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

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThere 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 MethodsWe 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. ResultsSeventy-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. ConclusionsThese 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. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

“…These results are in agreement with a retrospective study in which the incidence of TA-TMA in patients who were given TAC/SIR ± ATG was not significantly different from that in patients who received MTX with TAC or CYA (10.2% vs 4.3%), 23 or with those of a recently randomized phase II trial comparing TAC/SIR with TAC/MTX, 24 although the high incidence of TA-TMA reported in this latter trial (24.3% with TAC/SIR and 18.9% with TAC/MTX) should be noted. 24 Endothelial cells can be activated and damaged by several factors after HSCT.…”

“…These results are in agreement with a retrospective study in which the incidence of TA-TMA in patients who were given TAC/SIR ± ATG was not significantly different from that in patients who received MTX with TAC or CYA (10.2% vs 4.3%), 23 or with those of a recently randomized phase II trial comparing TAC/SIR with TAC/MTX, 24 although the high incidence of TA-TMA reported in this latter trial (24.3% with TAC/SIR and 18.9% with TAC/MTX) should be noted. 24 Endothelial cells can be activated and damaged by several factors after HSCT. 5 As this endothelial cell injury is critical for the development of TA-TMA, 3,5,12,27 it is not surprising that grade III-IV TA-TMA in allogeneic HSCT treated with tacrolimus J Labrador et al acute GVHD was the most important risk factor for TA-TMA in our series.…”

“…[17][18][19]21,22 In a recent phase II multicenter prospective trial conducted by our group, including some of the patients in this study, no differences were observed in the incidence of TA-TMA when TAC/SIR was compared with patients included in a prior prospective trial using CYA-mycophenolate (the overall incidences of TA-TMA were 10% and 6%, respectively). 25 In addition, very few studies 23,24 have evaluated the risk of TA-TMA among patients receiving the TAC/SIR combination in comparison with other TAC-based regimens. To shed further light on this matter, we performed a retrospective analysis in 102 allogeneic HSCT recipients who consecutively received TAC/SIR (n ¼ 68) or TAC/MTX ± ATG (n ¼ 34) for GVHD prophylaxis.…”

“…In fact, two recent studies suggest that TA-TMA incidence does not differ significantly between patients who received TAC/SIR and those who received TAC/MTX for GVHD prophylaxis. 23,24 However, these two studies were not focused on TA-TMA and only described the incidence of TA-TMA without analyzing risk factors for TA-TMA, management or clinical outcome.…”

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

“…Overall, these findings highlight the close relationship between graft-versus-host reactions and the potential benefit of the immune-mediated GVL effect in the RIC allo-SCT setting, but also underline the need for improving the prevention and treatment of severe GVHD in patients receiving RIC allo-SCT, perhaps through promoting regulatory T cells. 33,34 …”