Endothelial activation and stress index EASIX and it's variants as a prognostic marker for cytokine release syndrome in CAR-T cell therapy recipients: A systematic review and meta analysis

Abstract

Abstract INTRODUCTION Background: Chimeric antigen receptor (CAR) T-cell therapy, while being efficacious for haematological malignancies, is associated with toxicities like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This meta-analysis evaluates the prognostic utility of EASIX and its variants (m-EASIX, s-EASIX) in predicting CAR-T-associated complications. METHODS A systematic literature search was done in PubMed, EMBASE, Scopus, Cochrane Library (CENTRAL), and Google Scholar up to July 2025. Cohort studies reporting cytokine release syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), or other CAR-T-related complications about EASIX scores were included. Two reviewers independently screened the articles, extracted data, and assessed quality. From an initial pool of 16 studies found through bibliographic databases, 8 eligible studies met the inclusion criteria. To assess the association between EASIX scores and CRS and ICANS, a meta-analysis using the random-effects model was conducted to pool weighted odds ratios (ORs). CRS and ICANS severity grades were dichotomized for analysis. Meta-analysis was performed using RevMan 5.3, with random-assessed study quality and heterogeneity assessed using the I2 statistic. For effect sizes, a confidence interval of 95% was used, and a p-value of less than 0.05 was used for statistical significance. RESULTS After screening, a total of 8 studies were included. Day 0 EASIX displayed a statistically significant association with severe CRS (SMD 0.50; 95% CI 0.23–0.77; p < 0.001; I² = 0%). Pre-mEASIX produced a small but statistically significant effect (SMD 0.24; 95% CI 0.15–0.33; p < 0.001; I² = 0%). Pre-EASIX suggested a balanced association (SMD 0.69; 95% CI 0.18–1.20; p = 0.01) with high heterogeneity (I² = 64%). Post-EASIX reported the highest effect estimate (SMD 0.65; 95% CI 0.37–0.92; p < 0.001; I² = 0%). Pre-sEASIX and Post-mEASIX demonstrated moderate associations (SMD 0.35; 95% CI 0.12–0.58; p < 0.01) with low-to-moderate heterogeneity (I² ≈ 35%). Funnel plots of these studies revealed no evidence of publication bias. After performing Galbraith analysis, all studies fell within or near the 95% confidence interval limits. Sensitivity analyses indicated stability for most outcomes, except Pre-sEASIX, Pre-EASIX, and Post-mEASIX, which were influenced by individual studies. CONCLUSION There is an increased chance of severe CRS among patients receiving CAR-T therapy, which is correlated with elevated EASIX and its variants. The most consistent associations across studies are provided by Day 0 and post-treatment scores. The findings of this study reinforce the use of EASIX-based indicators for early risk estimation, though prospective evaluation remains essential.