title: Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease.
abstract: Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL-1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: J H
authors.initials: JH
authors.lastname: Antin
authors.forename: H J
authors.initials: HJ
authors.lastname: Weinstein
authors.forename: E C
authors.initials: EC
authors.lastname: Guinan
authors.forename: P
authors.initials: P
authors.lastname: McCarthy
authors.forename: B E
authors.initials: BE
authors.lastname: Bierer
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
authors.forename: S K
authors.initials: SK
authors.lastname: Parsons
authors.forename: K K
authors.initials: KK
authors.lastname: Ballen
authors.forename: I J
authors.initials: IJ
authors.lastname: Rimm
authors.forename: G
authors.initials: G
authors.lastname: Falzarano
mesh_terms: D000328:Adult; D000741:Anemia, Aplastic / Q000628:therapy; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004351:Drug Resistance; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007938:Leukemia / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012795:Sialoglycoproteins / Q000627:therapeutic use*; D013256:Steroids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D013256:Steroids