A score based on routinely measured clinical and laboratory parameters was developed and evaluated to facilitate prediction of neurotoxicity in patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, according to a study published in JAMA Neurology.

Three CD-19–directed CAR-T therapies are currently approved by the US Food and Drug Administration (FDA): axicabtagene ciloleucel, tisagenlecleucel, and brexucabtagene autoleucel.

The first 2 agents are indicated for the treatment of adult patients with refractory large B-cell lymphoma (DLBCL) after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.2,3 Tisagenlecleucel is also indicated for children and young adults aged 25 or younger with relapsed, refractory B-cell precursor acute lymphoblastic leukemia (ALL),3 whereas brexucabtagene autoleucel is indicated for adult patients with relapsed/refractory mantle cell lymphoma.4

Neurotoxicity is a common and potentially serious complication of CAR-T therapy that, according to the study authors, can manifest as “encephalopathy, aphasia, focal weakness, numbness, apraxia, seizures, or in rare cases, fulminant cerebral edema and death.”  Nevertheless, the delivery of CAR-T therapy is not associated with the development of neurotoxicity in all patients treated with this approach.


Continue Reading

Furthermore, while most patients who develop CAR-T–related neurotoxicity experience symptoms within 1 week of treatment, the timing of neurotoxicity, as well as the severity of symptoms, can vary across patients, leading the study authors to comment that “early identification of risk of neurotoxicity may allow for more appropriate triage and anticipatory care of patients receiving [CAR-T] therapy.”

This study included all consecutive patients with relapsed/refractory DLBCL, primary mediastinal B-cell lymphoma, follicular lymphoma, or marginal zone lymphoma admitted to Brigham and Women’s Hospital/Dana-Farber Cancer Institute in Boston, Massachusetts, for treatment with axicabtagene ciloleucel between April 2015 and February 2020.

Signs, symptoms, severity, and timing of cytokine release syndrome (CRS) and neurotoxicity, as well body temperature, serum levels of C-reactive protein, white blood cell (WBC) count, fibrinogen, ferritin, procalcitonin, lactate dehydrogenase, interleukin-6, and number of doses of tocilizumab administered were evaluated in this group of patients during the first 5 days of admission.

Those admitted for CAR-T therapy from April 2015 to April 2019 made up the derivation cohort (126 individuals) whereas those admitted between May 2019 and February 2020 were included in the internal validation cohort (78 individuals).

Approximately 58% of patients in both cohorts developed neurotoxicity.

Based on a multivariable analysis of these findings, a clinical score for prediction of neurotoxicity was developed in which 1 point was assigned for each of the following parameters: patient age 52 years or older, maximum serum CRP level of 8.95 ng/dL or higher, maximum serum ferritin level of 641 ng/mL or higher, minimum WBC count of 790/µL or lower, and any-grade CRS onset by day 2. In addition, 2 points were assigned for aggressive disease subtype, maximum body temperature of 38.5 degrees Celsius or higher, and CRS severity score of at least 1, and 3 points were given if at least 1 dose of tocilizumab was administered.

Hence, an overall score of between 0 and 14 points, representing lowest and highest probabilities of neurotoxicity, respectively, was possible for each patient.

Using a cutoff of 6 or higher to designate neurotoxicity, the accuracy of the score was found to be 77% in the internal validation cohort, with 82% and 70% sensitivity and specificity, respectively.

“The score developed in this study may allow clinicians to more precisely allocate resources, anticipate patient needs, and facilitate earlier discharge from the hospital,” the study authors noted in their concluding remarks.

References

  1. Rubin DB, Al Jarrah A, Li K, et al. Clinical predictors of neurotoxicity after chimeric antigen receptor T-cell therapy. JAMA Neurol. Published online August 10, 2020. doi:10.1001/jamaneurol.2020.2703
  2. Axicabtagene ciloleucel (Yescarta®)[package insert].[WU1]  Santa Monica, CA: Kite Pharma, Inc.; 2020.
  3. Tisagenlecleucel (Kymriah®) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2018.
  4. Brexucabtagene autoleucel (Tecartus™) [package insert]. Santa Monica, CA: Kite Pharma, Inc.; 2020.