Strategies for Graft Versus Host Disease Prophylaxis after Reduced-Intensity Conditioning Transplantation: Combination of Sirolimus Plus Tacrolimus Allows to Obtain the Best Outcome

INTRODUCTION AND AIMS: Different strategies for GVHD prophylaxis have been evaluated in the last decade in different clinical trials in the setting of reduced-intensity conditioning allogeneic transplantation (RIC-AlloSCT) within the Grupo Español de Trasplante Hematopoyetico (GETH). Following multicenter clinical trials, some of these strategies have been adopted as standard practice in some centers. With this background, we analyzed in a multicenter retrospective study the outcomes of the different strategies used as GVHD prophylaxis in the setting of RIC-AlloSCT.

MATHERIAL AND METHODS: A total of 558 patients from 6 Spanish centers underwent to RIC-AlloSCT from January 2007 to December 2013. Conditioning chemotherapy consisted of fludarabine plus melphalan or busulphan (for lymphoid and myeloid malignancies, respectively). Regarding GHVD prophylaxis, group 1 (n:170) received Sir-TKR, (plus ATG, n: 15); group 2 (n:161) a calcineurin-inhibitor (CNI)+MTX (plus ATG, n:23) and group 3 (n:217) received CNI+Mophetil Micophenolate (MMF), (plus ATG, n:28). Patients who received ATG, regardless the type of associated immunosuppression, were analyzed separately as well as within each subgroup. There were no statistically significant differences regarding transplant characteristics except for a higher frequency of unrelated donor in Sir-TKR subgroup and more frequent non-remission status of basal disease in CNI-MMF subgroup.

RESULTS: After a median follow-up of 31 months, (IC-95%: 27-34), the 3-year cumulative incidence of relapse was significantly higher with CNI-MTX (37.6%) as compared to the other two strategies (24,8% for Sir-TKR and 26,1% for CNI-MMF, p=003) whereas transplant-related mortality (TRM) was significantly higher within patients receiving CNI-MMF (27% at 1 year / 37,9% at 3 years) as compared to Sir-TKR (14,4% at 1 year / 20,2% at 3 years) and CNI-MTX (19,7% at 1 year / 25,6% at 3 years, p=0.01). Overall survival (OS)was higher in Sir-TKR subgroup (78% at 1 year/68% at 3 years) as compared to the other 2 groups (64% at 1 year / 47% at 3 years for patients receiving CNI-MTX and 57% at 1 year / 45% at 3 years for those receiving CNI-MMF, p:0.01). The addition of ATG as prophylaxis did not significantly modified the prognosis for any of the subgroups. In multivariate analysis, significant factors for OS were: chronic GVHD [HR=0,68 (95%CI=0,47-0,98), p=0,03], acute GVHD [HR=2,03 (95%CI=1,54-2,67), p< 0.001), age older than 50 years [HR=1,47 (95%CI=1,07-2), p=0,01], disease status at transplant [HR=1,36 (95% CI=1,02-1,82), p=0,03 in case of non-remission disease) and GVHD prophylaxis other than Sir-TKR [HR=1,85 (95%CI=1,19-2-87),p=0,006 for CNI-MTX and HR=1,94 (95%CI=1,32-2,86),p=0,0006 for CNI-MMF].

CONCLUSION: The present study shows a favorable impact of Sir-TKR in outcome as compared with other strategies in the setting of RIC-AlloSCT, with OS up to 68% at 3 years.