A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

作者：Pidala Joseph^*; Kim Jongphil; Jim Heather; Kharfan Dabaja Mohamed A; Nishihori Taiga; Fernandez Hugo F; Tomblyn Marcie; Perez Lia; Perkins Janelle; Xu Mian; Janssen William E; Veerapathran Anandaraman; Betts Brian C; Locke Frederick L; Ayala Ernesto; Field Teresa; Ochoa Leonel; Alsina Melissa; Anasetti Claudio

来源：Haematologica-The Hematology Journal, 2012, 97(12): 1882-1889.

DOI：10.3324/haematol.2012.067140

• tacrolimus
• sirolimus
• methotrexate
• combination therapy
• GVHD prophylaxis

Background %26lt;br%26gt;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. %26lt;br%26gt;Design and Methods %26lt;br%26gt;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. %26lt;br%26gt;Results %26lt;br%26gt;Seventy-four patients were randomized 1: 1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients%26apos; 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%26lt;0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 747%) 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. %26lt;br%26gt;Conclusions %26lt;br%26gt;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.

• 出版日期2012-12