Early intrathecal therapy shows promise for managing neurotoxicity related to CAR-T
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Early intrathecal therapy effectively resolved symptoms related to high-grade neurotoxicity among patients who received chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma, according to a research letter in JAMA Oncology.
Those who received early intrathecal therapy after developing high-grade steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS) achieved superior outcomes 1 year after therapy.
Background
Approximately 10% of patients experience high-grade ICANS after CAR T-cell therapy, but prevalence can be as high as 30% depending on the type of CAR-T and the disease being treated, according to Nirav N. Shah, MD, associate professor of hematology and medical oncology at Medical College of Wisconsin and member of the Healio | Cell Therapy Next Peer Perspective Board.
High-grade ICANS is a relatively rare toxicity, and there is considerable variability in the presentation of symptoms and how those symptoms are managed, Shah said.
“But ICANS can often be devastating when it occurs,” he told Healio.
The standard approach is to provide patients with dexamethasone to resolve high-grade ICANS, Shah said.
“When you give dexamethasone, you have to provide high doses to penetrate the central nervous system,” Shah said. “This has systemic side effects for the entire body and can theoretically impact the efficacy of CAR T cells.”
The intrathecal method is more effective because it treats the brain directly, as opposed to the additional time it takes systemic dexamethasone to reach cerebrospinal fluid, Shah said.
“Our approach is to treat the problem at the source,” he said. “By providing a steroid with or without chemotherapy intrathecally, we can eliminate the immune effector cells within the spinal fluid that are driving the toxicity and limit exposure to systemic corticosteroids.”
Methodology
Shah and colleagues conducted a retrospective study that included 74 patients who received CAR T cells at their institution either commercially or via one of two clinical trials.
The study group included 15 patients (mean age, 64.9 years [standard deviation, 10.8]; 53% men) who received commercial CD19-directed CAR-T cells or an investigational bispecific CD19/CD20-directed CAR-T for relapsed or refractory non-Hodgkin lymphoma and subsequently developed high-grade ICANS.
Seven patients had steroid-refractory ICANS and received early intrathecal therapy within 5 days of onset of high-grade symptoms. One patient received late intrathecal therapy 24 days after onset of ICANS. The other seven patients did not receive intrathecal therapy and instead received standard steroids.
Early intrathecal therapy included hydrocortisone. Patients whose ICANS did not respond to intrathecal hydrocortisone alone underwent combination therapy that included hydrocortisone plus chemotherapy.
Median follow-up was 611 days (range, 184-953).
Key findings
ICANS resolved in all seven patients who received early intrathecal therapy.
Patients with high-grade ICANS had symptoms improve to grade 1 a median 6 days (range, 1-15) after symptom onset. Patients who received early intrathecal therapy had their ICANS symptoms improve to grade 2 within a median 2 days (range, 1-5) or grade 1 by a median 5 days (range, 1-11).
Researchers reported estimated 1-year PFS and OS rates of 57.1% among patients with steroid-refractory ICANS who received early intrathecal therapy; 18.8% among patients who developed high-grade ICANS and received no/late intrathecal therapy; and 0% among patients with steroid-refractory ICANS who received no/late intrathecal therapy.
Clinical implications
Shah said his center’s positive experience with the use of early intrathecal therapy has led him and his colleagues to strongly consider its use closer to the onset of high-grade ICANS rather than waiting to see if patients respond to dexamethasone.
“I’ve seen incredible outcomes using this method,” he told Healio. “Our major motivation is to help patients, and this is something that could help patients immediately.”
Early intrathecal therapy to resolve ICANS is not common practice, Shah said, adding that some clinicians unfamiliar with its use for this purpose may be skeptical about its effectiveness.
“One of the reasons we wanted to publish this data is because clinicians can use this method today,” Shah said. “It's a low-risk, high-reward intervention.”
For more information:
Nirav N. Shah, MD, MS, can be reached at Blood and Marrow Transplant and Cellular Therapy Program, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226; email: nishah@mcw.edu.
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