Rifaximin for Preventing Acute Graft Versus Host Disease: Impact On Plasma Markers of Inflammation and T Cell Activation.

Translocation of commensal bacteria across the damaged gut mucosa is critical in the pathogenesis of acute graft versus host disease (AGVHD), promoting inflammation that primes donor T cells. Pre-clinical research has demonstrated that mitigating the effects of the gut flora prevents AGVHD, but preserves the graft versus leukemia effect of the transplant. Rifaximin is a very broadly acting, minimally absorbed oral antibiotic, which has been shown to be effective in inflammatory bowel disease. We conducted a pilot trial to test the hypothesis that rifaximin would abrogate systemic inflammation and resultant T cell activation in allogeneic transplant recipients. Twenty adult and pediatric (≥12 years) allogeneic (related or unrelated) blood and marrow transplant recipients with hematological malignancies were enrolled between January 2008 and May 2009. All patients received myeloablative conditioning. Rifaximin, 400 mg bid, was started on day -10 and continued through day 30. Enzyme-linked immunosorbent assays were performed on plasma samples obtained pre-transplant (as a baseline), day 0 (pre-transplant) and day 15 to measure changes in the levels of two markers of inflammation, soluble TNF receptor 1 (sTNFR1) and interleukin 6 (IL-6), and one marker of donor T cell activation, soluble IL-2 receptor (sIL-2R). A historical control group was formed from a previously conducted study (2006-2007) to assess the potential of soluble markers of immune activation to predict AGVHD. Of the 61 patients enrolled in that study, 24 met the criteria for the rifaximin trial and, thus, were selected as controls. There were no significant differences between the treatment and historical control groups in terms of conditioning regimen, the proportion of alternative donors or GVHD prophylaxis. The treatment group, however, was significantly younger (median age; 17.3 years vs. 38.8 years) and included significantly more unrelated cord blood transplant recipients (7 (3 single unit and 4 double unit) vs. 0, p=0.01). The mean percentage of doses of rifaximin that were successfully administered was 86.2%. There were no serious adverse events attributed to rifaximin. The cumulative incidences of grade 2-4 AGVHD, grade 3-4 AGVHD and stage 1-4 gastrointestinal AGVHD in the treatment group did not differ significantly from those of the historical control group (grade 2-4, treatment=69%, control=58%, p=0.63; grade 3-4, treatment=34%, control=22%, p=0.50; gastrointestinal, treatment=58%, control=45%, p=0.58). The median increase from baseline in the IL-6 level at day 0 was significantly lower for the treatment group (table 1). Otherwise, there was no other significant difference in measured biomarker levels. Controlling for age by stratified analysis, and excluding the cord blood transplants did not alter our results. The results of this pilot study demonstrate that administering rifaximin to prevent AGVHD is safe and feasible. Its effect on systemic inflammation, though, appears to be modest and insufficient to mitigate activation of donor T cells. It, therefore, may not be suitable for GVHD prophylaxis.

Salix Pharmaceuticals: Research Funding, investigator initiated clinical trial .

Off Label Use: Rifaximin is an oral non-absorbable antibiotic that is approved for the treatment of travelers' diarrhea. In this study we investigate the use of Rifaximin for prophylaxis of acute graft versus host disease.