Description of neurotoxicity in a series of patients treated with CAR T-cell therapy

Abstract

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities

“…The second major toxicity reported following CD19-targeted CAR-T cell therapy is neurotoxicity. Similar to CRS, neurotoxicity symptoms also range in severity and type, including headaches, delirium, dysphasia, ataxia, dysmetria, decrease in level of consciousness, seizures and acute cerebral edema [ 27 , 28 , 29 ]. The incidence of neurotoxicity among CAR-T cell-treated patients is quite variable, with some neurological events occurring in combination with CRS symptoms and others at different times or in the absence of CRS, suggesting that at least in some cases the mechanism of CAR-T cell induced neurotoxicity is different to that of CRS [ 30 , 31 ].…”

Severe Motor Weakness Due to Disturbance in Peripheral Nerves Following Tisagenlecleucel Treatment

“…ICANS, like CRS, is a severe adverse effect of CAR Tcell therapy, and the mechanisms are poorly understood. Motor weakness is a symptom of ICANS; however, there have been a few reports on motor weakness after CAR T-cell therapy (13)(14)(15)(16). In a report specific to neurotoxicity following CAR T-cell therapy, 11 cases of focal weakness were reported (15).…”

“…Cognitive impairment is the most common symptom, and it is usually resolved by appropriate therapy. On the other hand, there are few reports on motor weakness associated with CAR T-cell therapies, the details of which remain unclear (13)(14)(15)(16).…”

Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

“…NTX is another common complication of CAR-T cell immunotherapy that occurs in more than 40% of patients ( Belin et al, 2020 ). NTX described as CAR-T cell-related Encephalopathy (CRES) by Neelapu et al (2018) and, more recently described under the name of ICANS (Immune effector Cell–Associated Neurotoxicity Syndrome) ( Lee et al, 2019 ), is less understood than CRS and usually appears within one to 3 weeks after CAR-T cell infusion, which is frequently correlated with CRS ( Siegler and Kenderian, 2020 ).…”