Regenerating islet-derived protein 3-α 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 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.

Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: A systematic review

“…In two independent cohorts of a total of 289 cGvHD patients the proteomic plasma marker regenerating islet-derived protein 3-α (REG3α) was significantly increased in patients with GI cGvHD compared with those without ( 80 ). Patients with high REG3α had higher NRM and were 1.9 times more likely to die without relapse.…”

Unlocking protein-based biomarker potential for graft-versus-host disease following allogenic hematopoietic stem cell transplants

“…High concentrations of the two biomarkers tested in day 7 after transplant were associated with high GVHD related mortality and more frequent intestinal GVHD, demonstrating their usefulness in the prediction of GVHD before the clinical signs appear (63). Also, another study showed that higher levels of plasma Reg3a were found in patients with gastrointestinal-cGVHD, suggesting the utility of Reg3a as a prognostic biomarker of gastrointestinal-cGVHD (98).…”