Third-Party FMT Proves Safe For High-Risk Treatment-Naive Lower GI GVHD.

The intestinal microbiome’s imbalance has been linked to acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Earlier research suggests fecal microbiota transplantation (FMT) as an effective treatment for stubborn acute GVHD. This study explored the feasibility and safety of administering third-party FMT orally to treat high-risk treatment-naive lower GI GVHD.

This open-label, single-arm pilot study involved adult allo-HCT recipients with high-risk acute GVHD. Participants either had newly diagnosed high-risk GVHD according to Refined Minnesota Criteria or steroid-resistant GVHD, all with lower GI symptoms. The FMT regimen consisted of a standard dose (15 capsules/day for two days) followed by three maintenance doses (15 capsules/day, weekly). 

For newly diagnosed GVHD cases, FMT was combined with standard systemic corticosteroids. FMT capsules were sourced from a single donor after thorough screening. The study’s primary focus was on the feasibility of using FMT capsules for lower GI acute GVHD. Both donor capsules and participant stool samples underwent metagenomic shotgun sequencing for microbiome analysis. Levels of 3-indoxyl sulfate were also assessed in serial urine samples.

In the study, 10 participants were enrolled, consisting of nine with treatment-naïve GVHD and one with steroid-resistant (SR) GVHD. Nine of them successfully completed all the required doses, thereby meeting the study’s primary endpoint of feasibility. No significant adverse events related to the treatment were observed. Two instances of bacteremia occurred within 28 days post-FMT, but they were unrelated to the treatment. At the 28-day mark, the overall response rate (ORR) was 80% (60% complete response [CR], 20% partial response [PR]). 

All those who responded showed an initial clinical response within the first week. The complete response rate for lower GI issues at day 28 was 70%. These clinical responses have been sustainable, with no recurrence of lower GI GVHD in those achieving a complete response. Among those who responded, the median duration of the response was 152 days, and seven subjects had ongoing GI responses at the time of data cut-off. 

The median follow-up period among survivors was 311 days, ranging from 69 to 443 days. Non-relapse mortality (NRM) and overall survival (OS) at 6 months were 21% and 79%, respectively. Two deaths occurred, both attributed to GVHD in non-responders.

At baseline, all subjects encountered dysbiotic microbiomes characterized by low richness and high abundance of taxa. Responders showed a notable increase in microbial richness. Levels of 3-indoxyl sulfate (3-IS) also rose, corresponding with greater microbial diversity. Microbial community compositions shifted towards the donor’s microbial structure 28 days after FMT but did not achieve high similarity. 

A significant increase in specific bacteria like Alistipes finegoldii, Bacteroides uniformis, and Eggerthella lenta was observed seven days post-FMT among all complete responders, but not in the single non-responder.

Third-party FMT through oral capsules proved feasible and safe for treating high-risk lower GI GVHD. The study revealed high and durable responses. Further research is essential for optimizing interventions that target the microbiome in the treatment of LGI acute GVHD.

Source: https://ebmt2023.abstractserver.com/program/#/details/presentations/1794

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04139577

DeFilipp, Z., Damania, A., Kim, H., El-Jawahri, A., McAfee, S., Bottoms, AJ., Toncheva, V., Smith, M., Dolaher, M., Perry, L., White, M., Diana, B., Connolly, S., Dey, B., Frigault, M., O’Donnell, P., Spitzer, T., Mansour, M., Weber, D., Ajami, N., Jenq, R., Hohmann, E., Chen, Y-B. OS05-03 THIRD-PARTY FECAL MICROBIOTA TRANSPLANTATION FOR THE TREATMENT OF HIGH-RISK TREATMENT-NAIVE ACUTE GRAFT-VERSUS-HOST DISEASE OF THE LOWER GASTROINTESTINAL TRACT.