For Your Patients-Neurotoxicity
Neurotoxicity May Arise from CAR-T Cancer Therapy
By Edward Susman
June 7, 2018
ARTICLE IN BRIEF
Almost half of patients undergoing CAR-T therapy for treatment of relapsed/refractory B cell acute lymphoblastic leukemia developed Grade 3-4 neurotoxicity, investigators reported at the AAN Annual Meeting.
LOS ANGELES—Patients undergoing a novel cancer treatment — chimeric antigen receptor T-cell (CAR-T) therapy — are at high risk of developing neurological complications that occur after the cancer fighting cells are infused, researchers reported here at the AAN Annual Meeting in April.
CAR-Ts are T cells that have been genetically modified to bind to a ligand found on a target cell, such as a tumor cell. The binding of receptor and ligand causes the T cell to kill the tumor cell and to proliferate. [CAR-T therapy is being studied for use in glioblastoma; see the April 5, 2018 Neurology Today article, “At the Bench-Glioblastoma: Immunotherapy for Glioblastoma Has a New and Potentially Powerful Target.”]
While a so-called cytokine storm can affect the brain, so too can a subsequent second adverse event, said Bianca Santomasso, MD, PhD, neuro-oncologist assistant attending physician at Memorial Sloan-Kettering Cancer Center in New York.
In fact, she said that as many as 40 percent of patients undergoing CAR-T therapy develop neurological events. “This neurotoxicity reaction is related to cytokine release syndrome, which is thought to occur when the CAR-T cells engage the cancer target, but the cytokine release syndrome may occur exclusively of each other and with distinct timing and response to intervention,” she said.
“The clinical spectrum of cytokine release syndrome is fever, hypotension, capillary leak, respiratory insufficiency, hyperferritinemia/macrophage activation syndrome, coagulopathy/disseminated intravascular coagulation, and multi-organ failure,” Dr. Santomasso said. “Up until recently, neurotoxicity was lumped into cytokine release syndrome with the brain being ‘just another’ organ system in the multi-organ failure. But we now think it represents a distinct process with perhaps a distinct pathophysiology.”
“The clinical spectrum of neurotoxicity includes delirium, encephalopathy, aphasia, seizure and seizure-like activity, tremor/myoclonus, hallucinations and, in rare cases, diffuse cerebral edema. There have been some cases of fatal diffuse cerebral edema with CAR-T cell therapy,” she said.
Dr. Santomasso said that neurotoxicity might involve a distinct pathophysiology from cytokine release syndrome because while it can occur simultaneously with cytokine release syndrome, neurotoxicity often occurs a few days after the cytokine release syndrome has resolved. She added that while neurotoxicity may occur when there is a strong cytokine release syndrome event, neurotoxicity may also occur in the setting of a mild cytokine release syndrome event.
“The anti-interleukin 6 [IL-6] receptor monoclonal antibody tocilizumab rapidly ameliorates cytokine release syndrome, but our experience has been that it doesn't help neurotoxicity. We use dexamethasone to ameliorate neurotoxicity,” she said. “This may seem counterintuitive, since steroids could potentially interfere with the T cells' efficacy against the cancer, but other studies have shown that there is no statistically significant diminution in the anti-tumor response.”
In her study, Dr. Santomasso reported that 22 of 53 patients undergoing CAR-T therapy for treatment of relapsed/refractory B cell acute lymphoblastic leukemia developed Grade 3-4 neurotoxicity. These complications included aphasia, encephalopathy, depressed consciousness, myoclonus, and seizure.
Felipe Samaniego, MD, associate professor of medicine at University of Texas MD Anderson Cancer Center in Houston, who has treated patients with CAR-T therapy, told Neurology Today, “One form of neurotoxicity is associated with cytokine release syndrome primarily caused by IL-6 which can affect the brain and manifests as a cytokine-related encephalopathy and mental dysfunction. This occurs with the cytokine rise. This condition responds to treatments that block IL-6 such as tocilizumab.
“There is another form of encephalopathy, which occurs later and is not related to high cytokines, and this version is treated with steroids. When this occurs, we again check for IL-6 levels and if those levels are not high then we would think about using steroids to alleviate some of the brain problems.
“Our experience is consistent with what Dr. Santomasso has reported in her research,” Dr. Samaniego said. The treatment that produces the cytokine release syndrome is a double-edged sword — the cytokines attack and destroy the cancer cells, but they also have the effect of creating adverse effects such as neurotoxicity, which demands close management.
“When the cytokines build up too much and cause toxicity, we have to add drugs that slow down that cytokine response. There are risks to this therapy, but CAR T-cell therapy is given to patients who have no other options. This adds to what we can do for patients,” Dr. Samaniego said.
“We are still learning how to best manage patients,” he said. “Patients who are getting CAR T-cells are expected to stay in the hospital about 14 days, so we are able to take care of any problems like this that arise.”
“These neurotoxicity events usually begin to resolve after a few days for most patients,” said Olalekan Oluwole, MD, MPH, assistant professor of medicine at Vanderbilt University in Nashville, TN. “We have not yet seen any of these events in which the patients experienced long-term effects.”
Dr. Oluwole, who has been treated several patients undergoing CAR-T therapy, told Neurology Today: “We do see neurological events as described by Dr. Santomasso and colleagues. However, to be clear, the serious or more clinically significant events are closer to 30 percent in our experience.”
He said that at Vanderbilt the team that follows the CAR T-cell patients includes a neuro-oncologist. “However, the inclusion of a neuro-oncologist is institution-dependent,” he said. “What helps most is dose monitoring and early recognition of symptoms which allows prompt intervention.”
Dr. Santomasso concurred. “The ultimate goal is to develop safer CAR-T cells or preventative interventions to reduce neurotoxicity and cytokine release syndrome,” she said. “Until we get to this point, these treatments should only be given in trained facilities where a multidisciplinary approach can be implemented for response to these reactions.”