Dataset Information

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

ABSTRACT:

Background

Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD.

Methods

This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980).

Findings

Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters.

Interpretation

Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation.

Funding

MaaT Pharma.

SUBMITTER: Malard F

PROVIDER: S-EPMC10466244 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

Malard Florent F Loschi Michael M Huynh Anne A Cluzeau Thomas T Guenounou Sarah S Legrand Faezeh F Magro Leonardo L Orvain Corentin C Charbonnier Amandine A Panz-Klapuch Marta M Desmier Deborah D Mear Jean-Baptiste JB Cornillon Jérôme J Robin Christine C Daguindau Etienne E Bilger Karin K Vehreschild Maria J G T MJGT Chevallier Patrice P Labussière-Wallet Hélène H Mediavilla Clémence C Couturier Marie-Anne MA Bulabois Claude-Eric CE Camus Vincent V Chantepie Sylvain S Ceballos Patrice P Gaugler Béatrice B Holler Ernst E Doré Joël J Prestat Emmanuel E Gasc Cyrielle C Plantamura Emilie E Mohty Mohamad M

EClinicalMedicine 20230726

<h4>Background</h4>Failure of gastrointestinal acute graft-<i>versus</i>-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD.<h4>Methods</h4>This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, ...[more]

PMID: 37654670

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Project description:ImportanceRuxolitinib, a selective inhibitor of the Janus kinases 1/2 signaling pathway, has shown a significant response in steroid-refractory chronic graft-vs-host disease (SR-cGVHD), a major cause of morbidity and mortality in individuals who have undergone allogeneic hematopoietic stem cell transplantation (HSCT).ObjectivesTo investigate the clinical response to ruxolitinib in patients with SR-cGVHD after allogeneic HSCT and to evaluate its safety profile during the treatment course.Design, setting, and participantsThis single-center case series included 41 consecutive patients who were treated with ruxolitinib for SR-cGVHD after allogeneic HSCT between August 2017 and December 2019. Data were collected from each patient's medical record at the First Affiliated Hospital of Zhejiang University School of Medicine. Data analysis was conducted from March to May 2020.ExposureRuxolitinib.Main outcomes and measuresTreatment responses, factors associated with response, and adverse effects during ruxolitinib administration.FindingsOverall, 41 patients (median [range] age, 31 [17-56] years; 14 [34.1%] women) were treated with ruxolitinib and included in this study. A total of 15 patients (36.6%) had a complete remission, and 14 (34.1%) had a partial remission, with an overall response rate of 70.7% (29 patients; 95% CI, 56.2%-85.3%). Lung involvement (odds ratio, 0.112; 95% CI, 0.020-0.639; P = .01) and matched related donors (odds ratio, 0.149; 95% CI, 0.022-0.981; P = .048) were associated with less favorable treatment response. Major adverse events associated with ruxolitinib were cytopenias and infectious complications. The median (range) follow-up for this cohort was 14.9 (1.4-32.5) months. Prolonged survival was observed in patients with a male donor (P = .006), complete remission before transplantation (P = .02), baseline moderate cGVHD (P = .02), and skin cGVHD (P = .001).Conclusions and relevanceIn this small, single-site case series, ruxolitinib demonstrated a significant response in heavily pretreated patients with SR-cGVHD and a reasonably well-tolerated safety profile. The results add to the body of literature suggesting ruxolitinib as a promising treatment option in SR-cGVHD.

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Dataset Information

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

Background

Methods

Findings

Interpretation

Funding

Publications

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

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