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.

Trial registration: ClinicalTrials.gov NCT00803010.

Figure 1.

Cumulative incidence of grade II-IV acute GVHD over 100 days following HCT.

Figure 2.

Cumulative incidence of (A) any grade chronic GVHD and (B) moderate to severe chronic GVHD according to NIH criteria.

Figure 3.

Proportion of Treg (% Treg/total CD4⁺ cells) compared between patients in the SIR/TAC and MTX/TAC groups at baseline, and on days 0, 30, 90, and 360 following HCT. Day 30 (P<0.0001), day 90 (P=0.0009), day 180 (P=0.07), otherwise, P=NS. (box and whisker plot: box margins = interquartile range, line = median value, whiskers = 95% confidence interval, dots = outliers).