Tumor necrosis factor-α blockade for the treatment of acute GVHD

Abstract

Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Tumor necrosis factor-α (TNF-α) is implicated in the pathophysiology of GVHD at several steps in the process. Infliximab is a genetically constructed immunoglobulin G1 (IgG1) murine–human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of TNF-α, blocking its interaction with receptors and causing lysis of cells that produce TNF-α. In this study we retrospectively evaluated 134 patients who had steroid-refractory acute GVHD. Of these, 21 who received infliximab as a single agent were analyzed. The overall response rate was 67% (n = 14), and 13 patients (62%) experienced complete response (CR). Five patients (24%) did not respond, and 2 (10%) had progressive GVHD. None had a toxic reaction to infliximab. Ten patients (48%) had 18 fungal infections, including Aspergillus species in 7 and Candida species in 10. Seventeen patients (81%) had bacterial infections, including 32 gram-positive and 8 gram-negative infections. Viral infections, primarily cytomegalovirus reactivation, occurred in 14 patients (67%). The Kaplan-Meier estimate of overall survival was 38%. In conclusion, infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD, particularly with gastrointestinal tract involvement. Survival after steroid-resistant acute GVHD continues to be problematic. The possibility of excessive fungal and other infections must be explored further.