Regenerating islet-derived protein 3-a is a prognostic biomarker for gastrointestinal chronic graft-versus-host disease

Abstract

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late nonrelapse mortality (NRM) in survivors of allogeneic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed 3 proteomics markers (Regenerating islet-derived protein 3-a [Reg3a], C-X-C motif ligand 9 [CXCL9], and Stimulation-2 [ST2]) in 2 independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3a were significantly increased in patients with GI-cGVHD (P 5 .0012) compared with those without (P 5 .01), but plasma concentrations of CXCL9 and ST2 were not. Patients with high Reg3a ($72 ng/mL) vs low Reg3a had higher NRM (23% vs 11%; P 5 .015). Because Reg3a has been identified as a lower GI tract marker in acute GVHD, we correlated Reg3a with lower acute-like GI-cGVHD vs classical fibrotic-like esophageal manifestations and found that Reg3a did not differ between the subtypes. No difference was observed between upper GI tract and lower GI tract subtypes. Patients with extremely high Reg3a ($180 ng/mL) had higher GI scores but not higher scores for the lower GI tract. In a multivariable Cox regression model, patients with high Reg3a were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3a as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.