Gut Microbiome Diversity and Clinical Outcomes in Allo-HCT: Results From the BMT CTN 1801 Study

Key Clinical Takeaways:

• A randomized phase 3 trial compared two common graft-versus-host disease (GVHD) prophylaxis regimens—tacrolimus with methotrexate versus cyclophosphamide, mycophenolate mofetil, and tacrolimus—to evaluate their impacts on the gut microbiome.
• Microbiome alpha diversity at neutrophil engraftment showed no significant association with non-relapse mortality across 304 co-enrolled participants.
• Baseline microbial diversity and antibacterial exposure during the first 30 days following hematopoietic cell transplantation correlated with overall survival and acute GVHD risk, Nature reported.

Microbiome alpha diversity at neutrophil engraftment does not significantly predict non-relapse mortality in patients undergoing allogeneic hematopoietic cell transplantation, according to a randomized phase 3 companion study published in Nature. Researchers evaluated 304 participants who donated at least one stool sample out of 324 co-enrolled individuals in the BMT CTN 1801 trial, a companion study to BMT CTN 1703 conducted between July 23, 2019, and June 18, 2021.

The trial investigated two distinct GVHD prophylaxis regimens following reduced-intensity conditioning. Participants in the Tac/MTX arm received standard methotrexate and tacrolimus, while the PTCy arm received post-transplantation cyclophosphamide on days 3 and 4 followed by mycophenolate mofetil and tacrolimus. Acute myelogenous leukemia affected 50.0% of the study population (n = 152), and myelodysplastic syndrome accounted for 30.3% (n = 92).

Investigators collected 2,575 stool samples for metagenomic sequencing, with most participants providing six samples throughout their enrollment. Shannon’s index determined microbiome alpha diversity using species-level taxonomic profiles generated with the mOTUs21 profiler. Engraftment occurred on average slightly later in the PTCy group at 15.3 days compared to 14.6 days in the Tac/MTX group.

Evaluating the association between microbiome diversity at neutrophil engraftment and one-year non-relapse mortality served as the primary prespecified objective. Engraftment diversity showed no significant association with cumulative non-relapse mortality incidence, evaluated either by tertiles with a P value of 0.520 or as a linear effect with a P value of 0.314 in a Fine-Gray model.

Secondary outcomes similarly revealed no significant links between engraftment diversity and relapse, acute GVHD grades II-IV or III-IV, chronic GVHD, overall survival, or GVHD-free relapse-free survival.

Baseline microbiome diversity calculated on preconditioning samples demonstrated significant associations with clinical outcomes. Lower baseline diversity correlated with shorter overall survival both when categorized by tertiles (P = 0.031, hazard ratio 0.47) and as a linear predictor (P = 0.007, hazard ratio 0.63) in Cox proportional hazard models. GVHD-free relapse-free survival also associated with baseline microbiome diversity when treated as a continuous predictor with a P value of 0.047 and hazard ratio of 0.79.

Participants receiving higher antibacterial exposure during the first 30 days post-transplantation faced an increased risk for grade II-IV acute GVHD with a P value of 0.006 and a hazard ratio of 2.6. Most other outcomes showed no strong associations with antimicrobial exposure. Absolute microbial load, measured via 16S rRNA gene copies per extraction through digital droplet PCR and machine learning models, dropped after transplantation in both study arms.

The reduction in microbial load and alpha diversity proved more pronounced in the PTCy group. Between days 14 and 28 following transplantation, the microbial load in the PTCy group averaged smaller by a factor of two compared to the Tac/MTX group with a P value of 3 × 10⁻⁵ in a linear mixed-effect model. Shannon diversity also showed a significant decline between days 14 and 28 with a P value of 0.038.

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