Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Joseph H. Antin; Howard J. Weinstein; Eva C. Guinan; Philip McCarthy; Barbara E. Bierer; D. Gary Gilliland; Susan K. Parsons; Karen K. Ballen; Llonna J. Rimm; Giorgio Falzarano; Duane C. Bloedow; Lori Abate; Mel Lebsack; Steven J. Burakoff; James L.M. Ferrara

doi:10.1182/blood.v84.4.1342.bloodjournal8441342

Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Joseph H. Antin, Howard J. Weinstein, Eva C. Guinan, Philip McCarthy, Barbara E. Bierer, D. Gary Gilliland, Susan K. Parsons, Karen K. Ballen, Llonna J. Rimm, Giorgio Falzarano, Duane C. Bloedow, Lori Abate, Mel Lebsack, Steven J. Burakoff, James L.M. Ferrara

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

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-α (TNF-α) 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.

Original language	English
Pages (from-to)	1342-1348
Number of pages	7
Journal	Blood
Volume	84
Issue number	4
DOIs	https://doi.org/10.1182/blood.v84.4.1342.bloodjournal8441342
State	Published - 15 Aug 1994

Access to Document

10.1182/blood.v84.4.1342.bloodjournal8441342

Cite this

Antin, J. H., Weinstein, H. J., Guinan, E. C., McCarthy, P., Bierer, B. E., Gilliland, D. G., Parsons, S. K., Ballen, K. K., Rimm, L. J., Falzarano, G., Bloedow, D. C., Abate, L., Lebsack, M., Burakoff, S. J., & Ferrara, J. L. M. (1994). Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease. Blood, 84(4), 1342-1348. https://doi.org/10.1182/blood.v84.4.1342.bloodjournal8441342

@article{7f730f38ec6f42749f7a24d57f07cc14,

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-α (TNF-α) 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.",

author = "Antin, {Joseph H.} and Weinstein, {Howard J.} and Guinan, {Eva C.} and Philip McCarthy and Bierer, {Barbara E.} and Gilliland, {D. Gary} and Parsons, {Susan K.} and Ballen, {Karen K.} and Rimm, {Llonna J.} and Giorgio Falzarano and Bloedow, {Duane C.} and Lori Abate and Mel Lebsack and Burakoff, {Steven J.} and Ferrara, {James L.M.}",

year = "1994",

month = aug,

day = "15",

doi = "10.1182/blood.v84.4.1342.bloodjournal8441342",

language = "English",

volume = "84",

pages = "1342--1348",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier BV",

number = "4",

}

Antin, JH, Weinstein, HJ, Guinan, EC, McCarthy, P, Bierer, BE, Gilliland, DG, Parsons, SK, Ballen, KK, Rimm, LJ, Falzarano, G, Bloedow, DC, Abate, L, Lebsack, M, Burakoff, SJ & Ferrara, JLM 1994, 'Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease', Blood, vol. 84, no. 4, pp. 1342-1348. https://doi.org/10.1182/blood.v84.4.1342.bloodjournal8441342

TY - JOUR

T1 - Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

AU - Antin, Joseph H.

AU - Weinstein, Howard J.

AU - Guinan, Eva C.

AU - McCarthy, Philip

AU - Bierer, Barbara E.

AU - Gilliland, D. Gary

AU - Parsons, Susan K.

AU - Ballen, Karen K.

AU - Rimm, Llonna J.

AU - Falzarano, Giorgio

AU - Bloedow, Duane C.

AU - Abate, Lori

AU - Lebsack, Mel

AU - Burakoff, Steven J.

AU - Ferrara, James L.M.

PY - 1994/8/15

Y1 - 1994/8/15

N2 - 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-α (TNF-α) 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.

AB - 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-α (TNF-α) 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.

UR - http://www.scopus.com/inward/record.url?scp=0028086480&partnerID=8YFLogxK

U2 - 10.1182/blood.v84.4.1342.bloodjournal8441342

DO - 10.1182/blood.v84.4.1342.bloodjournal8441342

M3 - Article

C2 - 8049450

AN - SCOPUS:0028086480

SN - 0006-4971

VL - 84

SP - 1342

EP - 1348

JO - Blood

JF - Blood

IS - 4

ER -

Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Abstract

Access to Document

Fingerprint

Cite this