Infliximab for the Treatment of Chronic Graft Versus Host Disease.

Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic stem cell transplantation. Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of GVHD. Infliximab is a murine-human chimeric monoclonal antibody that binds TNF-α, preventing interaction with its receptor and its ability to mediate the development of GVHD. Infliximab is active in the treatment of steroid refractory acute GVHD, particularly for patients with GI GVHD (Couriel et al Blood. 2004 Aug 1;104(3):649–54).We performed a retrospective analysis to evaluate the activity of infliximab in 22 patients with AML/MDS (n=5), lymphoma (n=8), ALL (n=3), and others (n=6) with steroid refractory chronic extensive GVHD. Response was measured according to standard response criteria (Pavletic et al. Biology of Blood and Marrow Transplantation 2006 Mar;12(3):252–66). The median age of the patients was 50 years (range 20 – 64). Fourteen (64%) patients had matched sibling donors, 8 (36%) had matched unrelated donors, 9 (41%) underwent nonmyeloablative conditioning, one patient had a bone marrow transplant and the other 21 patients had peripheral blood stem cell transplants. All patients were given standard doses of tacrolimus or cyclosporine for GVHD prophylaxis with either short course methotrexate or mycophenolate mofetil. All patients were treated with systemic steroids at the onset of GVHD. Fifty percent of the patients initially presented with acute GVHD that progressed to chronic extensive GVHD. The other half presented with late onset or de novo chronic extensive GVHD. Nineteen had skin involvement (86%), 15 (68%) had gastrointestinal involvement, and 10 (45%) had liver involvement at the time of treatment with infliximab. All patients were considered refractory to tacrolimus/cyclosporine and systemic steroids, had intolerable side effects from steroids or could not be successfully tapered off steroids prior to infliximab administration. Median time from transplant to infliximab administration was 337days (range 122 to 932 days). The patients received a median of 4 weekly courses (range 1–20 courses) of infliximab at 10mg/kg. The overall response rate was 64% (n=14); 11 (50%) experienced a complete response (CR); 3 (14%) experienced a partial response (PR); 8 (36%) had progressive GVHD. The response rate for skin GVHD was 68%, GI was 60% and liver was 50%. One patient suffered an acute infusion reaction after the first infliximab dose and had no further drug administered. Median survival of all patients following initiation of infliximab was 223 days. Median survival of all responders was 625 days after infliximab, while median survival of the non-responders was 70 days after infliximab. Six patients remain alive at a median follow-up of 55 months (27%). Three of six survivors are on minimal immunosuppression with limited cGVHD and three are off all immunosuppression with no evidence of cGVHD. Of the patients who died, 7 (32%) died from infectious complications, 5 (23%) died from complications of progressive cGVHD, 4 (18%) died from hemorrhagic or embolic strokes, 2 died from complications of post-transplant lymphoproliferative disorder (PTLD), and one patient from relapse. In conclusion, infliximab has activity for cGVHD. Prospective trials investigating the activity of infliximab, the infectious risks, predictive measures responding patients and optimal timing of administration are needed.