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.

Donor interleukin 1 receptor antagonist genotype associated with acute graft‐versus‐host disease in human leucocyte antigen‐matched sibling allogeneic transplants

“…Studies in animal models have assessed the use of IL‐1Ra treatment to ameliorate the effects of GvHD; IL‐1Ra treatment produced a reduction of GvHD mortality, with no impairment in haematopoietic engraftment (McCarthy et al , 1991; Abhyankar et al , 1993). Results of a phase I/II clinical trial with escalating doses of IL‐1Ra in 17 patients with steroid‐resistant GvHD have demonstrated organ‐specific improvement of reduction in acute GvHD grade in 16 of the 17 patients (Antin et al , 1994). However, a recent clinical trial involving IL‐1Ra administration to patients (from d −4 to +10) found no efficacy in the prevention of aGvHD (Antin et al , 1999).…”

“…In vivo data from normal individuals (Hurme & Santtila, 1998) has shown that plasma levels vary in relation to IL‐1Ra genotype. We hypothesize that such genetic variation, which might affect endogenous IL‐1 levels, might influence the response to additional administration of IL‐1Ra, as has recently been studied (Antin et al , 1994, 1999) both as prophylaxis and treatment.…”

Why is graft‐versus‐host disease sometimes associated with leukoderma and fewer melanocytic naevi?

“…9,10 Inhibition of IL-1 activity with IL-1-receptor alpha (IL-1ra) is effective in acute GVHD that failed to respond to conventional treatment and can provide further evidence that IL-1 is a mediator of GVHD. 11 TGF-beta1 levels are also shown to be elevated in chronic GVHD, independent of platelet or WBC counts. 12 In sum, the important roles of IL-6, IL-1, TNF-alpha and TGF-beta in inhibition of melanocyte proliferation and function and the increase of these cytokines in GVHD may explain the negative association between GVHD and melanocytic lesions.…”

Allogeneic Hematopoietic Stem Cell Transplantation

“…An IL-1 receptor antagonist isbeinginvestigatedinrefractoryacute GVHD. 58 Acute GVHD is clinically graded (I-IV) based on the extent and severity of involvement of the skin, liver, and gastrointestinal tract. The risk factors for acute GVHD are given here.…”