Enhanced Risk of Cytokine Release Syndrome in Obese and Related Comorbidities Undergoing CAR-T Therapy for B-Cell Malignancies

Background

As the application of Chimeric Antigen Receptor T-cell (CAR-T) therapy expands to become a standard treatment for B-cell malignancies, it becomes crucial to understand how obesity and related underlying diseases such as diabetes, hypertension, and hyperlipidemia impact both the safety and efficacy of this potent therapeutic option. These conditions could modify the patient's immune system behavior, potentially leading to amplified adverse effects such as cytokine release syndrome (CRS) and neurotoxicity. Thus, assessing each patient's complete health profile is essential to tailor CAR-T treatment strategies optimally and enhance therapeutic outcomes.

Methods:

This retrospective analysis encompassed 115 patients diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) treated with CAR-T therapy at Tongji Medical College, Huazhong University of Science and Technology Union Hospital, from 2017 through October 2023. The study collected extensive data including body mass index (BMI), presence of hyperlipidemia, hypertension, diabetes, coronary heart disease, and fatty liver. Clinical outcomes such as cytokine release syndrome (CRS), CAR-T cell-related encephalopathy syndrome (CRES), treatment efficacy, overall survival (OS), and progression-free survival (PFS) were measured. Descriptive statistics summarized patient baseline characteristics, while logistic regression models explored the relationships between various health covariates and clinical outcomes. Statistical significance was considered for p-values less than 0.05, with all analyses conducted using R software (version 4.2).

Results:

The median BMI among the 115 participants was 21.91, with an interquartile range of 19.265 to 24.365. Out of the cohort, 32 patients were overweight (only one had a BMI over 30), 26 presented with hyperlipidemia, and 13 had hypertension. Patients classified within the high-risk group (n=53) included those with a BMI greater than 24 and/or the presence of any related comorbidity. In contrast, patients in the low-risk group (n=62) did not meet these criteria. The analysis revealed no significant differences in overall treatment efficacy or prognosis between the groups (p=0.75). Severe CRS occurred in 16 patients, with a higher proportion in those with obesity or related conditions (10.4% vs. 3.5%, p=0.01). Hyperlipidemia significantly increased the risk of severe CRS (OR=3.730, CI [1.204-11.556], p=0.022). However, being overweight, having diabetes, hypertension, coronary heart disease, or fatty liver were not significantly associated with severe CRS. Elevated total cholesterol was moderately correlated with increased IL-6 levels (R=0.637, p<0.001) and weakly with IFN-γ (R=0.337, p<0.001). Overweight patients had a lower proportion of CAR-T cells post-infusion (OR=0.98, CI [0.961-1.0], p=0.048).

Conclusion:

Obesity and related comorbidities, particularly hyperlipidemia, significantly elevate the risk of developing severe CRS among patients undergoing CAR-T therapy for B-cell malignancies, though they do not detrimentally affect the overall efficacy of the treatment. These findings underscore the critical need to integrate a comprehensive assessment of patients' metabolic and health profiles into the CAR-T therapy planning process. This approach aims to predict and mitigate the severity of CRS and customize preventative strategies to manage potential severe side effects, ensuring a more targeted and safer therapeutic journey for each patient undergoing this advanced treatment modality.

Keywords: CAR-T therapy, obesity, hyperlipidemia, B-cell malignancies, cytokine release syndrome, treatment efficacy.

No relevant conflicts of interest to declare.