Fecal Microbiota Transplantation for Grade IV Steroid Refractory GI-GvHD: Interim Results a Non-randomized, Open-label, Phase 1 Clinical Study

Abstract

Background: Gastrointestinal (GI) tract graft-vs-host disease (GvHD) is a major cause of post-allo-HCT morbidity and mortality. Patients with steroid-refractory GI-GvHD face a poor prognosis and limited therapeutic options. Here, we report an interim analysis on the safety and efficacy of fecal microbiota transplantation (FMT) in treating steroid-refractory GI-GvHD.Methods: We did a non-randomized, open-label, phase 1 clinical study on patients with grade IV steroid-refractory GI-GvHD. FMT efficacy was evaluated using indexes of abdominal pain, diarrhea and bloody purulent stool at 14 and 21 days after the diagnosis of steroid-refractory GI-GvHD. The primary outcomes referred to clinical complete remission or partial remission. Secondary outcomes referred to EFS (event free survival) and OS (overall survival) at Day 90 and the end of the research. Safety was evaluated according to adverse events during FMT and the whole follow-up period. The study was registered with ClinicalTrials.gov as #NCT03148743.Results: A total of 56 patients with steroid-refractory GI-GvHD were enrolled. Of them, 24 patients with grade IV steroid-refractory GI-GvHD were assigned to FMT and 18 to the control group. The characteristics of the two group patients at baseline were similar. At Day 14 after FMT, 13 (54.2%) patients in FMT group and none (0%) of 18 control group achieved clinical remission (p<0.05), while 20(83%) patients in FMT group and 7(39%) in control group showed effective response (clinical remission+partial remission) (RR 7.86, 95% CI 1.88–32.9; p=0.005). At Day 21, the clinical remission was significantly greater in FMT group than in control group (14 (58.3%) of 24 vs 3(16%) of 18; RR 6.0, 95% CI 1.22–29.45; p=0.027). Within a follow up of 90 days, the FMT group showed better OS (HR, 7.0; 95% CI, 1.53-32.08; p=0.012). At the end of the research, the median survival time was >600 days in FMT group and 107 days in control group (HR, 4.73; 95% CI, 1.58-14.14; p=0.005). Both the EFS (HR, 0.24; 95% CI, 0.06-0.95; p=0.055) and OS (HR, 5.97; 95% CI, 1.52-23.43; p=0.01) kept increasing during the follow-up in FMT group. Overall, the mortality rate was lower in FMT group (HR, 5.97; 95% CI, 1.52-23.43; p=0.01). No difference was observed in the occurrence of other side effects, such as hemorrhagic cystitis, infection of bacteria & fungi, CMV&EBV, septicemia, TMA, cardiac events, thrombocytopenia and epilepsy.Conclusions: The diversity of intestinal microbiota can be affected by allo-HSCT. FMT is effective and safe in treating grade IV steroid refractory GI–GvHD.