Targeting Cell Migration to Prevent Graft-Versus-Host Disease: A New Strategy

Acute graft-versus-host disease (GVHD), particularly of the lower gastrointestinal tract, is one of the most severe complications of allogeneic stem cell transplantation. Pharmacological strategies to prevent the development of acute GVHD are predominantly focused on reducing the number of T cells or limiting their function (e.g., by using calcineurin inhibitors, methotrexate, and, more recently, post-transplant cyclophosphamide).¹ 

In a recent multicenter trial, Yi-Bin Chen, MD, and colleagues have proven the efficacy of a different approach. The researchers used vedolizumab, an antibody that blocks the interaction between integrin a4b7 (also known as lymphocyte Peyer’s patch adhesion molecule 1) on leukocytes and the MAdCAM-1 (also known as mucosal addressin cell adhesion molecule 1) present on the surface of intestinal epithelial cells. This humanized monoclonal antibody already has an established role in inflammatory bowel disease and given that its mechanism of action is to disrupt T-cell homing to the gut, it was thought to be a promising strategy for GVHD prevention. Prior to this randomized phase III trial, a phase Ib study involving 24 participants demonstrated promising results: the drug was well-tolerated, with low rates of lower gastrointestinal (GI) GVHD.² 

In the trial, 343 allogeneic transplant recipients were randomized to receive either placebo (n=169) or vedolizumab (n=174). The patients were treated at 95 transplant centers throughout North and South America, Europe, Asia, and Australia. Randomization was stratified for age, human leukocyte antigen match, intensity of treatment regimen, and use of antithymocyte globulin, with the placebo and treatment groups well-balanced for these factors. The majority of patients received GVHD prophylaxis with a calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate.

The treatment schedule involved the administration of seven doses of vedolizumab commencing on the first day after transplantation and then again on days 13, 41, 69, 97, 125, and 153 post-transplantation. The primary endpoint was lower GI acute GVHD (aGVHD)-free survival at day 180 after transplantation. Rates of lower GI aGVHD were comparatively lower in vedolizumab-treated patients than in those receiving placebo (24 vs. 47 patients, respectively, or 14.3% vs 28.5%). The statistical estimate for lower GI aGVHD-free survival was 85.5% among vedolizumab-treated patients and 70.9% in those receiving placebo. Adverse events, including infectious complications, did not appear to be different between groups, nor did relapse at 12 months. Longer-term complications, including chronic GVHD, could not be fully explored.