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February 27, 2020

For patients undergoing allogeneic hematopoietic cell transplantation, higher diversity of intestinal microbiota at the time of neutrophil engraftment was linked with lower mortality, according to study findings published today.

For patients undergoing allogeneic hematopoietic cell transplantation (HCT), higher diversity of intestinal microbiota at the time of neutrophil engraftment was linked with lower mortality, according to study findings published today in The New England Journal of Medicine.

Allogeneic HCT is an effective therapy for patients with hematologic malignancies. During the procedure, a patient is administered a cytotoxic conditioning regimen followed by infusion of hematopoietic precursor cells from a donor matched for major histocompatibility antigens. However, applicability of the therapy is limited due to complications such as graft-versus-host disease (GVHD), relapse, and infection, which can prove fatal.

In a previous study, researchers determined that patients undergoing allogeneic HCT have microbiota disruption characterized by expansions of potentially pathogenic bacteria and loss of alpha diversity, a variable known to reflect the number of unique bacterial taxa present and their relative frequencies.

The type of taxa represented in the alpha diversity could prove crucial as prior single-center studies show that domination of intestinal communities by a single bacterial taxon leads to an increased risk of bloodstream infection by a bacterium of that same taxon, and exposure to certain antibiotic agents at specific times is associated with transplantation-related mortality and GVHD-related mortality.

The researchers noted that geographic variations in the composition of human microbial communities and differences in clinical practices across institutions may complicate findings on whether these associations are applicable to various populations. They sought to examine this potential factor by analyzing the relationship between microbiota composition and clinical outcomes after allogeneic HCT in patients treated in 4 centers (n = 1362), who were split into 2 cohorts based on geography.

Cohort 1 was represented by a New York center, with patients from 3 centers in Germany, Japan, and North Carolina representing cohort 2. Cox proportional hazards were used to determine associations between microbiota diversity and mortality based on fecal samples (n = 8767) of the 1362 patients undergoing allogeneic HCT. The researchers delineated overall survival as the primary outcome and transplantation-related death, relapse (defined as relapse/disease progression), and GVHD-related death as secondary endpoints.

In cohort 1, higher diversity of intestinal microbiota was associated with a lower risk of death (104 deaths among 354 patients) compared with those in the lower-diversity group (136 deaths among 350 patients) (adjusted hazard ratio [AHR], 0.71; 95% CI, 0.55-0.92). Cohort 2 exhibited similarly significant associations of a lower risk of death in patients with high intestinal microbiota diversity (18 deaths among 87 patients) compared with the lower-diversity group (35 deaths among 92 patients) (AHR, 0.49; 95% CI, 0.27-0.90).

In subgroup analyses examining the secondary endpoints, an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to GVHD were found, stressing the role of microbiota diversity in mortality risk for patients undergoing allogeneic HCT.

“Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival,” said the study authors.

They noted that a key limitation to the study was that data can only show correlations and not causative relationships. However, they stressed that study findings were consistent with preclinical models of allogeneic transplantation and GVHD.

“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,” said the study authors.

Reference

Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation [published online February 26, 2020]. N Engl J Med. doi: 10.1056/NEJMoa1900623.