Introduction
Whilst it has been long established that opportunistic infections occurring during periods of chemotherapy-associated neutropenia, it is thought they often arise from translocation of intestinal commensal organisms. To date, the full role of the intestinal microbiota in outcome from haematopoietic stem cell transplant (HCT) in patients with haematological malignancy has been hugely underappreciated.
The development of next generation microbial sequencing techniques (e.g. 16S rRNA gene sequencing and shotgun metagenomics) has demonstrated just how diverse the intestinal microbiota is in healthy subjects. The evolving high throughput ‘multi-omic’ systems biology techniques (including proteomics and metabolomics) are starting to unravel how critical the gut microbiota is to health, gut barrier function, the immune system and gene expression and the impact of disrupting it has on all these features.
In health, the intestine is home to a vast array of microbes termed the microbiota. This microbiota has a dynamic symbiotic relationship with their host, and together with reciprocal interactions with their host environment, result in a balanced, diverse microbiota. The microbiota impacts on nutrition, pathogen resistance and immune development, all of which play key roles in the success of HCT.
Whilst there are a number of metrics of microbiome health, microbiota diversity is straightforward to measure, and is considered a robust surrogate for gut microbiome health. Large scale profiling of intestinal microbiota samples during HCT has recently shown that reduced diversity during HCT is associated with poorer overall survival.
This survival difference is likely to be multifactorial, derived from differences in infections, nutrition, and immune reconstitution. Whilst some of these factors (such as pathogen resistance, infections, and nutrition) have the potential to impact on early non-relapse mortality, others (and particularly immune reconstitution) may have impact on the longer-term modulators of HCT, such as immune tolerance and graft versus host disease.
Intestinal Microbiota Transplantation
Intestinal microbiota transplantation (IMT) has the potential to increase the diversity in a low diversity microbiota, and has an established role in the management of recurrent Clostridioides difficile infection (rCDI). The reduced microbiota diversity observed in the setting of rCDI occurs because of broad-spectrum antibiotic use and can be restored to the level of healthy donors with one or two treatments as rapidly as within 72 hours. The remarkable clinical responses, in up to 90% of patients, has led to exploration of this therapy in other settings where disruption of the microbiota composition has been observed, such as inflammatory bowel disease or cirrhotic liver disease and a number of clinical studies are ongoing in the immune-oncological therapies as well, e.g. response to anti PDL1 biologics for some cancers.
The observation that the intestinal microbiota frequently serves as a reservoir for multidrug-resistant organism (MDRO)-mediated infections, coupled with the suggestion that the predominance of MDROs within the intestinal niche reflects a global reduction in microbiota diversity, has led several groups to employ IMT as a novel biological approach to rescue the microbiota. In this context, while IMT may not eradicate MDRO, restoration of a more diverse microbiota reduces the incidence of clinical infections, reinforcing the impact of reduced diversity.
A striking observation in many of the IMT studies reported in immunocompromised patients is the safety and tolerability profile of the intervention, even with marked immunocompromise/ immunosuppression, and this profile has been supported with systematic review evidence; as such, current IMT guidelines support the use of IMT within such populations, albeit with certain additional caution (including consideration of the use of CMV and EBV-negative donors).
We have previously used IMT prior to HCT in patients with MDRO colonisation. Patients with a history of MDRO colonisation, or a history of MDRO-mediated clinical infections were offered IMT initially as part of a compassionate-use programme, and later as part of a cohort study. Patients whose infections pre-dated access to a compassionate use program, or who declined participation in the program, had a high incidence of MDRO-infections during HCT, as well as a high incidence of intensive care unit admission, and non-relapse mortality. By comparison, those undergoing IMT had fewer days of fever, zero episodes of ITU admission, and a significantly better survival.
Rationale for the study
While MDRO colonisation may represent an extreme phenotype of a perturbed microbiota, skewed intestinal dominance, and depletion of obligate anaerobes resulting from antimicrobial use is associated with an increased incidence of blood stream infections (BSI) in HCT recipients. Furthermore, most patients undergoing HCT have received prior courses of neutropenia-inducing chemotherapy, which is associated with intestinal mucosal damage, recurrent episodes of neutropenic fevers and further widespread use of broad-spectrum antimicrobials.
