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


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.
Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 Magnolia Drive, FOB 3308, Tampa, FL 33612, USA. joseph.pidala@moffitt.org
Joseph
J
Pidala
Jongphil
J
Kim
Heather
H
Jim
Mohamed A
MA
Kharfan-Dabaja
Taiga
T
Nishihori
Hugo F
HF
Fernandez
Marcie
M
Tomblyn
Lia
L
Perez
Janelle
J
Perkins
Mian
M
Xu
William E
WE
Janssen
Anandaraman
A
Veerapathran
Brian C
BC
Betts
Frederick L
FL
Locke
Ernesto
E
Ayala
Teresa
T
Field
Leonel
L
Ochoa
Melissa
M
Alsina
Claudio
C
Anasetti
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000150:complications* / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy; D009367:Neoplasm Staging; D011446:Prospective Studies; D011788:Quality of Life; D020123:Sirolimus / Q000627:therapeutic use*; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate