Incidence and impact of non-traumatic intracranial hemorrhage on outcomes in chimeric antigen receptor T-cell therapy: Insights from a six-year nationwide analysis

Abstract Background Chimeric Antigen Receptor (CAR) T-cell therapy is a transformative treatment for relapsed or refractory non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). However, its use is often complicated by cytokine release syndrome, thrombocytopenia, and coagulopathy, which in rare cases can lead to life-threatening hemorrhagic events. Non-traumatic intracranial hemorrhage (ICH) is one such severe complication, with limited data suggesting mortality rates approaching 90%. In this study, we evaluated the incidence and clinical outcomes of ICH among CAR T-cell recipients using a nationally representative U.S. cohort. Methods Using the National Inpatient Sample (NIS) database from 2017 to 2022, we identified adult patients with NHL, MM, or ALL who received CAR T-cell therapy. Patients were stratified by the presence or absence of ICH. Weighted analyses were conducted to ensure national representation, and multivariate logistic regression was used to evaluate associations between ICH and clinical outcomes. A p-value of <0.05 was considered statistically significant. Results Among 5,705 adults who underwent CAR T-cell therapy (78.7% with NHL, 15.6% with MM, and 5.7% with ALL), 65 patients (1.1%) developed ICH. Patients with ICH were more likely to be on Medicaid (23.1% vs. 7.5%, p < 0.05) and to have concurrent SARS-CoV-2 infection (7.7% vs. 1.0%, p < 0.05). ICH was independently associated with significantly higher in-hospital mortality (23.1% vs. 2.4%, p < 0.001; adjusted odds ratio [aOR] 15.5, 95% confidence interval [CI] 3.3–73.8). ICH was also associated with increased risks of acute kidney injury (aOR 14.1, 95% CI 4.9–40.5), respiratory failure (aOR 7.5, 95% CI 2.4–24.2), and all-cause shock (aOR 4.8, 95% CI 1.1–21.9). Use of renal replacement therapy (aOR 9.0, 95% CI 1.2–67.9) and mechanical ventilation (aOR 13.9, 95% CI 4.4–43.2) were also significantly higher in patients with ICH. Furthermore, ICH was associated with increased transfusion requirements, including whole blood or red cell transfusion (aOR 4.4, 95% CI 1.5–12.9), platelet transfusion (aOR 14.0, 95% CI 5.3–37.5), and cryoprecipitate or fresh frozen plasma (aOR 28.6, 95% CI 8.0–102.4). No significant associations were found between ICH and disseminated intravascular coagulation (aOR 6.1, 95% CI 0.6–56.2) or vasopressor use (aOR 2.0, 95% CI 0.2–19.5). Patients with ICH experienced significantly longer hospitalizations, with an adjusted increase of 9.9 days (p < 0.05). The mean hospitalization charge for CAR T-cell therapy was $1,321,248.00, with no significant difference between ICH and non-ICH cohorts. Conclusion In this large, nationally representative analysis, non-traumatic intracranial hemorrhage occurred in approximately 1% of CAR T-cell therapy recipients and was strongly associated with increased in-hospital mortality, multi-organ dysfunction, critical care resource utilization, and prolonged hospitalization. These findings highlight ICH as a rare but highly consequential complication of CAR T-cell therapy, likely reflecting severe underlying coagulopathy, thrombocytopenia, and systemic inflammation. Future research should focus on identifying pathophysiologic mechanisms and early clinical predictors to guide risk stratification, prevention, and targeted interventions to improve outcomes in this high-risk population.