Chemotherapy, intestinal mucosal inflammation, and the use of broad-spectrum antibiotics are all risk factors for a perturbed, low diversity microbiota, meaning that few patients undergoing HCT have a healthy diverse gut microbiota at the time of HCT. IMT therefore offers the prospect of restoring intestinal microbiota diversity prior to HCT, with potential to reduce early treatment-associated complications such as BSI originating in the intestine and improve intestinal absorption.
The use of autologous IMT, harvested pre-HCT from the patient and delivered post-engraftment, to the same patient, has been tested in a single centre study. In this setting, IMT is delivered as a retention enema, and was reported to restore diversity, to pre-HCT levels, but follow-up for clinical endpoints, particularly GvHD and C. difficile infections, are ongoing. This approach however does not address the pre-existing skewed diversity immediately prior to transplant and excluded patients with a perturbed microbiota on the screening sample.
A phase 2 clinical study of allogeneic, healthy donor IMT, delivered post-HCT was terminated early after it emerged that donor screening had been inadequate, and two patients contracted extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteraemia originating from donor stool. Importantly, there are robust donor screening criteria in the UK that avoid this scenario if they are adhered to.
The method of optimal IMT delivery is also important. Early studies used duodenal delivery of cryopreserved slurry, while some groups prefer rectal retention enemas. However, both approaches are relatively invasive, and can deter patients from undergoing the procedure. The recent development of lyophilised capsule IMT has been shown to be equivalent to faecal slurry delivered endoscopically (at least in the context of rCDI) and is potentially more tolerable for patients (PPIE feedback).
In this trial we aim to explore the use of capsule IMT to restore microbiota diversity in the setting of HCT. While the primary focus of the study is restoration of intestinal diversity, the deliverability and tolerability of such a strategy at multiple UK sites will be a key focus. Furthermore, the trial will collect laboratory and clinical outcome data to inform subsequent larger clinical studies.
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TITLE: Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST) Trial
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DESIGN: A randomised multicentre phase 2A double-blind placebo-controlled trial
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OBJECTIVES: The primary objective of this trial is to determine the ability of capsule intestinal microbiota transplant (IMT) given prior to allogeneic haematopoietic stem cell transplantation (HCT) to increase and maintain stool microbiota diversity after HCT from baseline. Secondary objectives are to determine clinical tolerability and effects of capsule IMT on clinical outcomes.
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PRIMARY OUTCOME: The change in alpha diversity 28 +/-3 days after HCT (i.e., at trial registration, prior to IMT/ placebo visit) in patients receiving capsulised IMT versus placebo.
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SECONDARY OUTCOMES:
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Tolerability: Tolerability and acceptability of IMT versus placebo (as assessed via patient perspective questionnaires).
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Gut microbiome endpoints: Assessment of changes in inverse Simpson’s index and other measures of gut microbiome diversity, changes in taxonomic composition (using shallow shotgun sequencing)., alpha diversity and richness (measured via Chao-1, Shannon, Faith’s PD), and beta diversity (Aitchinson’s distance) across all timepoints assessed.
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Clinical endpoints: Markers of general health, infective/microbiological and haematological outcomes including days of fever, admission to intensive care unit, survival, non-relapsed mortality, and incidence of graft-versus-host disease across all time points measured.
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RESEARCH QUESTION: Can capsulised intestinal microbiota transplantation prior to allogeneic HCT restore intestinal microbial diversity, and potentially impact upon clinical outcomes?
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POPULATION: Adults with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), acute leukaemia (AL) of ambiguous lineage, high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML), and chronic myeloid leukaemia (CML) in blast phase are considered suitable/fit for an allogeneic HCT will be recruited to this trial.
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ELIGIBILITY: Patients aged 18 years and over scheduled to undergo allogeneic HCT for ALL, AML, AL of ambiguous lineage, MDS, CMML, and CML in blast phase who achieved first or second complete remission defined as < 5% blasts, and who received at least two cycles of intensive chemotherapy and required administration of broad-spectrum intravenous antibiotics within 3 months of HCT.
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EXCLUSION CRITERIA: Refractory disease, active infection, chronic intestinal disease, allergies to capsule components, difficulties in swallowing, infection with HIV, hepatitis B or C, prior malignancy (see section 4 for exceptions), administration of IMT within 3 months prior to enrolment, use of probiotics during after recruitment, pregnancy, and refusal to use contraception. Patients undergoing umbilical cord transplant are also excluded.
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IMP: Intestinal microbiota transplant (IMT) by capsule made by EnteroBiotix Ltd., EBX-102-02.
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The MAST study: Intestinal Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST) study