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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-03-0985.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3479-3482
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
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.M. Ferrara
From the Department of Medical Oncology and
Biostatistical Science, Dana-Farber Cancer Institute, Departments of
Medicine and Surgery, Brigham and Women's Hospital, Boston, MA;
Departments of Medicine and Pediatrics, Blood and Marrow Transplant
Program, University of Minnesota, Minneapolis, MN.
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  , and interferon  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.
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