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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-03-0985.
Submitted April 1, 2002
Accepted May 21, 2002
Interleukin-1 Blockade Does Not Prevent Acute Graft Versus Host Disease. Results of a Randomized, Double Blind, Placebo-Controlled Trial of Interleukin 1 Receptor Antagonist in Allogeneic Bone Marrow Transplantation
Joseph H Antin*, Daniel Weisdorf, Donna Neuberg, Roberta Nicklow, Shawn Clouthier, Stephanie J Lee, Edwin Alyea, Carol McGarigle, Bruce R Blazar, Stephen Sonis, Robert J Soiffer, and James L Ferrara
Department of Adult Oncology, Pediatric Oncology, and Biostatistical Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
* Corresponding author; email: jantin{at}partners.org.
Acute graft-v-host disease (GVHD) is thought to derive from direct T cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as IL-1, TNF , and INF may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double blind, placebo-controlled randomized trial of recombinant human interleukin-1 receptor antagonist in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day -4 to day +10. Randomization was stratified according to GVHD risk. The two groups were well matched for pre-treatment characteristics. Moderate to severe GVHD (Grade B-D) developed in 57/94 (61%) patients receiving IL-1RA and in 51/86 (59%) patients on placebo (p=0.88). There was no difference in hematologic recovery, transplant-related toxicity, event-free survival or overall survival. We conclude that blockade of IL-1 using IL-1RA during conditioning and 10 days immediately after transplant is not sufficient to reduce GVHD, toxicity, or improve survival.
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