Baseline Neurofilament Light Levels Predict Neurotoxicity With CAR T-Cell Therapy

The risk of developing immune effector cell–associated neurotoxicity syndrome (ICANS) in patients treated with chimeric antigen receptor (CAR) T-cell therapy is associated with plasma neurofilament light chain (NfL) levels and therefore preexisting neuroaxonal injury, according to a paper published in JAMA Oncology.¹

“Our study suggests that some patients receiving CAR-T cell therapy have previously undetected damage to neurons present at baseline, before we even begin preparing them for this treatment,” lead author Omar H. Butt, MD, PhD, instructor of medicine, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University in St. Louis (WUSTL) School of Medicine, said in a statement.² “We don’t know the origin of this damage, but it appears to predispose them to developing neurotoxic complications. If we understand who is at risk of these complications, we can take early steps to prevent it or reduce the severity.”

Butt and colleagues evaluated data from 30 patients with a history of diffuse large B-cell lymphoma that received CAR T-cell therapy in a retrospective, 2-center study.¹ These patients had a median age of 4 years (range, 22-80) and 40% were women (n = 12). Investigators compared NfL levels at baseline, during lymphodepletion, and at 1, 3, 7, 14, and 30 days after infusion. They used receiver operating characteristic (ROC) classification to model prediction accuracy for developing ICANS and univariate and multivariate modeling to examine associations between NfL, ICANS, and other risk factors including demographics and oncologic, neurologic, and neurotoxic histories.

“Measures of NfL in the blood are being used as a way to evaluate the effectiveness of potential new therapies for multiple sclerosis,” co-senior author Beau M. Ances, MD, PhD, Daniel J. Brennan Professor of Neurology, WUSTL, added to the statement.² “We plan to continue our studies to find the origin of neuronal damage in these cancer patients. This is a unique collaboration that was possible at Washington University because we have some of the top experts in CAR-T cell therapy and leading expertise in neurodegenerative diseases. It presents a great opportunity to bridge gaps and bring these fields together to try to solve a vexing problem and help patients.”

READ MORE: Axi-Cel More Efficacious With Higher Toxicity Than Tisa-Cel in Diffuse Large B-Cell Lymphoma

The study found that patients who developed any grade ICANS had NfL elevations (mean, 87.6 pg/mL) prior to lymphodepletion and CAR T-cell infusion compared with those who did not develop ICANS (mean, 29.4 pg/mL; P < .001).¹ Patients with low-grade (1-2) ICANS had a mean 115.3 pg/mL NfL level and patients with grade 3 or higher had a mean 71.7 pg/mL NfL level. The low-grade and high-grade subgroups did not significantly differ from one another.

“We’re just seeing the tip of the iceberg in terms of the actual disease process, and that’s where many of our future studies are going,” Butt added.² “We’re trying to get a better sense of what is causing these changes to begin with. And in later stages, even after symptoms have resolved, we still see these elevated NfL levels.”

ICANS grade and NfL baseline levels had an r correlation factor of 0.74 and baseline NfL accurately predicted ICANS development (area under the curve [AUC], 0.96; sensitivity, 0.91; specificity, 0.95).¹ Baseline NfL levels did not correlate with any demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies. NfL levels remained elevated at all timepoints up to 30 days after infusion.

“We have a study ongoing at Siteman to see if, in fact, these patients continue to have subtle symptoms in terms of cognitive changes or deficits that persist long term,” co-senior author Armin Ghobadi, MD, associate professor of medicine and clinical director, Center for Gene and Cellular Immunotherapy, Washington University School of Medicine and Siteman Cancer Center, added to the statement.²

REFERENCES

1. Butt OH, Zhou AY, Caimi PF, et al. Assessment of pretreatment and posttreatment evolution of neurofilament light chain levels in patients who develop immune effector cell–associated neurotoxicity syndrome. JAMA Oncol. Published online September 01, 2022. doi:10.1001/jamaoncol.2022.3738
2. Simple blood test predicts neurotoxic complications of CAR-T cell therapy. News release. Washington University in St. Louis. August 31, 2022. https://www.newswise.com/articles/simple-blood-test-predicts-neurotoxic-complications-of-car-t-cell-therapy