Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+ CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.
Bibliographical noteFunding Information:
The authors thank centers that contributed to the Chronic GVHD Consortium, including Vanderbilt (Madan Jagasia), Roswell Park (George Chen), Stanford University (Sally Arai), Cleveland Clinic Taussig Cancer Institute (Betty Hamilton), Washington University (Iskra Pusic), and Cornell University (Sebastian Ma). This work was supported by a Canadian Institutes of Health Operating Grant; by the CIHR/Wyeth Clinical Research Chair in Transplantation (K.R.S.); by the Canadian National Transplant Research Program (funded by the CIHR); by the Office of Research in Women's Health and the National Institute of Child Health and Human Development, Oregon Building Interdisciplinary Research Careers in Women's Health Award No. 2K12HD043488 (S.G.H.); by the Medical Foundation of Oregon (S.G.H.); and by the Deutsche Jos? Carreras Leuk?mie-Stiftung (D.W.). The Chronic GVHD Consortium is funded via collaboration between the Center for Advancing Translational Sciences and the National Cancer Institute (NCI) (U54CA163438). Support for the discovery samples was provided by grant CA118953 from NCI. The Canadian Bone Marrow Transplant Group Clinical Trials Network provided samples from CBMTG 0601 (funded by National Institutes of Health/NCI 1R01CA108752-01A2) and samples from CBMTG 0801 (funded by CIHR).
© 2016 by The American Society of Hematology.