In a study reported in The New England Journal of Medicine, Jonathan U. Peled, MD, PhD, of the Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center (MSK), New York, and colleagues found that intestinal microbiota from patients undergoing allogeneic hematopoietic cell transplantation (HCT) at four centers showed patterns of disruption characterized by loss of diversity. That lower diversity was associated with significantly poorer overall survival.¹

Jonathan U. Peled, MD, PhD

Study Details

The study involved identification of microbiota composition of 8,767 fecal samples from 1,362 patients undergoing allogeneic HCT at MSK (cohort 1, n = 1,076); Duke University Medical Center (n = 142); the University Medical Center, University Hospital Regensburg, Germany (n = 78); and Hokkaido University, Sapporo, Japan (n = 66; cohort 2, n = 286). All patients had at least one evaluable stool sample obtained no more than 30 days before allogeneic HCT, and stool samples were obtained throughout the transplantation period. (The main analysis focused on samples collected between days 7 and 21.) Acute leukemia was the most common indication for transplantation.

The median diversity value of microbiota at MSK (cohort 1; 2.64) was used to distinguish between higher-diversity (> 2.64) and lower-diversity microbiota in both cohorts. Loss of diversity was observed between the baseline samples and the peri-engraftment period (days 7 to 21) in patients from all four centers during the course of the transplantation period (P < .001 for each center), with domination by single taxa being observed. Several of the lower-diversity compositions were characterized by domination by Enterococcus, Klebsiella, Escherichia, Staphylococcus, and Streptococcus; Enterococcus domination was observed at all four study centers.

Association of Diversity and Mortality

The median follow-up for survivors was 25.2 months among all patients, including a median of 34.2 months in cohort 1 and 32.5, 15.0, and 8.3 months at the University Hospital Regensburg, Duke University, and Hokkaido University, respectively.

Among patients at MSK (cohort 1), death occurred in 104 of 354 patients in the higher-diversity group vs 136 of 350 patients in the lower-diversity group (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.58–0.96). The association remained significant in multivariate analyses adjusting for age, intensity of conditioning regimen, graft source, and HCT comorbidity index (adjusted HR = 0.71, 95% CI = 0.55–0.92). The association was also observed in multivariate analyses including diversity as a continuous variable (adjusted HR = 0.50, 95% CI = 0.31–0.80).

In cohort 2, there were 18 deaths among 87 patients in the higher-diversity group vs 35 deaths among 92 patients in the lower-diversity group (HR = 0.46, 95% CI = 0.26–0.82). The association remained significant in the multivariate analysis (adjusted HR = 0.49, 95% CI = 0.27–0.90). In analysis with diversity as a continuous variable, the association was significant in univariate analysis (HR = 0.33, 95% CI = 0.13–0.84) but not in the multivariate model.

Subgroup analyses indicated an association between lower diversity and higher risk of transplantation-related death and death attributable to graft-vs-host disease. Among recipients of unmodified grafts in cohort 1, there were 30 transplantation-related deaths among 244 patients in the higher-diversity group vs 46 among 184 patients in the lower-diversity group (HR = 0.49, 95% CI = 0.31–0.77); no significant association was observed among recipients of T-cell–depleted grafts. Among recipients of unmodified grafts, there were 17 graft-vs-host–related deaths among 244 patients in the higher-diversity group vs 26 among 184 patients in the lower-diversity group (HR = 0.49, 95% CI = 0.26–0.90).

Diversity in Pretransplantation Samples

In cohort 1, higher diversity in pretransplantation samples, with diversity assessed as a continuous variable, was associated with improved survival (adjusted HR = 0.41, 95% CI = 0.24–0.71). There was a weak correlation between baseline and transplantation period diversity (r = 0.22). No association between baseline diversity and survival was observed in cohort 2.

The investigators concluded: “Patterns of microbiota disruption during allogeneic hematopoietic cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality.” 

DISCLOSURE: For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Peled JU, Gomes ALC, Devlin SM, et al: Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med 382:822-834, 2020.