A case report in describes a multiple myeloma patient who developed neurocognitive and hypokinetic movement disorders with features of parkinsonism 3 months after receiving an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy.
Symptoms in the patient -- who received the product, ciltacabtagene autoleucel (cilta-cel), as part of a clinical trial -- included gait changes and psychomotor retardation, study author Samir Parekh, MD, of Icahn School of Medicine at Mount Sinai in New York City, told 鶹ý.
"Subsequent evaluation by two independent neurologists confirmed a clinical syndrome with features of parkinsonism, including bradykinesia, postural instability, hypophonia, hypomimia, micrographia and a mild right-sided (action and resting) tremor, as well as saccadic intrusions on smooth pursuit and impaired short-term memory," he and his co-authors wrote.
"Alarmingly, symptoms were getting worse week after week, and this has not been described before," Parekh said.
The team started treatments for Parkinson's disease like levodopa, as well as intrathecal chemotherapy in an attempt to kill the CAR-T cells, but nothing worked. "The CAR-T cells did not get killed, the patient got progressively worse, and ultimately he died," said Parekh.
On autopsy "we found, to our surprise, that the patient had scarring in the area of the brain known as the caudate within the basal ganglia," Parekh said, explaining that this is the area of the brain involved in motor movement -- "so the symptoms fit with where we saw the scarring."
In addition to the scarring in the caudate nucleus, a T-cell infiltrate in the periventricular area of the basal ganglia was identified via immunohistochemistry, along with evidence of the BCMA protein itself.
In other words, Parekh said, neurons in this area of the brain were expressing the BCMA antigen. Myeloma cells are known to express high levels of the same antigen, which is why CAR-T products such as cilta-cel used in the trial this patient was enrolled in () was selected as a potentially effective therapy, Parekh explained.
He and his co-authors noted that there have been several other reports of patients who developed similar symptoms while receiving BCMA-directed CAR T-cell therapy. For example, three additional patients in CARTITUDE-1 developed grade 3 or greater parkinsonism following cilta-cel treatment and another developed the same severe neurological toxicity following treatment with an approved BCMA-directed CAR-T product, idecabtagene vicleucel (ide-cel; Abecma).
Since the early CAR T-cell therapy trials, neurotoxicity has been one of the more concerning side effects, along with cytokine release syndrome. Ide-cel's , for instance, notes that patients should be monitored daily for 7 days following infusion for signs and symptoms of neurological toxicities.
"Rule out other causes of neurologic symptoms," the package insert states. "Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed," and patients should be counseled "to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time."
The labeling also mentions that grade 3 parkinsonism occurred after treatment with ide-cel, suggesting that this complication is not necessarily specific to only one BCMA-targeted CAR-T product, Parekh and co-authors observed. There have been reports of neurotoxicity in general among treated with ide-cel and in treated with cilta-cel.
Parekh and co-authors noted that an analysis of banked blood samples from their patient showed that 70-90% of the T cells in the peripheral blood were CAR-T cells.
"This observation suggested a role for persistent CAR-T cells in the development of the patient's neurologic complaints," the team suggested.
"We also found there are genes in the CAR-T cells that make them more stem-cell like and that this results in the CAR-T cells persisting longer than usual," Parekh added. Thus, there is an opportunity to monitor the CAR-T cells in the blood itself and not wait until the cells have crossed the blood-brain barrier where they can cause neurological damage, he said.
"Using chemotherapy to destroy CAR-T cells after infusion is itself associated with toxicity, as this case shows, because the patient died of infectious complications," the researchers wrote.
Parekh suggested that manufacturers of CAR-T therapies could modify the CAR structure to selectively deactivate the T cells.
Disclosures
Parekh reported relationships with Amgen, Celgene/Bristol Myers Squibb, Foundation Medicine, and Karyopharm.
Primary Source
Nature Medicine
Van Oekelen O, et al "Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy" Nature Medicine 2021; DOI: 10.1038/s41591-021-01564-7.