Gvhd Prophylaxis With Mycophenolate Mofetil and Calcineurin Inhibitor In Allogeneic Hematopoietic Cell Transplantation From HLA-Matched Siblings Or 7–8/8 HLA-Matched Unrelated Volunteer Donors: A Japanese, Multicenter, Phase II Trial
Authors: Nakane Takahiko , Nakamae Hirohisa , Kurosawa Saiko , Okamura Atsuo , Hidaka Michihiro , Yamashita Takuya , Kohno Akio , Saito Takeshi , Aoyama Yasutaka , Hatanaka Kazuo , Katayama Yoshio , Yakushijin Kimikazu , Matsui Toshimitsu , Takami Akiyoshi , Yamaguchi Takuhiro , Hino Masayuki , Fukuda Takahiro 
Published: October 2019

Background
In allogeneic hematopoietic cell transplantation (allo-HCT), graft versus host disease (GVHD) remains a major cause of non-relapse mortality. Although methotrexate (MTX) combined with a calcineurin inhibitor (CI) is the current standard for GVHD prophylaxis, several recent studies have also reported the utility of mycophenolate mofetil (MMF) combined with CI, in terms of earlier hematological recovery and less mucositis with a similar incidence of GVHD. In Asian populations, however, there have been few prospective studies with MMF and CI as GVHD prophylaxis, and we thus carried out this Japanese multicenter prospective trial of allo-HCT with MMF and CI.

Methods
From April 2010 to September 2012, we prospectively registered patients with hematological malignancy who received their first T cell-replete allo-HCT from HLA-matched related donors (MRD group) or 8/8 or 7/8 matched unrelated volunteer donors (URD group). The primary endpoint was the cumulative incidence of grade II to IV acute GVHD at day 100. The expected and threshold incidences were 30% and 60% in MRD group, and 40% and 65% in URD group, respectively. With a statistical power of 80% and a one-sided, type I error of 5%, the each number of eligible patients required for these studies was calculated to be 17 and 25 in MRD and URD groups, respectively, and the each maximal number of registerable patients was set to be 30 and 45, respectively. As of June 2013, the primary endpoint for evaluation of all patients has been attained.
As GVHD prophylaxis, MMF (500mg three times/day) and cyclosporine were used in MRD group, and MMF (1000mg three times/day) and tacrolimus were used in URD group. The MMF dose was tapered according to plan, starting on day 30–40 with cessation by day 100. The cyclosporine and tacrolimus were continued until days 60 and 100 and then tapered and stopped on days 150 and 180, respectively, unless GVHD developed.

Results
There were 20 patients (median age:47.5) in the MRD group and 31 patients (median age:45) in the URD group (HLA 8/8 matches:23, HLA 7/8 matches:8). In the MRD and URD groups, acute leukemia was present in 90% and 65%, and standard risk disease comprised 90% and 65%, respectively. In the MRD and URD groups, 75% (15/20) and 55% (17/31) received standard myeloablative conditioning (BuCy or CyTBI), and the remainder received reduced intensity conditioning (FluBu±TBI or FluMel±TBI). In the MRD group, peripheral blood stem cells and bone marrow were used in seven and 13 patients, respectively. In the URD group, all 31 patients received allo-HCT from a bone marrow donor.
The cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 45% (90% confidence interval [CI]:26.9-63.1) and 15% in the MRD group, respectively. The primary endpoint was not achieved in the MRD group, although the dose of MMF in the MRD group (1.5g/day) was lower than the URD group (3g/day). In contrast, the cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 19.4% (90%CI:8.0-30.8) and 6.5% in the URD group, respectively. The primary endpoint was achieved in the setting of allo-HCT form URD.
In the MRD and URD groups, cumulative incidences of neutrophil engraftment were 94.7% and 96.8%, and the median times to neutrophil engraftment were 12 days (range:10–13) and 13 days (range:8–26), respectively. Although one patient in the MRD group and 3 patients in the URD group experienced secondary graft failure, all of them recovered with dose adjustment of myelosuppressive drugs including MMF. Grade 3 stomatitis occurred only in 10% of the MRD group and 13% of the URD group, and there was no grade 4 stomatitis in either group. The cumulative incidences of late onset acute GVHD and chronic GVHD at one year were 12.5% and 37.5% in the MRD group, and 7.4% and 29.6% in URD group, respectively. With a median follow-up of 589 days in surviving patients, 1-year overall survival was 89.1% in the MRD group and 86.0% in the URD group. The 1-year cumulative incidences of non-relapse mortality and relapse were 10.9% and 11.9% in the MRD group, and 6.5% and 31.6% in URD group, respectively.

Conclusion
Our study confirmed that GVHD prophylaxis with MMF plus CI was associated with earlier hematological recovery and less mucositis. The use of MMF (3g/day) plus tacrolimus was a feasible and effective option as GVHD prevention in allo-HCT from 7/8 or 8/8 HLA-matched URD. Further studies will be needed to clarify the optimal dose of MMF in allo-HCT from MRD.

Disclosures:
Nakane: Chugai Pharma: Travel/accommodations/meeting expenses Other. Off Label Use: CellCept (mycophenolate mofetil). This drug was a primary drug to be evaluated for GVHD prophylaxis in this study. Nakamae:Chugai Pharma: Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.