Long-Term Neurological Outcomes of Patients Treated with CAR-T Therapy

By Evan Noch, MD, PhD

Assistant Professor, Department of Neurology, Weill Cornell Medicine

SYNOPSIS: Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of lymphoma, leukemia, and multiple myeloma, but its use is associated with early neurotoxicity in almost half of patients. Despite the incidence of neurotoxicity, long-term follow-up of patients after CAR-T infusion suggests that patients’ neurological examination, neuro-imaging studies, and cognition remain unaffected by this treatment.

SOURCE: Ursu R, Maillet D, Belin C, et al. Long-term neurologic safety in patients with B-cell lymphoma treated with anti-CD19 chimeric antigen receptor T-cell therapy. Neurology 2022;99;511-515.

Chimeric antigen receptor (CAR)-T cell therapy was first developed in the 1980s and has revolutionized the treatment of lymphoma, being approved by the U.S. Food and Drug Administration (FDA) in 2017 for relapsed/refractory lymphoma. The FDA now has approved six CAR-T therapies exclusively for the treatment of lymphoma, leukemia, and multiple myeloma. However, the efficacy of CAR-T therapy for solid malignancies is under active investigation.

Despite the therapeutic success of CAR-T-directed therapy, use of this cell-based therapy is limited by cytokine release syndrome and neurotoxicity, the latter of which occurs in approximately half of patients in the form of direct neurotoxicity and/or immune effector cell-associated neurotoxicity (ICANS). Several studies have examined short-term neurocognitive sequelae of CAR-T therapy, but few studies have defined the long-term trajectories of neurotoxicity in patients.

In the study by Ursu et al, the authors enrolled patients at the Assistance Publique-Hôpitaux de Paris who received CAR-T therapy between October 2018 and August 2019. They followed these patients for two years after initial therapy and obtained the following studies at baseline and at two years: complete neurological examination, brain magnetic resonance imaging (MRI), neuropsychological testing, and self-administered questionnaires. Fifty-two patients were included for analysis. Of these, 20 patients died and 13 exhibited disease progression by two years after CAR-T infusion, leaving 19 patients who remained disease-free at two years after CAR-T infusion.

After CAR-T treatment, 11 patients exhibited neurotoxicity, with cognitive dysfunction being the most common toxicity reported. Steroids were administered to six patients and anticonvulsants to five patients. Within 42 days, neurotoxicity resolved in all patients.

Remarkably, in this population of 19 patients, none exhibited neurotoxicity at two years after CAR-T-cell infusion. One patient exhibited mild and fluctuating paresthesia, with blood and cerebrospinal fluid testing, electromyography, and metabolic, infectious, and autoimmune work-up unrevealing. To analyze neuro-imaging correlates of neurotoxicity, MRI brain scans were performed in all patients but did not show any changes from baseline. Likewise, neuropsychological testing, which included tests of episodic memory, short-term memory, executive function, language, and praxis, were all similar to baseline. Interestingly, the authors found no correlation between the incidence of ICANS and cognitive function two years after treatment.

In self-administered questionnaires, patients reported greater cognitive dysfunction at two years, but this was not statistically significant. However, the authors did find that levels of anxiety and depression improved at two years, likely an indicator of the long period of remission.

COMMENTARY

CAR-T therapy is a powerful tool in the treatment of liquid malignancies, including lymphoma, leukemia, and multiple myeloma, and is being tested in the treatment of solid tumors. Despite its therapeutic success, about half of patients will experience neurotoxicity within the first two weeks after CAR-T infusion. This neurotoxicity often necessitates the use of corticosteroids and/or anticonvulsants to control cerebral edema and seizures, respectively. However, the long-term neurological outcomes of patients after CAR-T therapy remain undefined.

In this study of 19 patients who survived after CAR-T infusion and remained disease-free after two years, none exhibited any changes in their neurological exam, neuro-imaging studies, or cognition based on in-depth objective assessments. The incidence of ICANS after initial CAR-T therapy also did not herald worse neurological prognosis at two years and had no effect on long-term cognition. Interestingly, the authors found that anxiety improved two years after treatment, which likely is explained by patients’ remission from lymphoma.

Together, these results provide reassurance regarding the long-term neurological safety of CAR-T therapy and may help to assuage patients’ fears going into treatment. Future studies are needed to expand the number of CAR-T-treated patients studied over the long term, to examine the neurological outcomes of patients treated with other CAR-T products, and to define the neurological outcomes of CAR-T therapy in the treatment of other malignancies.