The Odyssee Study: Prevention of Dysbiosis Complications with Autologous Fecal Microbiota Transfer (FMT) in Acute Myeloid Leukemia (AML) Patients Undergoing Intensive Treatment: Results of a Prospective Multicenter Trial

Abstract

Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p<0.001). Ten days after FMT administration (S3), the Simpson index returned to its initial baseline level (0.50 to 0.86; p<0.001). In addition to variations of the diversity, we demonstrated using the Bray-Curtis dissimilarity index (BC) a profound shift in the microbial communities following IC (mean BC S1-S2: 0.76) and the restoration of the initial microbial profile after FMT (mean BC S1-S3: 0.40). Moreover, IC and associated antibiotic treatments induced a significant increase in the mean number of readouts mapped against antibioresistance genes at S2 (167546 to 371466 reads, p<0.01) that reflect ARGC. Then, a significant reduction of 43% of the mean number of reads mapped was observed at S3 after FMT (211128 reads, p<0.001). No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT. Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days). Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

A Guide for Ex Vivo Handling and Storage of Stool Samples Intended for Fecal Microbiota Transplantation

“…After air removal, the probe is installed, and instillation can begin by simple gravity, taking about 15 minutes for complete administration. No discomfort has been reported by the patients 23 . Over a period of one year, we performed a hundred viability tests on a reference sample to certify the measurement of transplant viability by flow cytometry.…”

Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients

“…A planned interim analysis was performed on the first 9 patients fulfilling inclusion and exclusion criteria 42 . The correlation R between St and Sf was 0.83 (Spearman correlation), higher than the requested (0.5).…”

Introduction to host microbiome symbiosis in health and disease

“…Furthermore, in this trial, auto-FMT showed an excellent safety profile and there was on average a reduction of 43% of genes coding for antimicrobial resistance. 91 Furthermore, two studies recently reported that either autologous or third-party fecal microbiota transplantation was safe and effective for gut microbiota reconstitution after allo-HSCT. 93,94 However, the ability of such strategies to reverse the deleterious effect of an impaired gut microbiota during the allo-HSCT course and thus impact a patient's outcome, remains to be demonstrated.…”

“… 90 We also conducted a proof of concept study (Phase 1b/2a) evaluating autologuous FMT in 25 acute myeloid leukemia (AML) patients. 91 Intensive chemotherapy of AML and subsequent use of large spectrum antibiotics are known to negatively impact gut microbiota composition, generating a profound state of dysbiosis accompanied by an inflammatory burst and to induce MDRB acquisition. 92 Stool were screened, conditioned and frozen at diagnosis and before patients received any induction chemotherapy and antibiotic treatment.…”