Impact of pulmonary and cardiac comorbidities on cytokine release syndrome incidence in chimeric antigen receptor (CAR) t-treated diffuse large B-cell lymphoma (DLBCL) patients: A real-world data analysis

Abstract

Abstract Background: CAR T-cell therapies using genetically modified autologous T cells targeting CD19 have been approved for third-line therapy of DLBCL, demonstrating promising results with durable remissions. The most notable associated toxicity is cytokine release syndrome (CRS), a systemic inflammatory response resulting from massive cytokine secretion. There is a paucity of research examining how pre-existing common comorbidities, specifically pulmonary and cardiac diseases, influence the development of CRS in patients treated with CAR T-cell therapy. To address this knowledge gap, this analysis leverages real-world data (RWD) to evaluate the risk of development and potential differences in CRS rates, as well as the impact on overall survival (OS) for DLBCL patients with and without pulmonary and cardiac comorbidities who have undergone CAR T-cell therapy. Methods: A retrospective, multicenter RWD analysis was conducted using the TriNetX database on 7th July 2025. Two cohorts were analyzed: 1) DLBCL patients with pulmonary and/or cardiac comorbidities, and 2) DLBCL patients without pulmonary and cardiac comorbidities. All patients received CAR–T–cell therapy with either tisagenlecleucel, lisocabtagene maraleucel, or axicabtagene ciloleucel. We analyzed the demographic characteristics of both cohorts. Cardiac comorbidities included angina pectoris, atherosclerosis, or hypertensive diseases. Pulmonary comorbidities included asthma, acute or chronic sinusitis, chronic obstructive pulmonary disease, or sleep apnea. In addition, Kaplan-Meier analysis, log-rank test hazard ratios (HR), risk ratios (RR), and 95% confidence intervals (CI) were used to assess the primary outcomes, which were the risk of development of CRS (any grade or unspecified grade) and potential impact on overall survival. Results: We identified 2,590 patients with DLBCL whose data regarding CRS development were available within 90 days after CAR-T therapy. The patients' mean age at the index event for Cohorts 1 and 2 was 63.9±12.2 years and 58.3±14.1 years, respectively. 63.22% of patients were male in Cohort 1, whereas 60.57% were male in Cohort 2. 40% of patients in Cohort 1 experienced CRS compared to 28% in Cohort 2 (p<0.001). For a 3-month time window from the index event (time of CAR-T therapy), Cohort 1 had a statistically significantly higher risk of CRS development compared to Cohort 2 (RR 1.434, 95% CI 1.278-1.610). Twelve month overall survival probability did not differ between Cohort 1 and Cohort 2 patients who developed CRS (survival probability at 12-months 70.16% vs. 73.82%, respectively; log-rank test χ2=1.060, p=0.303), nor was there a significant difference in risk of death at 12 months (HR 1.153, 95% CI 0.879-1.511). A key limitation of this analysis is the absence of patient-level data detailing the specific nature and severity of individual comorbidities.Conclusions: This real-world analysis demonstrates that DLBCL patients with pre-existing pulmonary and/or cardiac comorbidities have a significantly higher risk of developing CRS following CAR T-cell therapy compared to those without such comorbidities. Interestingly, despite the increased incidence of CRS, the presence of these comorbidities did not significantly impact short-term overall survival among patients who developed CRS. These findings underscore the importance of careful patient selection and vigilant monitoring for CRS in DLBCL patients with pulmonary and/or cardiac comorbidities undergoing CAR T-cell therapy. Further research is warranted to elucidate the long-term outcomes and to develop personalized management strategies for this high-risk patient population.