title: 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.
abstract: Acute graft-versus-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 interleukin-1 (IL-1), tumor necrosis factor alpha, and interferon gamma 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 IL-1 receptor antagonist (IL-1Ra) 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 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P =.88). There was no difference in hematologic recovery, transplantation-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 transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.
authors.affiliation: Department of Medical Oncology and Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA. jantin@partners.org
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Roberta
authors.initials: R
authors.lastname: Nicklow
authors.forename: Shawn
authors.initials: S
authors.lastname: Clouthier
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Edwin
authors.initials: E
authors.lastname: Alyea
authors.forename: Carol
authors.initials: C
authors.lastname: McGarigle
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Stephen
authors.initials: S
authors.lastname: Sonis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation / Q000401:mortality; D010919:Placebos; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000008:administration & dosage*; D016019:Survival Analysis; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000401:mortality; D017211:Treatment Failure
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D010919:Placebos; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins