MRI studies show evidence of CAR-T neurotoxicity after clinical symptoms resolve
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ORLANDO — Younger patients who receive chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia may develop brain abnormalities that can take a month or more to resolve, according to interim results of an ongoing prospective, longitudinal study presented at ASH Annual Meeting and Exposition.
Abnormalities related to immune effector cell-associated neurotoxicity syndrome (ICANS) were seen in some patients at 28 days after infusion, after the point at which most ICANS-related abnormalities typically would resolve.
“We are excited about CAR T-cell therapy’s potential to provide a curative therapy for children with ALL, but CAR T-cell therapy can be very toxic, with nearly 40% of patients suffering from a form of neurotoxicity,” Deepa Bhojwani, MD, director of the leukemia and lymphoma program at Children’s Hospital Los Angeles and one of the study’s co-authors, told Healio.
Furthermore, she added, clinicians currently are unable to predict which patients will experience CAR T-cell therapy-related ICANS or why it occurs.
“We have this great opportunity to do this study because we are collaborating with the Institute for the Developing Mind at Children’s Hospital Los Angeles, which has expertise in neurological assessments,” Bhojwani explained.
The collaboration, along with Keck School of Medicine of University of Southern California, will perform several neurological tests on younger patients receiving CAR T-cell therapy to understand the source of the neurotoxicity.
“As we gather more information, we hope to figure out how to prevent neurotoxicity or perhaps how to treat it more effectively once it occurs,” Bhojwani said.
One of the key takeaways from the study’s preliminary results is that assessments of the brain show changes in cortex thickness and blood flow after patients receive CAR T-cell therapy.
changes persist, so we are doing further neuropsychological testing to figure out what these changes really mean for the patient,” Bhojwani said. “The bottom line is that we do see imaging changes while children receive this therapy and develop neurotoxicity, so we want to correlate this with the neuropsychological testing.”
Bhojwani and colleagues presented data on the first seven patients (age range, 5-19 years; 5 males) with relapsed ALL who enrolled in the study. All patients received comprehensive neurological assessments at baseline before a lymphodepleting chemotherapy regimen with fludarabine and cyclophosphamide followed by an infusion of anti-CD19 CAR T cells. Subsequent assessments were performed after infusion on days 10 and 28.
Evaluations included multimodal MRI of the brain, neurophysiological testing, serum measurements of blood-brain barrier permeability and cytokines, and immune cell profiles in peripheral blood.
Researchers also gathered baseline multimodal MRI and neuropsychological testing results from a healthy control group of nine patients (age range, 5-20 years; 7 males).
Five of the patients in the study group developed cytokine release syndrome, whereas four patients had ICANS.
Patients who received CAR T-cell therapy had a thinner cortex across large portions of the brain at baseline compared with healthy controls. Brain imaging of cortical thickness and blood perfusion showed that by day 10 after CAR T-cell infusion, cortical thickness decreased in the postcentral gyrus (PoG) and posterior temporal lobe (pTL).
Assessments at day 28 showed that the cortex had thickened in the PoG but continued thinning in the pTL among those who received CAR T-cell therapy.
Blood flow results showed that patients with ALL who received CAR T-cell therapy had lower regional cerebral blood flow (rCBF) in the thalamus, insular cortex and cingulate gyrus, and higher rCBF in the genu of the corpus callosum (gCC).
Regional CBF increased in the thalamus and decreased in the putamen and gCC by day 10 after CAR T-cell infusion; rCBF in the thalamus decreased and reverted toward baseline values by day 28 after infusion, whereas rCBF in gCC continued to decrease away from baseline values.
Peripheral blood analyses showed expansion of monocytes and myeloid-derived suppressor cells by day 10 after CAR T-cell infusion.
“In these immune cells, phosphorylation of key signaling proteins (eg, extracellular-signal regulated kinase, ERK 1/2) increased in response to external stimulation,” Bhojwani and colleagues wrote in their analysis.
“If we identify those children who are likely to have severe neurotoxicity before providing CAR T-cell therapy, then we will be able to monitor them closely and even offer them so prophylactic therapy to decrease the severity of the neurotoxicity,” Bhojwani told Healio.
She added that if the study can provide insights into why neurotoxicity occurs, for example by examining changes in the brain, blood, cytokines or spinal fluid that are precursors to ICANS, then future research could lead to therapies that could mediate or even prevent the neurotoxicity.
One of the suspiring findings from the study so far are the changes in MRI findings that persist after 28 days — a period in which neurotoxicity symptoms usually resolve, according to Bhojwani.
“Even if the patient has recovered from the clinical symptoms of neurotoxicity, these changes persist, and it’s important for us to follow these patients up to 6 months or 1 year, to determine if these changes are permanent,” she said. “Most of our thought processes are that these changes are transient, but they may be subtle changes that require more refined neuropsychological measures to determine if they have a lasting effect in these patients.” – by Drew Amorosi
Reference:
Bhojwani D, et al. Abstract 1946. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
For more information:
Deepa Bhojwani, MD, can be reached at Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027; email: dbhojwani@chla.usc.edu.
Disclosures : Bhojwani reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.