Microbiota composition — specifically the abundance of bacterial taxa before engraftment — may be prognostic of survival for patients with hematologic malignancies undergoing allogeneic hematopoietic-cell transplantation (HCT), an international investigation found.
In two cohorts comprised of more than 1,300 HCT patients, relative reductions in the risk of death of 29% and 51% were seen for those with higher diversity in their intestinal microbiota at the time of engraftment compared to those with lower diversity, reported Marcel R.M. van den Brink, MD, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and colleagues.
“This study defines opportunities for rational interventions to restore integrity to the intestinal microbiota, such as with fecal microbiota replacement or other strategies, which could also be evaluated in clinical settings beyond allogeneic hematopoietic-cell transplantation,” the group wrote in the New England Journal of Medicine.
In the first and larger cohort, made up of those treated at MSKCC, there were 104 deaths among 354 individuals (29.4%) in the higher-diversity group versus 136 deaths among 350 (38.9%) in the lower-diversity group (adjusted HR 0.71, 95% CI 0.55-0.92), driven in part by HCT-related mortality (HR 0.63, 95% CI 0.44-0.89), as no differences in rates of disease relapse were observed between the two groups.
Subgroup analyses in the MSKCC cohort revealed that the association between gut bacterial diversity with both survival and HCT-related mortality was only in recipients of unmodified grafts and not among those that received T cell-depleted grafts. Further, in the group with unmodified grafts, death from graft-vs-host-disease (GVHD) also appeared to play a role, with lower GVHD-related death in the higher- versus lower-diversity group (HR 0.49, 95% CI 0.26-0.90).
“The similarities we observed in patterns of microbiota injury and their associations with clinical outcomes highlight the important interactions that occur between microbial communities and their hosts,” van den Brink’s group noted.
In the second cohort, drawn from another U.S. center and two international sites, 18 of 87 patients (20.7%) died in the higher-diversity group versus 35 of 92 (38.0%) in the lower-diversity group (adjusted HR 0.49, 95% CI 0.27-0.90).
The overall association between gut diversity and survival in the two cohorts held across regions and after multivariable adjustment for age, intensity of conditioning regimen, graft source, and HCT comorbidity index, as well as in an analysis treating intestinal bacteria diversity as a continuous variable.
Carlos Ramos, MD, of Baylor College of Medicine in Houston, agreed that the study demonstrates an association between lower mortality after HCT and a more diverse microbiome, even at baseline.
“Despite this association, it is unknown whether manipulation of the microbiome would improve outcomes or is even feasible,” Ramos, who was not involved in the study, told MedPage Today. “This should be the object of future studies, but this work does not establish microbiome testing as standard of care, especially if the results of such testing would not lead to change of planned management.”
Conducted at two U.S. centers and one each in Germany and Japan, the study profiled 8,767 recent fecal samples from 1,362 patients undergoing allogeneic HCT, most commonly for acute myeloid leukemia (36%), and followed by myelodysplastic syndrome or myeloproliferative neoplasms (19%), non-Hodgkin lymphoma (17%), acute lymphoid leukemia (9%), and myeloma (8%).
Fecal microbiota was profiled with 16S ribosomal RNA gene sequencing and higher diversity was defined as a median value greater than 2.64, a cutoff used in both cohorts. Mean patient age was 52.9 and 61% were male.
The analysis found similar patterns of microbiota disruption across all geographic regions, suggesting that the findings are more generalizable than those from previous single-center studies. Dysbiosis related to loss of diversity and domination by single taxa.
Also, patients at the four centers had similar baseline microbiota diversity scores, showing evidence of microbiome disruption and lower diversity compared to healthy volunteers. These lower baseline samples, taken prior to the pre-engraftment period, suggest that microbiota status before transplant could help guide decisions about antibiotic use, prophylaxis for GVHD, and microbiota injury remediation strategies, according to van den Brink’s team.
Despite the clinical heterogeneity of the participants, the study also showed that a microbiota-composition risk score trained in cohort 1 predicted survival in cohort 2. “It may be of interest to integrate microbiota classifiers into prospective trials of GVHD-predictive biomarkers,” the researchers concluded.
A limitation of the study, the authors said, was the diversity of clinical practices across institutions as well as differences in underlying diseases, conditioning regimens, antibiotic exposures, and graft sources, all of which led to considerable heterogeneity in the sample population. Earlier findings from the study were presented at the 2018 meeting of the American Society of Hematology.
This research was funded by grants from various agencies of the National Institutes of Health as well as from research-support organizations and charitable foundations.
van den Brink reported support from Seres Therapeutics. Coauthor Khan reported support from Gilead Sciences and Seres Therapeutics.
Ramos reported having no conflicts of interest relevant to his comments.
New England Journal of Medicine
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