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Inflammatory markers linked to neurotoxicity severity after CAR T-cell infusion for DLBCL
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Neurotoxicity from chimeric antigen receptor T-cell therapy appeared associated with cytokine release syndrome, with blood levels of cytokines and other inflammatory markers linked to symptom severity, according to a retrospective study published in Blood.
Moreover, severe neurotoxicity among patients treated with CAR T-cell therapy negatively correlated with OS, and a short course of steroids did not improve outcomes, according to Philipp Karschnia, MD, of the department of neurology in the division of neurology at Massachusetts General Hospital Cancer Center and the department of neurology at Yale School of Medicine, and colleagues.
“Cytokine release syndrome and neurotoxicity are among the most commonly observed toxicities after adoptive immunotherapy with CAR T cells,” Karschnia and colleagues wrote. “Neurologic symptoms have been consistently reported in clinical trials of T cell-activating agents such as bi-specific T cell-engaging (BiTE) antibodies or CD19-directed CAR T-cell therapy, and also for CAR T cells targeting antigens other than CD19.”
Karschnia and colleagues reviewed the institutional database at Massachusetts General Hospital to identify 25 patients treated at the hospital between 2016 and 2018 for neurotoxicity after CAR T-cell infusion.
The study group primarily included patients treated for diffuse large B-cell lymphoma (n = 21), as well as one patient each treated for primary mediastinal large B-cell lymphoma, chronic lymphocytic leukemia/small cell lymphocytic lymphoma, acute lymphoblastic leukemia and hepatocellular carcinoma.
All patients received lymphodepletion with fludarabine and cyclophosphamide before CAR T-cell infusion. Twenty-four patients received CD19-directed CAR T cells and the patient with hepatocellular carcinoma received CAR T-cell therapy targeted against alpha-fetoprotein (AFP).
Twelve patients in the cohort (48%) experienced grade 1 to grade 2 neurotoxicity, and 13 patients (52%) demonstrated grade 3 to grade 4 neurotoxicity. Lower platelet counts at the time of CAR T-cell infusion were linked to more severe neurotoxicity (P = .03). All but one patient developed cytokine release syndrome.
The researchers observed no significant differences in absolute levels of C-reactive protein and ferritin between patients who subsequently developed low- or high-grade neurotoxicity.
C-reactive protein concentrations reached a peak shortly before development of neurological symptoms, whereas levels of ferritin peaked shortly after neurological symptoms occurred. Patients with high-grade vs. low-grade neurotoxicity had higher absolute peak ferritin concentrations (4,533 ± 930 ng/mL vs. 1646 ± 472 ng/mL; P = .007), but similar peak C-reactive protein concentrations (116 ± 28 mg/L vs. 119 ± 21 mg/L).
Higher ferritin levels appeared associated with higher neurotoxicity grade.
Median OS among all patients was 54.7 weeks.
Grade 3 to grade 4 neurotoxicity was inversely associated with OS (P = .013).
At the time of database closure, eight patients (32%) with grade 3 to grade 4 neurotoxicity had died, whereas all of the patients with grade 1 to grade 2 neurotoxicity remained alive.
Patients with lymphoma and grade 3 to grade 4 neurotoxicity often exhibited high lactate dehydrogenase levels prior to treatment, which was negatively associated with PFS (P = .048). Steroid use for a week or more did not appear to affect outcomes compared with less than a week of steroids.
“Collectively, CAR T-cell therapy is emerging as a powerful therapeutic strategy in [patients with] cancer, though potentially fatal neurotoxicity can be associated with such therapy,” the researchers wrote. “Considering the high frequency of neurotoxicity events, randomized prospective studies of treatment algorithms are urgently needed to improve patient monitoring and management. Blood biomarkers and electroencephalography monitoring may be useful tools in optimizing patient care and safety and will also need to be evaluated.” – by Jennifer Byrne
Disclosures: Karschnia reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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