Endothelial dysfunction and proinflammatory state determine severe hematotoxicity and inferior outcome of CAR‐T therapy

Abstract Hematotoxicity and infections are the main drivers of non‐relapse mortality after chimeric antigen receptor (CAR)‐T therapy. Consequently, reliable predictive biomarkers are highly needed to improve risk assessment and optimize patient management. In this study, we applied the immune‐related adverse outcome pathway concept to delineate key events and risk factors of CAR‐T‐associated hematotoxicity. To identify predictive biomarkers, we performed flow cytometry and multiplex assays before and early after CAR‐T infusion on 78 patients (ide‐cel n = 31; axi‐cel n = 24; and cilta‐cel n = 23) undergoing CAR‐T therapy. Severe hematotoxicity was linked to endothelial dysfunction, as evidenced by reduced levels of ANG1, soluble selectins, and increased soluble VCAM‐1 (sVCAM‐1) early after CAR‐T infusion. Increased sVCAM‐1, reflecting endothelial dysfunction, elevated soluble IL‐2R (sIL‐2R), indicating a proinflammatory state, and high tumor burden before lymphodepletion were key risk factors for CAR‐T‐associated hematotoxicity. Patients with elevated sVCAM‐1 and sIL‐2R at baseline (pre‐lymphodepletion) exhibited significantly reduced overall survival (OS) (sVCAM‐1; P = 0.0009), prolonged Grade 4 neutropenia (sVCAM‐1; 12.1 vs. 6.0 days; P = 0.0016), more aplastic neutrophil recovery (5% vs. 30%; P = 0.007), and more severe infections (22.4% vs. 55%; P = 0.011). Baseline sIL‐2R and sVCAM‐1 demonstrated robust predictive value for prolonged neutropenia, severe infections, and mortality independently of key clinical variables such as the underlying disease and CAR‐T product. Integration of these markers improves existing models and can help to refine risk assessment and guide individualized patient management in CAR‐T therapy.