Long-Term Follow-up of a Randomized Trial Comparing Cyclosporine and Short Course Methotrexate with Cyclosporine and Mycophenolate Mofetil for Graft Versus Host Disease Prophylaxis in Myeloablative HLA-Identical Sibling Hematopoietic Cell Transplantation.
Authors: Hamilton Betty K. , Bolwell Brian J. , Kalaycio Matt , Rybicki Lisa , Hanna Rabi , Sobecks Ronald , Pohlman Brad , Andresen Steven , Dean Robert M , Duong Hien K. , Hill Brian T. , Copelan Edward A. 
Published: October 2019

Abstract
Abstract 3073
The combination of a calcineurin inhibitor and methotrexate (MTX) is currently the gold standard for GVHD prophylaxis. MTX, however, is associated with toxicity including mucositis, delayed engraftment and other organ toxicity. We conducted a randomized trial comparing cyclosporine (CSA) and mycophenolate (MMF) with CSA and MTX for GVHD prophylaxis in recipients of myeloablative allogeneic hematopoietic cell transplants (HCT) with matched sibling donors (Bolwell et al, BMT 2004, 34:621). We showed reduced toxicity without an increased relapse rate in patients treated with MMF instead of MTX. Now, with a median follow up of almost 10 years, we report long-term outcomes of this study.
From May 2001 until February 2003, 40 patients with hematologic malignancies were randomized to receive CSA (300mg/m2) and MMF (500mg three times daily) or CSA and short course MTX (5mg/m2 days 1, 3, 6, 11). Study endpoints included incidence of acute GVHD, severity of mucositis, time to engraftment of neutrophils and platelets and 100 day survival. Baseline variables were compared using the Wilcoxon rank sum tests or Chi square test. Outcomes were compared between MMF and MTX using the Pepe-Mori test. The two treatment arms were similar in patient characteristics such as age, disease, disease status, and CMV status. In total, 21 patients received MMF and 19 patients received MTX. The study was stopped early when an interim analysis demonstrated less mucositis, shorter length of stay and no difference in the incidence of GVHD or relapse with a median of 6 months of follow up. Currently, with a median follow up of 119 months (range 46–129 months) in survivors, there remains no difference in the incidence of or degree of acute (p≥0.35) or chronic GVHD (p≥0.53), overall survival (p=0.84) or relapse (p=0.41). There are 6 long term survivors in the MMF arm and 4 in the MTX arm. Of those that received MMF, 3 have mild chronic GVHD of the skin or upper GI tract and 1 has moderate chronic GVHD involving the skin, fascia, and vulva. Three of those who received MTX have mild chronic GVHD primarily of the skin. Only 3 patients (2 MMF and 1 MTX) remain off of all immunosuppression without evidence of GVHD. Eight patients (38%) died of relapse in the MMF arm versus 7 (37%) in the MTX arm which was also not statistically different (p=0.86). Death from GVHD was similar in both groups.
Results from this updated analysis support our original conclusion that the combination of CSA and MMF results in decreased mucositis and more rapid engraftment compared with CSA and MTX, with no significant difference in GVHD, survival or relapse on long-term follow up. The primary limitation of this trial remains sample size and the ability to detect modest differences in survival. There remains limited data and virtually no long-term data comparing standard MTX based regimens with less toxic prophylaxis in myeloablative allogeneic HCT. Larger prospective studies with long-term follow up comparing GVHD prophylaxis regimens are warranted.

Disclosures:
No relevant conflicts of interest to declare.