Pedraza A, Salas MQ, Rodríguez-Lobato LG, Escribano-Serrat S, Suárez-Lledo M, Martínez-Cebrian N, Solano MT, Arcarons J, Rosiñol L, Gutiérrez-García G, Fernández-Avilés F, Moreno-Castaño AB, Molina P, Pino M, Carreras E, Díaz-Ricart M, Rovira M, Palomo M, Martínez C.


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 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 vascular cell adhesion molecule -1 (VCAM-1), tumor necrosis factor receptor 1 (TNFR1), and VWF:Ag plasma levels and the 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 cutoff 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 -transplantation dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log -2 EASIX score on day 7 after transplantation with an increased likelihood of developing aGVHD (hazard ratio [HR] = 1, P = .002; HR = 2.31, P = .013, respectively). Patients with TNFR1 >1300 ng/mL (HR = 7.19, P= .006) and Log2-EASIX >3 (HR = 14.7, P <.001) at day 7 after transplantation 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 after transplantation presented a significantly higher incidence of grade II -IV aGVHD (HR = 1.94, P = .004) independent of GVHD prophylaxis (HR = 0.38, P = .004), conditioning regimen (HR = 0.59, P =.02) and type of donor (HR = 2.38, P = .014). Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early posttransplantation 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. on behalf of The American Society for Transplantation and Cellular Therapy.

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