Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation

Abstract

Summary:We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days posttransplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P Ͻ 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P = 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLAmatched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors. Bone Marrow Transplantation (2001) 28, 181-185.

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…Unfortunately, only one phase 3 study has been conducted in Japan [28]. A prospective, randomized study of GVHD treatment is extremely difficult, partly due to the small number of eligible patients in each transplant institute, the need for prompt initiation of therapy, and, maybe in Japan, the thought of leaving the question of GVHD to other countries.…”

“…Hiraoka et al [28] conducted a phase 3 study comparing Tac with CsA as GVHD prophylaxis in BMT from related and unrelated donors. The cumulative incidence of grade II-IV acute GVHD was significantly lower in the Tac-based regimen than in the CsA-based regimen, but there was no difference in survival rates between the two groups, presumably due to the lack of a graft-versus-leukemia effect.…”

Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

“…18 Moreover, a combination of tacrolimus and MTX was tested in three randomized clinical trials, showing a significantly lower incidence of aGvHD as compared with the combination of CsA and MTX in both matched related and unrelated transplantations. [24][25][26] In this report, we show for the first time in the context of NM conditioning that tacrolimus in combination with MMF is an efficient and well-tolerated GvHD prophylaxis in patients receiving an unrelated donor graft. The only side effect, which was attributable to tacrolimus, was nephrotoxicity.…”

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

“…There have been substantial improvements in HLA typing over the period of 1997-2008, with more accuracy in defining HLA haplotypes at highresolution. 26,27 In addition to high-resolution donor-recipient HLA matching, the more frequent use of tacrolimus, [28][29][30] the prompt initiation of treatment after a more thorough examination to diagnose GVHD, 31 and supportive care and nutritional management 32 may have contributed to the reduced risk of GVHD-related mortality as did in allo-HCT in remission. Alternatively, the unique HLA epidemiological genetics of Japanese patients may have affected the results.…”