Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation

Abstract

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Fig 1.

(A) Phylogenetic tree of operational taxonomic units (OTUs) and clusters of related OTUs (crOTUs). Each black point is a crOTU. Phylum is color coded along the circumference. A schematic of how the tree was constructed and a detailed tree are presented in the Data Supplement. (B) Volcano plot of multivariable P values of crOTUs against the multivariable hazard ratios for relapse/progression of disease (POD) in the discovery set. crOTUs are color coded by P value. Multivariable adjustment was performed for refined disease risk index, graft source, and conditioning intensity. The most abundant species in each of the labeled crOTUs are as follows: Eubacterium limosum in crOTU 1614; Streptococcus sinensis in crOTU 2022-3; E. limosum in crOTU 1638; E. limosum in crOTU 1630-1; Parvimonas micra in crOTU 1790; Leptotrichia hongkongensis in crOTU 0951-3; Flavonifractor plautii in crOTU 2986; and Actinomyces odontolyticus in crOTU 1439. OTU-level analysis and univariable analysis results are presented in the Data Supplement. crOTU composition at the species level and numeric values are tabulated for the top candidates and for all candidates in the Data Supplement.

Fig 2.

Cluster of related operational taxonomic units (crOTU) 1614, which includes members of the family Eubacteriaceae, is associated with decreased relapse/progression of disease (POD) after allogenic hematopoietic-cell transplantation (allo-HCT). (A) Cumulative incidence of relapse/POD in the discovery (n = 271) and validation (n = 270) sets stratified by presence or absence of crOTU 1614. (B) Cumulative incidence of relapse/POD in the whole cohort (N = 541) stratified by crOTU 1614 abundance. (C) Upper panel, mean abundance of crOTU 1614 in the four strata (error bars are standard error of the mean) and, lower panel, cumulative incidence of relapse/POD at 2 years in the four strata (error bars are 95% CIs). (D) Far left: refined disease risk index (DRI) alone stratifies the relapse/POD risk in this cohort. Three right panels: crOTU 1614 presence further stratifies relapse among patients with high-risk and intermediate-risk DRIs. Patients with very-high-risk DRIs were grouped together with those who had high-risk DRIs. HR, hazard ratio.

Fig 3.

(A) Presence of cluster of related operational taxonomic units (crOTUs) 1614 in the 3 weeks after allogenic hematopoietic-cell transplantation (allo-HCT) is associated with increased overall survival and decreased cumulative incidence of relapse/progression of disease (POD), but it is not associated with cumulative incidence of acute grades 2 to 4 graft-versus-host disease (GVHD) or with transplantation-related mortality (TRM). (*)Seventeen patients developed grades 2 to 4 GVHD before landmark day 21 and were excluded from this panel. (B) Among 143 recipients of unmodified peripheral-blood stem-cell (PBSC)/bone marrow (BM) stem-cell grafts with available pretransplantation microbiota data, those with the highest abundance of crOTU 1614 in a single sample collected before allo-HCT had a reduced risk of relapse/POD (P = .02; for all four groups P = .10). The pretransplantation analysis for recipients of all graft types is plotted in the Data Supplement. HR, hazard ratio.

Fig 4.

Association of the presence of cluster of related operational taxonomic units (crOTU) 1614 with relapse/progression of disease (POD) in patient subsets according to graft source, conditioning intensity, degree of HLA match, refined disease index (DRI), and disease type. The size of the gold box is proportional to number of patients in the subgroup. Cumulative incidence curves by graft source are plotted in the Data Supplement. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow stem cells; CLL, chronic lymphocytic leukemia; HR, hazard ratio; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin lymphoma; PBSC, peripheral-blood stem cells.