National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report

Abstract

Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT) or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include: a) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity, b) prognostic risk to develop chronic GVHD, and c) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well-documented following established quality control guidelines for sample acquisition, processing, preservation and testing, at intervals that are both calendar- and event-driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for utilization in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a four-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines.

Biomarker Panel for Chronic Graft-Versus-Host Disease

“…First, a major strength of this study was our ability to reproduce a correlation of the four-biomarker panel with cGVHD in a second verification cohort that included samples from eight different sites, which meets the current preferred requirement for the identification of biomarkers according to the 2014 NIH biomarker consensus. 9 Unfortunately, the association of biomarkers with cGVHD severity and NRM in the first verification cohort was not seen in the second verification cohort, possibly because of the number of controls on corticosteroids at the time of sampling in cohort 2 as compared with that in cohort 1, which could mask the biomarker levels, and the low numbers of NRM events, respectively. Second, the fact that a biomarker panel at day +100 after HCT was associated with subsequent cGVHD and remained elevated at the time of onset suggests that serial measurements from day +100 after HCT and beyond may identify high-risk patients for earlier intervention.…”

“…4,5 In 2014, the National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD published an updated series of articles to help standardize the clinical approach to treating these patients, thereby promoting new interest in this important post-transplantation complication and motivating the development of well-defined biomarkers for future use as an aid in clinical trials. [6][7][8][9][10] The development of acute graft-versus-host disease (aGVHD) biomarkers [11][12][13][14] has increased interest in identifying biomarkers that provide meaningful information for cGVHD. Several studies have reported the discovery of cGVHD biomarkers, 9,15 but verification studies of these biomarkers in independent cohorts are currently lacking.…”

“…[6][7][8][9][10] The development of acute graft-versus-host disease (aGVHD) biomarkers [11][12][13][14] has increased interest in identifying biomarkers that provide meaningful information for cGVHD. Several studies have reported the discovery of cGVHD biomarkers, 9,15 but verification studies of these biomarkers in independent cohorts are currently lacking. Here, we used in-depth proteomic profiling using gel-free, high-resolution tandem mass spectrometry (MS/MS).…”

“…Here, we used in-depth proteomic profiling using gel-free, high-resolution tandem mass spectrometry (MS/MS). Following the recent recommendations from the NIH consensus, 9 we then verified the concentrations of individual candidate proteins in samples from an independent cohort of 211 HCT patients using high-throughput immunoassays. The leading proteins were then tested in a second independent verification cohort of 180 HCT patients.…”

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells

“…Criteria for such biomarkers are well defined in the recent National Institutes of Health (NIH) Chronic GVHD consensus report. 5 Many candidate plasma or serum cGVHD diagnostic biomarkers have been identified but none have been validated for use in clinical practice. 6 Many recurring The online version of this article contains a data supplement.…”