Cytokine Release Syndrome in Adults Undergoing Chimeric Antigen Receptor (CAR) T-Cell Therapy in the United States; A Retrospective Analysis Via the 2021 National Inpatient Sample

Introduction: Cytokine release syndrome (CRS), characterized by immune cell activation and release of inflammatory cytokines, is a common complication of Chimeric Antigen Receptor (CAR) T-cell Therapy, which is used in the treatment of various leukemias, lymphomas, and multiple myeloma. CRS can progress to shock, and it causes higher morbidity, mortality, and increased healthcare burden. Since the incidence of CRS may be impacted by multiple characteristics like age, sex, ethnicity, and body mass index (BMI), we conducted this retrospective analysis to study the statistical correlation between them.

Methods: Our retrospective study utilized de-identified hospital records from the 2021 National Inpatient Sample (NIS), a part of the Healthcare Cost and Utilization Project(HCUP). Procedural codes were applied to extract patients who underwent CAR-T cell therapy between January 1st, 2021, and December 31st, 2021. We excluded all cases younger than 18 years. Events of CRS were identified using the ICD-10 code D89.83x. Potential risk factors for such events were estimated using logistic regression models for multiple patient characteristics and demographics and reported as adjusted odds ratio(aOR), 95% confidence interval (95% CI), and p-values. The impact of CRS on mortality was also calculated.

Results: We identified 2065 patients undergoing CAR T-cell therapy in 2021 that matched our selection criteria. Around 1235 (59.8%) patients reported CRS, and they were older (mean age 60.68 vs. 57.17 years, p<0.01). Further analysis showed that 33.4% of all CAR T cell therapy patients reported CRS grade 1, 20.8% had grade 2, 4.4% had grade 3, and 1.7% had grade 4. Around 1.2% were classified as unspecified grade. Events of CRS were more likely to involve Females (vs. Males, aOR 1.421, 95% CI 1.168-1.730, p<0.01), patients ages 60 or older (aOR 1.659, 95% CI 1.307-2.107, p<0.01), and cases with obesity (aOR 1.761, 95% CI 1.140-2.721, p<0.01). Racial differences were noted with higher odds among Hispanics (aOR 1.475, 95% CI 1.074-2.026, p=0.016) but lower among Blacks (aOR 0.597, 95% CI 0.409-0.870, p<0.01), as compared to Whites. On the contrary, the odds were lower among patients with liver cirrhosis (aOR 0.560, 95% CI 0.339-0.923, p=0.023) and patients covered by Medicaid (vs. Medicare, aOR 0.560, 95% CI 0.362-0.866, p<0.01), while no differences were found for hypertension (aOR 0.963, 95% CI 0.771-1.203, p=0.742), dyslipidemia (aOR 0.823, 95% CI 0.645-1.052, p=0.120 ), diabetes(aOR 1.222, 95% CI 0.911-1.640, p=0.180), chronic kidney disease (CKD)(aOR 0.734, 95% CI 0.515-1.045, p=0.086), weekend(vs. weekday) admissions(aOR 1.196, 95% CI 0.915-1.564, p=0.191), cachexia(aOR 0.889, 95% CI 0.453-1.744, p=0.732), and smoking status(aOR 0.808, 95% CI 0.652-1.001, p=0.052). In addition, CRS grade 4(aOR 8.676, 95% CI 3.434-21.918, p<0.01) was linked with higher odds of death, while grade 1(aOR 0.599, 95% CI 0.269-1.336, p=0.211) showed no statistically significant differences, and grade 2 recorded lower odds (aOR 0.233, 95% CI 0.077-0.701, p=0.01). Finally, CRS patients had a longer hospitalization (mean of 18.39 days vs. 16.10 days, p<0.01), with a higher mean hospital charge ($1207395 vs. $948265, p<0.01).

Conclusion: A considerable number of patients undergoing CAR-T cell therapy experienced events of CRS, which were influenced by various factors. Our study also showed that the odds were higher in the elderly (ages≥60 years), females, Hispanics, and obese patients. Conversely, the patients with liver cirrhosis and having Medicaid coverage had lower odds of having CRS on CAR-T cell therapy. Grade 1 was the most common form of CRS, while grade 4 was the most lethal. As our findings bring forward several crucial implications and given the limitations of the database, it is vital to encourage additional center-based retrospective and prospective studies to map other factors that affect the outcomes of CRS patients.

No relevant conflicts of interest to declare.