Immuno-Oncology Resource Center
Immuno-Oncology Resource Center
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Source: Rubin DB, et al. Brain. 2019;doi;10.1093/brain/awz053.
July 25, 2019
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Neurotoxicity Affects Nearly Half of Patients Receiving CAR T-cell Therapy

Source/Disclosures
Source: Rubin DB, et al. Brain. 2019;doi;10.1093/brain/awz053.
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New data revealed that 48% of patients who received chimeric antigen receptor T-cell therapy for cancer treatment experienced neurological toxicity, according to a retrospective review published in Brain.

The research also indicated that transcranial Doppler ultrasound may be a useful adjunct biomarker for CAR T-cell–induced neurotoxicity.

“We now know what an expected course of neurotoxicity after CAR-T infusion is,” Henrikas Vaitkevicius, MD, an assistant professor of neurology at Brigham and Women’s Hospital and one of the study’s coauthors, told Cell Therapy Next.

Henrikas Vaitkevicius, MD
Henrikas Vaitkevicius

Vaitkevicius said that previous studies showed “severe neurological toxicities with unusual features [that] were poorly characterized.” Therefore, his group “attempted to systematically catalog the toxicity pattern observed” up to 2 months after infusion in a consecutive series of the first 100 patients who received CAR T-cell therapy at Dana-Farber Cancer Institute and Brigham and Women’s Hospital. The CAR T-cell infusions took place between 2015 and 2018.

Researchers obtained 28 patients’ data via chart review; the remaining patients were observed prospectively. Median age of the cohort was 64.5 years (range, 21-78 years), and 39% were women. The treatment diagnoses included lymphoma (74%), multiple myeloma (14%), leukemia (10%) and sarcoma (2%).

The study used the NCI’s Common Terminology Criteria for Adverse Events (CTCAE) to grade symptoms of toxicity.

CRS occurred in 77% of patients; the median day of CRS onset was day 1 after infusion and median day of peak CRS severity was day 4 after infusion. The median duration of CRS symptoms was 6 days, and the median CTCAE grade of maximum CRS severity was 2.

Grade 2 CRS was most frequently experienced (34%) by patients in the study, followed by grade 1 (30%), grade 3, (9%) and grade 4 or 5 (2% for both).

Neurotoxicity was specifically graded in 48 patients, with a median of 6 days (range, 1-34 days) to neurotoxicity onset; peak toxicity occurred at a median of 8 days after infusion, with a median of 8.5 days’ duration. All patients in this study who experienced neurotoxicity had CRS.

The median CTCAE severity grade of neurotoxicity was 2.

The most common neurological symptoms observed included encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%).

“Neuroimaging studies were commonly performed for the evaluation of neurotoxicity but rarely revealed structural abnormalities,” Vaitkevicius and colleagues wrote. Among the neuroimaging studies they reviewed were electroencephalogram, PET, CT, MRI and transcranial Doppler.

However, the study showed increased flow velocity via TCD in patients with CAR T-cell therapy–induced neurotoxicity. The investigators noted that patients with focal neurological deficits had significantly greater flow velocities in all vessels compared with patients who had non-localizing neurological symptoms.

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“Neurotoxicity from CAR-T is frequent and mostly reversible, likely triggered by CRS and not mediated by ischemia or seizures,” Vaitkevicius told Cell Therapy Next. “TCDs may prove to be a valuable biomarker.”

Vaitkevicius said that the lack of structural abnormalities in a setting of such severe neurotoxicity surprised his group.

All neurologists should familiarize themselves with the neurotoxic effects of CAR T-cell therapy, he added.

“This paper sets a stage for predictive scores and potential biomarkers of toxicity,” Vaitkevicius said. – by Drew Amorosi

Disclosures: Vaitkevicius reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.