Easix Score Correlates With Endothelial Dysfunction Biomarkers and Predicts Risk of Acute Graft-Versus-Host Disease After Allogeneic Transplantation

Abstract

Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome (SOS) and transplant-associated thrombotic microangiopathy (TA-TMA).This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD.We assessed VCAM-1, TNFR1, and VWF:Ag plasma levels, and EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT), and on days 0, +3, +7, +14, and +21 in an experimental cohort (n=33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cut-off values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution.Plasma biomarkers and EASIX showed similar post-transplant dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day +7 post-transplant with an increased likelihood of developing aGVHD (HR 1, P=0.002; HR 2.31, P=0.013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR 7.19, P=0.006) and Log2-EASIX ≥3 (HR 14.7, P<0.001) at day +7 post-transplant were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥ 3 on day +7 post-transplant presented a significantly higher incidence of grade II-IV aGVHD (HR 1.94, P=0.004) independent of GVHD prophylaxis (HR 0.38, P=0.004), conditioning regimen (HR 0.59, P=0.02) and type of donor (HR 2.38, P=0.014).Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplant period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.Published by Elsevier Inc.