Addition of Mycophenolate Mofetil to Methotrexate and Tacrolimus Does Not Improve Gvhd Outcomes in Reduced Intensity Allogeneic Hematopoietic Cell Transplantation
Authors: Han Se young , Bhamidipati Pavan Kumar , Vu Khoan , Dipersio John F , Gao Feng , Pusic Iskra , Uy Geoffrey L. , Westervelt Peter , Vij Ravi , Schroeder Mark A. , Abboud Camille N. , Stockerl-Goldstein Keith , Cashen Amanda F. , Fehniger Todd A , Romee Rizwan 
Published: October 2019

Abstract
Introduction: The introduction of reduced intensity conditioning (RIC) regimens, associated with less NRM, has significantly broadened transplant eligibility to older patients. However, graft-versus-host disease (GVHD) continues to be a major problem, even with RIC allo-HCTs. At our institution, we have been routinely adding mycophenolate mofetil (MMF) to the standard methotrexate (MTX) plus Tacrolimus combination in the majority of RIC allo-HCT recipients from unrelated donors. However, there is a paucity of data on whether this approach further decreases GVHD rates without increasing NRM and risk of relapse. To answer these questions, we retrospectively analyzed data from 177 patients who received MMF, MTX and Tacrolimus (MMF + Tac/MTX) as part of their GVHD prophylaxis and compared their outcomes to those of 117 patients who received MTX and Tacrolimus alone (Tac/MTX).
Patients and methods: The study included a total of 294 consecutive patients who underwent RIC allo-HCT at Washington University Medical Center between January 2006 and December 2013. The data was analyzed for patients who received GVHD prophylaxis with either tacrolimus/methotrexate (Tac/MTX) or tacrolimus/mycophenolate mofetil/methotrexate (MMF+Tac/MTX). Cumulative incidence of relapse was estimated treating death in remission as competing risk event. Cumulative incidence of NRM was calculated considering death in relapse as competing risk event. Univariate analysis was performed to evaluate variables, and multivariate Cox models with a backward selection procedure were done to assess whether GVHD prophylaxis was an independent predictor after adjusting other factors significant in the univariate analysis. All analyses were two-sided, and significance was set at a p-value of 0.05. Statistical analyses were performed using library cmprsk in statistical package R for competing risk analysis and SAS 9.4 (SAS Institutes, Cary, NC) for all other analyses.
Results: 177 patients (60.2%) received MMF+Tac/MTX whereas 117 patients (39.8%) received Tac/MTX. Median age was 61 years in the MMF+Tac/MTX group and 58 years in the Tac/MTX group, and the most common diagnosis was AML(31%) followed by NHL (26%) and MDS (19%) in the MMF+Tac/MTX group vs. AML (45%) followed by MDS (14%) and NHL (13%) in the Tac/MTX group. There were more transplants from unrelated and mismatched donors, higher intermediate ASMBT RFI risk group patients and more frequent use of conditioning with Flu/Bu/Thymo regimen in the MMF+Tac/MTX cohort. In particular 160 (90.4%) patients in MMF+Tac/MTX group received thymoglobulin as part of their conditioning, compared to 64 (54.7%) patients in the Tac/MTX group (p < 0.001).
The cumulative incidence of grade 2-4 aGVHD at day 100 was 31.0% in the MMF+Tac/MTX group vs. 36.2% in the Tac/MTX group (p=0.191) while as grade 3-4 aGVHD at day 100 and 1 year were 16.8% and 25.9% in the Tac/MTX group compared to 8.0% and 12.4% in the MMF+Tac/MTX group, respectively (p=0.010). However, after adjusting for the thymoglobin use there was no significant difference in the incidence of grade 3-4 aGVHD in these two groups (p=0.129). To eliminate the confounding effect of thymoglobulin, we performed a subgroup analysis of patients without thymoglobulin. Given the small number of samples (n=17 in MMF+Tac/MTX and n=53 in Tac/MTX), propensity score matching was used and the results again showed no significant difference in severe aGVHD between two groups (p=0.219).
The incidence of cGVHD at 1 year was 15.3% and 21.6% in MMF+Tac/MTX and Tac/MTX, respectively (p=0.645). Although patients in the MMF+Tac/MTX group had more unfavorable disease risk, the cumulative incidence of relapse at 3 years was not significantly different: 40.8% in the MMF+Tac/MTX group and 39.8% in the Tac/MTX group (p=0.941). 5-year OS was 33.7% in the MMF+Tac/MTX group, compared to 35.1% in the Tac/MTX group (p=0.769).
Conclusion: Here we report transplant outcomes of RIC allo-HCT patients who received MMF in addition to Tac/MTX for GVHD prophylaxis. Interestingly we did not see any increase in NRM or relapse rates with additional immune-suppression from adding MMF in these patients. However, addition of MMF to the Tac/MTX regimen did not result in any significant improvement in acute or chronic GVHD outcomes in our patients. Based on these results we do not recommend adding MMF to Tac/MTX regimen for GVHD prophylaxis in RIC allo-HCT patients.

Disclosures
Uy: Novartis: Research Funding. Schroeder:Incyte: Consultancy; Celgene: Other: Azacitidine provided for this trial by Celgene. Abboud:Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy. Cashen:Celgene: Speakers Bureau.