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Diverse gut microbiota may improve OS in allogeneic hematopoietic cell transplantation
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SALT LAKE CITY — Diversity of gut microbiota at the time of neutrophil engraftment in allogeneic hematopoietic stem cell transplantation appeared associated with OS, according to results of an international multicenter cohort study presented at BMT Tandem Meetings.
“Our group and others have reported associations between microbiota composition and OS, as well as relapse, graft-versus-host disease, infections and toxicities,” Jonathan U. Peled, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation. “One of the striking findings early on was this association between diversity in the gut and OS. ... A question I ask ... is, are the patterns of microbiota injury described in single-center studies and their associations with survival consistent across geography?”
Peled and colleagues compared microbiota diversity among patients who underwent allogeneic HSCT at Memorial Sloan Kettering, Duke University Medical Center and University of Regensburg in Germany.
Researchers sequenced and analyzed 5,823 samples from 1,118 patients.
The samples revealed no transplant center-specific effect. In addition, Enterococcus domination — a low-diversity state associated with Enterococcal bacteremia — occurred in all centers.
“The early samples tend to be more diverse. Many of the later clusters tend to be low-diversity states or injured microbiota compositions,” Peled said. “A typical transplantation patient may start out in this early diverse, healthy cluster but, as microbiota injury occurs, a patient may move into a various low-diversity injured state.”
Researchers used a multivariate linear regression model of diversity dynamics in a separate cohort at Memorial Sloan Kettering (n = 21) to determine relative contributions of antibiotics, nutrition and recovery from microbiota injury after discharge.
Results showed exposure to piperacillin-tazobactam (P < .01) and calorie intake (P < .05) served as predictors. Samples collected on the days of piperacillin-tazobactam administration contained lower diversity those collected on days without piperacillin-tazobactam (Simpson reciprocal, 4.15 ± 0.35 vs. 7.75 ± 0.21; P = 1.6-12).
Researchers also observed a correlation between calorie intake and diversity in the absence of piperacillin-tazobactam (r = 0.22; P = 2.95 x 10-5).
In the separate Memorial Sloan Kettering cohort, analysis of 37 samples indicated recovery from microbiota injury after allogeneic-HSCT. Samples showed gradual recovery of diversity at a rate in Simpson reciprocal of 2.17 per 100 days (P = .004).
Researchers confirmed an association between low diversity at the time of neutrophil engraftment and poor OS among a cohort from Memorial Sloan Kettering (n = 651; P = .006 for below- vs. above-median Simpson reciprocal) and a cohort from Regensburg (n = 59; P = .015).
“Microbiota injury occurs across geography. The association of diversity with OS is reproducible over time and geography,” Peled said. “Recovery from microbiota injury occurs gradually; with diversity increasing but often to a configuration distinct from the pretransplant state.” – by Melinda Stevens
Reference:
Peled JU, et al. Abstract 3. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: HemOnc Today could not confirm the researchers’ relevant financial disclosures at the time of reporting.
Perspective
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Marco Mielcarek, MD
Over the past several years, there has been mounting scientific evidence that loss of diversity of bacterial communities in the gastrointestinal tract is associated with worse outcomes after allogeneic hematopoietic cell transplantation. It has been reported, for example, that high bacterial diversity and relative abundance of certain bacterial commensals within the Clostridialis order are protective against GVHD-associated mortality. A decrease in GI microbial diversity — or microbial injury — during transplant has been attributed to the use of certain antibiotics and low caloric intake. These findings suggest that preserving GI microbial diversity during the transplant procedure, or restoring loss of diversity, might lead to better outcomes through reduced GVHD-related morbidity and mortality.
Peled and colleagues analyzed approximately 6,000 serial stool samples from more than 1,000 patients who had received allogeneic stem cell transplants for GI microbial diversity over time. Results from patients treated at all three centers showed that low diversity at the time of neutrophil engraftment appeared associated with shorter survival, and diversity continued to decrease during and soon after transplant. Subgroup analysis of Memorial Sloan Kettering patients further showed that recovery from low diversity states typically took several months after transplant. Factors causing low GI microbial diversity included the use of certain antibiotics (eg, piperacillin-tazobactam), low caloric intake and higher-intensity preparative regimens. The authors concluded that strategies aimed at preventing or restoring microbiota injuries might help improve outcomes after allogeneic transplantation.
This study is important because it shows that previous associations between low-diversity states and poor outcomes do not appear to be a center-specific phenomenon but are reproducible at other institutions, including internationally. In my view, the finding of an association between low caloric oral intake and loss of microbial diversity is of particular importance because it could motivate efforts to initiate oral feeding among patients who would otherwise be considered candidates for parenteral nutrition only.
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