Spectrum and prognosis of CAR-T-related endocrine toxicity: glucose/calcium dysregulation, pituitary axis disorders, and overlap with CRS.

BACKGROUND

Chimeric antigen receptor (CAR) T-cell therapy is increasingly used for hematologic malignancies, yet the spectrum and clinical significance of its endocrine adverse events (AEs) remain poorly characterized.

OBJECTIVE

To identify and clinically contextualize signals of endocrine AEs associated with CAR T-cell therapy, with a focus on their overlap with cytokine release syndrome (CRS).

METHODS

We performed a retrospective disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database (2017 to Q2 2025). Reporting odds ratio (ROR) and information component (IC) were calculated for endocrine AEs associated with six CAR T-cell products. To validate and elaborate these pharmacovigilance signals, a structured literature review was conducted to identify published clinical evidence.

RESULTS

The FAERS analysis identified 269 endocrine AE reports, yielding 14 significant disproportionality signals. Hyperglycemia was the most frequently reported event, while estrogen deficiency showed the strongest signal strength (ROR₀₂₅ = 14.93). Signals for adrenal insufficiency and hypothalamo-pituitary disorders were primarily associated with axicabtagene. Critically, mortality was frequently reported among cases with positive endocrine signals, particularly when the endocrine AE co-occurred with CRS. The literature review provided direct clinical validation: a retrospective study confirmed a 39% incidence of CRS-associated hyperglycemia, and independent case reports documented the first instances of CAR T-cell therapy-induced Hashimoto's thyroiditis and central diabetes insipidus. These clinical cases corroborated the FAERS signals and suggested immune-inflammatory mechanisms, often independent of corticosteroid use.

CONCLUSION

This integrated analysis reveals a distinct spectrum of CAR T-cell-related endocrine toxicities, encompassing glucose and calcium dysregulation, pituitary axis disorders, and autoimmune phenomena. The frequent and potentially fatal overlap with CRS underscores the need for enhanced clinical vigilance. Proactive monitoring of endocrine function, especially in patients experiencing CRS, is warranted to mitigate these underrecognized complications.