Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease

Abstract Background: Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients receiving hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD. However, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT patients is GI GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3a) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. Objective: To analyze serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and to compare it to ST2 and REG3a in a large group of patients treated at multiple centers. Study Design: 526 patients who received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed from the Mount Sinai Acute GVHD International Consortium (MAGIC). Serum concentrations of elafin, ST2 and REG3a were measured for all patients using ELISA. Patients were divided randomly into equal training and validation sets and a competing risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3a, or the combination of all three biomarkers as predictors. ROC curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival, and four-week treatment response were compared between risk groups. Results: Patients in the low-risk elafin group unexpectedly demonstrated a higher incidence of 6-month NRM, although this difference was not statistically significant (17% vs. 11%, P=0.19). Overall survival at 6 months (68% vs. 68%, P>0.99) and four-week response (78% vs. 78%, P=0.98) were similar in the low- and high-risk elafin groups. The area under the receiver operating curve (AUROC) for elafin was 0.55 whereas it was 0.75 for the combination of ST2 and REG3a. The addition of elafin to the other two biomarkers did not improve the AUROC. Conclusion: Serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD do not predict 6-month NRM, overall survival, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3a were significant predictors of NRM and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.