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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 non-relapse mortality (NRM) in survivors of allogenic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed three proteomics markers [Regenerating-islet-derived-3-alpha (Reg3α), C-X-C-motif-ligand (CXCL9) and Stimulation-2 (ST2)] in two independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD compared to those without (p=0.0012, p=0.01 respectively), CXCL9 and ST2 were not. Patients with high Reg3α (≥72ng/mL) vs. low Reg3α had higher NRM (23% vs. 11%, p=0.015). Since Reg3α has been identified as a lower GI-tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs. classical fibrotic-like esophageal manifestations and found Reg3a did not differ between the subtypes. No difference was observed between upper and lower subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI-scores but not higher lower-GI-scores. In multivariate Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

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