steven M. Devine, Jared L. Klein, Daniel Weisdorf, Joseph W. Fay, Auayporn Nademanee, Joseph H. Antin, Neal P. Christiansen, Richard Van der Jagt, Roger H. Herzig, Mark R. Litzow, Steven N. Wolff, Walter L. Longo, Finn B. Petersen, Chatchada Karanes, Belinda Avalos, Rainer Storb, Donald N. BuellRochelle M. Maher, William E. Fitzsimmons, John R. Wingard

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Abstract

We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v ≤40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly 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). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P= .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = .03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm 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 result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P= .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.

Original languageEnglish (US)
Pages (from-to)2303-2314
Number of pages12
JournalBlood
Volume92
Issue number7
StatePublished - Oct 1 1998

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    Ratanatharathorn, V., Nash, R. A., Przepiorka, D., Devine, S. M., Klein, J. L., Weisdorf, D., Fay, J. W., Nademanee, A., Antin, J. H., Christiansen, N. P., Van der Jagt, R., Herzig, R. H., Litzow, M. R., Wolff, S. N., Longo, W. L., Petersen, F. B., Karanes, C., Avalos, B., Storb, R., ... Wingard, J. R. (1998). 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. Blood, 92(7), 2303-2314.