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

Abstract

ObjectivesChronic graft-versus-host disease (cGvHD) is the most frequent cause of late non-relapse mortality after allogeneic haematopoietic stem cell transplantation (alloHCT). Nevertheless, established biomarkers of cGvHD are still missing. The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGvHD provided recommendations for biomarker research. We evaluated to which extent studies on cellular and soluble biomarkers in cGvHD published in the last 10 years complied with these recommendations. Also, we highlight the most promising biomarker candidates, verified in independent cohorts and/or repeatedly identified by separate studies.MethodsWe searched Medline and EMBASE for “cGvHD”, “biomarkers”, “soluble” and “cells” as MeSH terms or emtree subject headings, and their variations on July 28th, 2021, limited to human subjects, English language and last ten years. Reviews, case reports, conference abstracts and single nucleotide polymorphism studies were excluded. Criteria based on the set of recommendations from the NIH group for biomarker research in cGvHD were used for scoring and ranking the references.ResultsA total of 91 references encompassing 15,089 participants were included, 54 prospective, 17 retrospective, 18 cross-sectional, and 2 studies included both prospective and retrospective cohorts. Thirty-five papers included time-matched controls without cGvHD and 20 studies did not have any control subjects. Only 9 studies were randomized, and 8 were multicentric. Test and verification cohorts were included in 11 studies. Predominantly, diagnostic biomarkers were explored (n=54). Assigned scores ranged from 5-34. None of the studies fulfilled all 24 criteria (48 points). Nevertheless, the scores improved during the last years. Three cell subsets (CXCR3+CD56bright NK cells, CD19+CD21low and BAFF/CD19+ B cells) and several soluble factors (BAFF, IL-15, CD163, DKK3, CXCL10 and the panel of ST2, CXCL9, MMP3 and OPN) had the highest potential as diagnostic and/or prognostic biomarkers in cGvHD.ConclusionDespite several limitations of this review (limited applicability for paediatric population, definition of verification, missing data on comorbidities), we identified promising candidate biomarkers for further evaluation in multicentre collaborative studies. This review confirms the importance of the NIH consensus group criteria for improving the quality and reproducibility of cGvHD biomarker research.

Clinical and Biological Concepts for Mastering Immune Reconstitution After Hematopoietic Cell Transplantation: Toward Practical Guidelines and Greater Harmonization

“…As examples, proteins, such as interleukin (IL)-6, granulocyte-macrophage colonystimulating factor (GM-CSF), hepatocyte growth factor (HGF), ST2 (suppressor of tumorgenicity 2), and soluble IL-2a, have shown to be biomarkers of GvHD, whereas increased levels of tumor necrosis factor-alpha (TNF-α) and IL-6 are associated with robust immune responses to viral reactivations (de Koning et al 2016). It is noteworthy that these biomarkers show diagnostic and prognostic potential (Milosevic et al 2022), can be informative in predicting more severe GvHD and NRM (McDonald et al 2015;Srinagesh et al 2019), and may be informative to categorize patients based on their likelihood to respond to therapy (Hess et al 2021). The main challenge, however, remains to identify predictors very early after or even before cell infusion.…”

Dynamic forecasting module for chronic graft-versus-host disease progression based on a disease-specific subpopulation of B cells

“…However, it remains challenging to recognize the earliest signs and symptoms of cGVHD 11 . The standardization provided by the 2005 and 2014 NIH consensus projects helped improve the diagnostic accuracy and severity scoring for clinical trials, but the consensus criteria cannot be used to recognize or predict the imminent onset of cGVHD at an early stage, and some patients who do not meet the NIH criteria may still be at risk for developing active cGVHD 12 .…”

Biomarkers for early complications post hematopoietic cell transplantation: Insights and challenges

“…Excluding the known likely causal factors for some of the adverse effects (such as the donor status, age, comorbidity, sex mismatch between donor and recipient, conditioning, and post-HCT immunosuppressive drug levels), various centers performing allogeneic HCT are concentrating on finding efficient, reliable and robust markers from biological fluids for informative, early detection or differential diagnosis of these complications to optimize the treatment as well as improving the outcome (4)(5)(6). Many have successfully reported a variety of blood plasma, serum, and fecal biomarkers, while only a handful of these is repeatedly tested and validated and likely to be used as a biomarker routinely (7). The biomarkers from these sources may be soluble factors, cellular markers, or genetic markers.…”