In the JournalsPerspective

Neurotoxicity Affects Nearly Half of Patients Receiving CAR T-cell Therapy

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.

“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.

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.

PAGE BREAK

“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.

    Perspective
    Bianca D. Santomasso

    Bianca D. Santomasso

    This study adeptly chronicles the clinical aspects of neurotoxicity after the administration of CAR T-cell therapy, many of which have been previously described. However, the strength of this study is the large number of patients and new data included from EEG, FDG-PET, and transcranial Doppler (TCD) testing.

    There have been a few previously described MRI neuroimaging findings, but it is known that CT and MRI imaging do not usually show any structural abnormalities to explain the focal symptoms that are sometimes seen after CAR T-cells are administered.

    The TCD findings are intriguing. TCD can be a way to measure changes in vasculature and/or intracranial pressure, and this study may have picked up on small changes during neurotoxicity. There is some suggestion from other studies that vascular endothelium dysfunction correlates with severe neurotoxicity.

    Vaitkevicius and colleagues were able to show that patients who developed focal neurological changes as part of their neurotoxicity also experienced changes in TCD readings. The only limitation to this finding may be how sensitive the TCD measurements were because not all patients who experience neurotoxicity had TCD changes.

    The TCD results dont appear to predict the grade of neurotoxicity; rather, it appears associated with one very specific aspect of the study group that is, patients who had focal neurologic deficits. Nevertheless, its a noninvasive test and these preliminary results are something that warrant further investigation.

    It was interesting that Vaitkevicius and colleagues found focal FDG-PET changes in some patients and found the same brain regions affected on EEG. They note hypometabolism rather than the hypermetabolism that may often be seen during focal status epilepticus. The question here is whether the PET was done during the ictal-interictal EEG events or if it was done after. Depending on the timing of a seizure, the area of seizure focus can show up as hypometabolic, so the finding doesnt rule out that subclinical seizures are occurring.

    This study confirms that neurological toxicities resulting from CAR T-cell therapy are generally reversible, and even though the course of its clinical symptoms has been previously characterized, the account by Vaitkevicius and colleagues is extremely detailed and it is a good narrative for clinicians to understand which symptoms they may encounter and the order in which they will appear.

    With a focus on the clinical aspects of post-CAR T-cell symptoms, this study is compelling reading material for people who want to better understand what neurotoxicity looks like.

    References:

    Gust J, et al. Cancer Discov. 2017;doi:10.1158/2159-8290.CD-17-0698.

    Santomasso BD, et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-17-1319.

    • Bianca D. Santomasso, MD, PhD
    • Memorial Sloan Kettering Cancer Center

    Disclosures: Santomasso has served as a consultant to Juno/Celgene, Kite/Gilead and Novartis.

    See more from Immuno-Oncology Resource Center