CAR T-cell therapy-associated central hypothyroidism: a case of a novel onco-endocrine toxicity

Abstract Chimeric antigen receptor T-cell (CAR T-cell) therapy is a cellular-based immunotherapy in which autologous T-lymphocytes are genetically modified to recognize tumor-associated antigens (TAAs). However, TAAs can also be present at low levels in normal tissues, resulting in off-target toxicities. We present a case of a 66-year-old male with relapsing mantle cell lymphoma (MCL) and no prior endocrinopathies who received brexucabtagene autoleucel CAR T-cell therapy. Ten days post-infusion, he developed cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), with severe symptomatic hypothyroidism with undetectable free thyroxine (free T4) and inappropriately low thyroid-stimulating hormone (TSH). Brain magnetic resonance imaging (MRI) with and without contrast did not reveal any pituitary abnormalities, and comprehensive CSF analysis was unrevealing. Levothyroxine therapy was initiated, with subsequent normalization of thyroid function. This report describes an exceedingly rare case of central hypothyroidism following CAR T-cell therapy. We hypothesize that, during CAR T-cell-related acute toxicities, both direct CAR T-cell trafficking to the central nervous system and secondary inflammatory mechanisms may occur, contributing to blood-brain barrier disruption and potential pituitary dysfunction. Baseline thyroid and adrenal function testing may be considered prior to CAR T-cell therapy. If central hypothyroidism is diagnosed, a comprehensive pituitary hormonal evaluation is recommended.