Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day –7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P <.05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P =.02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P <.001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD.
Bibliographical noteFunding Information:
Financial disclosure: This research was supported by National Institutes of Health (NIH) grant P30 CA77598 using the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center (University of Minnesota), the National Center for Advancing Translational Sciences of NIH Award UL1TR000114, and NIH grant R37 AI-34495. This research was also supported by an American Blood and Marrow Transplantation Young Investigator Award (to A.R.). Any views, opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not reflect the views or the official policy or position of the above-mentioned parties.
- Graft-versus-host disease
- Gut barrier
- Nonrelapse mortality