Results of a retrospective study suggest that development of neurotoxicity following administration of adoptive immunotherapy with chimeric antigen receptor T (CAR-T) cell therapy was associated with the presence of a number of clinical manifestations and pretreatment and posttreatment clinical marker levels, and that severe neurotoxicity postadministration of CAR-T therapy correlated with poor overall survival (OS). This study was published online in Blood.
Two CAR-T cell therapies have recently received approval from the United States Food and Drug Administration (FDA) for patients with relapsed or refractory diffuse large B-cell lymphoma and B-cell acute lymphoblastic leukemia. However, a potential limitation to the use of these treatments include 2 relatively common adverse effects: cytokine release syndrome (CRS) and neurotoxicity, with symptoms of the latter ranging from mild confusion to cerebral edema with coma and, potentially, death.
In this retrospective study, reflecting the experience at the Massachusetts General Hospital for patients treated with CAR-T therapy between 2016 and 2018, demographic characteristics, clinical manifestations, potential biomarkers, imaging and electroencephalographic findings, treatment histories, and clinical outcomes of 25 adult patients who developed CAR-T–associated neurotoxicity were examined. Included in this cohort were 24 patients treated with CD19-directed CAR-T cells for non-Hodgkin lymphoma (23 individuals) and acute lymphoblastic leukemia (ALL) (1 individual), and 1 patient treated with alpha-fetoprotein–directed CAR-T for hepatocellular carcinoma. Grade 1/2 and grade 3/4 CAR-T–related neurotoxicity developed in 48% (12 individuals) and 52% (13 individuals) of these patients, respectively.
Some of the main findings of this study include the following:
- Median time from CAR-T infusion to first neurologic symptoms of any grade was 5 plus or minus 0.9 days, and median time to first severe neurotoxicity was 7 plus or minus 1.9 days
- Lower platelet counts at time of CAR-T infusion were more likely in patients developing severe neurotoxicity compared with those developing lower-grade neurotoxicity (P =.030)
- CRS occurred in 96% of patients, and was preceded by fever in most cases
- Serum levels of CRP peaked before onset of neurologic symptoms, whereas serum levels of ferritin peaked shortly after onset of neurologic symptoms, and higher ferritin levels were significantly associated with higher compared with lower neurotoxicity grade (P =.007)
- High pretreatment level of serum lactate dehydrogenase (LDH), found in most patients who developed severe neurotoxicity, was associated with worse progression-free survival (PFS) (P =.048)
- Neurologic symptoms often improved within a few days of corticosteroid therapy
- Corticosteroid use of a minimum of 7 days and a maximum of 10 days not a prognostic marker for OS (P =.874) or for PFS (P =.808) when compared with corticosteroid use fewer than 7 days, although a prolonged course of more than 10 days of steroids appeared to be associated with worse OS compared with 10 days or fewer (P =.030)
- Grade 3/4 neurotoxicity was associated with worse OS compared with grade 1/2 neurotoxicity (P =.013)
“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 EEG monitoring may be useful tools in optimizing patient care and safety and will also need to be evaluated,” the study authors wrote in conclusion.
Karschnia P, Jordan JT, Forst DA, et al. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T-cells [published online February 26, 2019]. Blood. doi: 10.1182/blood-2018-12-893396