BACKGROUND: There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. DESIGN AND METHODS: We conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. RESULTS:Seventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4(+) cells in the peripheral blood, and isolated regulatory T cells were functional. CONCLUSIONS: These data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation.
RCT Entities:
BACKGROUND: There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. DESIGN AND METHODS: We conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. RESULTS: Seventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4(+) cells in the peripheral blood, and isolated regulatory T cells were functional. CONCLUSIONS: These data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation.
Authors: Steven J Bensinger; Patrick T Walsh; Jidong Zhang; Martin Carroll; Ramon Parsons; Jeffrey C Rathmell; Craig B Thompson; Matthew A Burchill; Michael A Farrar; Laurence A Turka Journal: J Immunol Date: 2004-05-01 Impact factor: 5.422
Authors: R P McQuellon; G B Russell; D F Cella; B L Craven; M Brady; A Bonomi; D D Hurd Journal: Bone Marrow Transplant Date: 1997-02 Impact factor: 5.483
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Authors: Joseph H Antin; Haesook T Kim; Corey Cutler; Vincent T Ho; Stephanie J Lee; David B Miklos; Ephraim P Hochberg; Catherine J Wu; Edwin P Alyea; Robert J Soiffer Journal: Blood Date: 2003-05-01 Impact factor: 22.113
Authors: Paul J Martin; George B McDonald; Jean E Sanders; Claudio Anasetti; Frederick R Appelbaum; H Joachim Deeg; Richard A Nash; Effie W Petersdorf; John A Hansen; Rainer Storb Journal: Biol Blood Marrow Transplant Date: 2004-05 Impact factor: 5.742
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Authors: D Przepiorka; D Weisdorf; P Martin; H G Klingemann; P Beatty; J Hows; E D Thomas Journal: Bone Marrow Transplant Date: 1995-06 Impact factor: 5.483
Authors: V Ratanatharathorn; R A Nash; D Przepiorka; S M Devine; J L Klein; D Weisdorf; J W Fay; A Nademanee; J H Antin; N P Christiansen; R van der Jagt; R H Herzig; M R Litzow; S N Wolff; W L Longo; F B Petersen; C Karanes; B Avalos; R Storb; D N Buell; R M Maher; W E Fitzsimmons; J R Wingard Journal: Blood Date: 1998-10-01 Impact factor: 22.113
Authors: G B McDonald; M S Hinds; L D Fisher; H G Schoch; J L Wolford; M Banaji; B J Hardin; H M Shulman; R A Clift Journal: Ann Intern Med Date: 1993-02-15 Impact factor: 25.391
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