Microbiome Predicts Blood-Cell Transplant Success

A large multicenter international study concludes that the composition of the intestinal microbiome in patients undergoing allogenic hematopoietic-cell transplants (HCT) for leukemia and other blood cancers can predict treatment success. The findings may help assess patients' transplantation-related mortality risk and aid in developing strategies to prevent or mitigate microbiome changes that influence HCT outcomes.

Investigators conducted PCR amplification of bacterial 16S ribosomal RNA genes and sequencing to analyze the microbial composition of 8,767 fecal samples from 1,362 patients undergoing HCT at four centers in the United States, Germany, and Japan. They found similar patterns of microbiota disruption across centers and geographic regions and identified an association between lower intestinal diversity and higher risk of transplantation-related death, mostly due to graft-versus-host disease (GVHD; N Engl J Med 2020;382:822–34).

“We observed that the diversity within the microbiome changes rapidly within a few days, and actually starts in the first week before transplantation,” says lead investigator Marcel van den Brink, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY. “Patients with the most diversity loss had the worst outcomes.”

Notably, patients had lower-diversity microbiomes both before transplantation and for about 14 days after—during the time of neutrophil engraftment, he says. Diversity loss prior to transplant is likely tied to taking broad-spectrum antibiotics that are often prescribed for emergent infections during chemotherapy and radiation.

Smaller, single-center studies have noted associations between the gut microbiome and treatment responses, notes David Fredricks, MD, who leads the Microbiome Research Initiative at Fred Hutchinson Cancer Research Center in Seattle, WA. The much larger size and scope of this study builds on those observations and provides a strong scientific rationale for pursuing new treatments based on manipulating the microbiome.

For example, fecal microbiota transplantation prior to HCT or at the time of neutrophil engraftment might restore diversity and improve outcomes, he says. In addition, several research groups are testing engineered microbial communities and dietary manipulation to modulate GVHD risk.

Future studies should determine whether microbial diversity is a driver or a marker of clinical outcomes, notes Fredricks. For now, these findings suggest that the microbiota could be a useful biomarker for calculating patients' risk and identifying those who may require more intense interventions to prevent or treat GVHD.

The study also suggests a rationale for improving antibiotic stewardship to minimize or prevent diversity loss prior to transplantation. For example, investigators noted that less diverse microbiomes were often dominated by certain bacteria, particularly enterococcus and streptococcus, with corresponding loss of anaerobic gut bacteria.

“Providers tend to use very broad-spectrum antibiotics when we don't know the source of an infection in order to have the biggest impact,” says Fredricks. “However, these findings suggest that we might first consider more narrow-spectrum antibiotics that target common causes of bloodstream infections in order to preserve gut bacterial diversity.”

The findings have implications beyond HCT, he adds. For example, patients undergoing treatment with immune checkpoint inhibitors often have enhanced antitumor responses when they have a particular gut microbiota. Trying to preserve beneficial gut microbiota in these patients might enhance therapeutic response.

“There is still a lot we need to learn about this area before we jump on clinical strategies,” van den Brink cautions. “However, our findings suggest that microbiota composition is an important risk factor to consider before transplant.” –Janet Colwell

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.