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

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 <i>n</i> = 31; axi-cel <i>n</i> = 24; and cilta-cel <i>n</i> = 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.