Fecal microbiota transplantation combined with ruxolitinib as a salvage treatment for intestinal steroid-refractory acute GVHD

Abstract

Acute graft-versus-host disease (aGVHD), especially intestinal aGVHD, is one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) has been applied to the treatment of intestinal steroid-refractory aGVHD (SR-aGVHD). Ruxolitinib is the first drug recommended for SR-aGVHD. Here, we reported the outcome data from 21 patients who had received the combined treatment of FMT with ruxolitinib as a salvage treatment in intestinal SR-aGVHD after HSCT. The overall response rate on day 28 was 71.4% (95% CI 50.4-92.5%), including 10 patients with complete responses. The durable overall response at day 56 in responders was 80%. GVHD relapse rate was 33.3% in responders. The levels of inflammatory cytokines as well as T cells and NK cells activation declined. The diversity of the intestinal microbiota was improved in responders. Viral reactivations and severe cytopenia were the major adverse events (61.9% and 81% respectively). The estimated 6-month overall survival was 57.1% (95% CI: 35.9-78.3%), while event-free survival was 52.4% (95% CI: 21.7%-64.1%). Collectively, FMT with ruxolitinib could be an effective treatment for intestinal SR-aGVHD after HSCT.Trial registration: ClinicalTrials.gov identifier: NCT03148743.

Keywords: FMT; HSCT; Intestinal GVHD; Ruxolitinib; Steroid-refractory GVHD.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1

Acute GVHD therapy profile and treatment response. A Long-term outcomes of 21 patients with intestinal SR-aGVHD after the initiation of fecal microbiota transplantation combined with ruxolitinib. B The primary endpoint was the overall response (complete response or partial response) on day 28, and the key secondary endpoint was the durable overall response on day 56. C The best response to combination treatment in intestinal SR-aGVHD patients was demonstrated in different target organs. D The overall survival of all patients treated with combination treatment for SR-aGVHD. E The event-free survival of all patients treated with combination treatment for SR-aGVHD. F The cumulative incidence of aGVHD relapse in responsive patients; the competing risks were transplant-related mortality and relapse. G The cumulative incidence of malignancy relapse in all patients; the competing risk was transplant-related mortality. H Comparison of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A levels detected in peripheral blood between baseline and within 3 weeks of the initiation of ruxolitinib treatment. The levels of IL-2 and IL-17A significantly declined. I Relative percentages of T cell subsets were examined before and during the use of ruxolitinib in peripheral blood by flow cytometry. The percentage of activated T cells (CD3+CD69+ cells) cells and NK cells (CD16+CD56+ cells) significantly decreased after the combination treatment. J The composition of the gut microbiota in four selected patients before and after the combination of ruxolitinib and FMT at the genus level. Patients 1 and 2 failed to respond to the treatment, while patients 3 and 4 showed complete responses. K The Shannon index of gut microbiota was measured to demonstrate the diversity of the intestinal microbiota before and after the combination of ruxolitinib and FMT. A restoration of diversity with a higher Shannon index was observed in CRs