A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation

Abstract

Summary:Interleukin-11 (IL-11) decreases cytokine release and increases survival in murine BMT models. In these systems, it reduces gut permeability, partially polarizes T cells to a Th2 phenotype, down-regulates IL-12, prevents mucositis, and accelerates recovery of oral and bowel mucosa. We conducted a randomized doubleblind pilot study of rhIL-11 administered with cyclosporine/MTX prophylaxis after cytoxan/TBI conditioning and allogeneic stem cell transplantation for hematologic malignancies. Patients received rhIL-11, 50 g/kg subcutaneously daily or placebo in a 3:1 ratio. Treatment was administered prior to the start of conditioning and continued up to 21 days. The study was designed to assess safety with stopping rules for cardiac arrhythmias and mortality. Although projected to accrue 20 patients, only 13 patients (10 IL-11, three placebo) were enrolled because the early stopping rule for mortality was triggered. Of 10 evaluable patients who received IL-11, four died by day 40 and one died on day 85. Deaths were attributable to transplant-related toxicity. One of three placebo recipients died of suicide, the other two are alive. Patients receiving IL-11 had severe fluid retention and early mortality, making it impossible to determine whether IL-11 given in this schedule can reduce the rate of GVHD. Grade B-D acute GVHD occurred in two of eight evaluable patients on IL-11 and one of three patients on placebo. The primary adverse events of the study were severe fluid retention resistant to diuresis (average weight gain 9 ± 4%) and multiorgan failure in five of 10 evaluable patients. The use of IL-11 as GVHD prophylaxis in allogeneic transplantation cannot be recommended as administered in this trial.

Emerging evidence on the pathobiology of mucositis

“…Furthermore, cytokines directed at inhibiting pro-inflammatory cytokines may be useful as interventions for mucositis [56]. For example, IL-11, a cytokine secreted by bone marrow stromal cells, has demonstrated ability to reduce the severity of GI mucositis in an animal model, although this was not seen clinically [57,58]. The putative mechanism of action of IL-11 is partly through its ability to inhibit cytokine release and downregulate inflammatory mediators such as TNF.…”

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients

“…A mouthwash with bovine milk-derived whey growth factors (PV-701) was well tolerated, and as compared to historical controls, the severity as well as the duration of oral mucositis seemed to be decreased in autologous HSCT recipients [83]. With respect to the use of topical EGF, the panel expressed concerns about the potential unfavorable effects of this growth factor on tumor growth [84][85][86], whereas the use of subcutaneous IL-11 was associated with severe side effects and mortality [87]. ATL-104 mouthwash reduced the duration of oral mucositis, whereas its effect on the incidence of mucositis was unclear [88].…”

Mucositis in patients with hematologic malignancies: an overview

“…KGF may be useful for lowering levels of LPS and TNF-α, 80 while cyclosporine, mycophenolate, tacrolimus, anti-CD40 ligand antibodies and sirolimus (rapamycin) block donor Tcell activation and differentiation. 81 Furthermore, daclizumab (IL-2 receptor antagonist) or infliximab (anti-TNF-α antibody), coupled with antifungal therapy, are …”