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

Abstract

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: Joseph Pidala, Jongphil Kim, Heather Jim, Mohamed A Kharfan-Dabaja, Taiga Nishihori, Hugo F Fernandez, Marcie Tomblyn, Lia Perez, Janelle Perkins, Mian Xu, William E Janssen, Anandaraman Veerapathran, Brian C Betts, Frederick L Locke, Ernesto Ayala, Teresa Field, Leonel Ochoa, Melissa Alsina, Claudio Anasetti
• Journal: Haematologica (Haematologica) Vol. 97 Issue 12 Pg. 1882-9 (Dec 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22689677 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Sirolimus
• Tacrolimus
• Methotrexate

Topics

• Adult
• Aged
• Case-Control Studies
• Combined Modality Therapy
• Drug Therapy, Combination
• Female
• Follow-Up Studies
• Graft vs Host Disease (etiology, prevention & control)
• Hematologic Neoplasms (complications, mortality, therapy)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Immunosuppressive Agents (therapeutic use)
• Male
• Methotrexate (therapeutic use)
• Middle Aged
• Neoplasm Recurrence, Local (diagnosis, mortality, therapy)
• Neoplasm Staging
• Prospective Studies
• Quality of Life
• Sirolimus (therapeutic use)
• Survival Rate
• T-Lymphocytes, Regulatory (immunology, pathology)
• Tacrolimus (therapeutic use)
• Transplantation, Homologous
• Treatment Outcome
• Young Adult