Treatment with CD19 chimeric antigen receptor (CAR) T cells represents a novel treatment approach for patients with relapsed or refractory diffuse large B cell lymphoma (r/rDLBCL) or B-lineage acute lymphoblastic leukemia (ALL). However, impressive therapeutic response rates are often accompanied by specific and severe toxicities. Besides the common cytokine release syndrome (CRS) which is characterized by fever, hypotension, hypoxia, and in more severe cases multisystem organ dysfunction, specific neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS) has been observed as well and is treated as a separate entity with distinct timing and treatment requirements. Although symptoms can be more diverse than those of CRS, many patients with neurotoxicity show specific clinical features with expressive aphasia being one of the most characteristic ones.
Eleven r/rDLBCL patients have been treated with Tisagenlecleucel at Hannover Medical School between April 2019 and November 2019. All patients received an extensive neurological examination prior to CAR T cell infusion. This included clinical examination, handwriting sample, cognitive testing (Montreal-Cognitive-Assessment (MoCA)), brain magnetic resonance imaging (MRI), electroencephalogram (EEG), electroneurography (ENG), and analysis of cerebrospinal fluid (CSF) in 8/11 patients. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Up to 4 weeks following infusion, we assessed all patients at least once a week.
Baseline clinical neurological examination and ENG showed signs of axonal polyneuropathy in 10 of 11 patients before CAR T cell therapy indicating damage due to prior chemotherapy. Two patients presented with slightly impaired MoCA-results (25/30 points) and 1 patient achieved only 23/30 points prior to CAR T cell treatment. Brain MRI was unremarkable in all cases. CSF did not show signs of inflammation in all 8 patients (cell count 1-3/µl, oligoclonal bands negative) and no relevant disturbance of the blood-CSF-barrier (Qalbumin 4.7-8.5). No one exhibited antineuronal or autoimmune encephalitis antibodies. During the four-week follow-up period one patient developed a severe CRS at day 5 accompanied by mild signs of cognitive impairment (MoCA minimum 23/30), but without abnormalities in brain MRI. He died on day 23 following CAR T cell therapy due to infection. Two patients exhibited signs of cognitive impairment at day 4 and 5, respectively. Both patients showed very similar symptoms including apraxia, expressive aphasia, disorientation, and hallucinations. Symptoms developed very quickly, while brain MRI was inconspicuous in either case. Grade 2 ICANS was assumed in both patients and both were treated with dexamethasone 40 mg/d. As symptoms rapidly resolved steroid treatment was quickly tapered and stopped after 5 days. Both patients showed neither signs of cognitive nor neurological impairment afterwards.
Neurotoxicity is a feared complication of CD19 CAR T cell therapy and initial symptoms can be very subtle. Our longitudinal examinations in 11 patients revealed specific clinical symptoms of ICANS in 2 patients without relevant radiological abnormalities. Further studies with higher numbers of patients including a structured and detailed neurological examination are required to uncover CD19 CAR T cell-related neurotoxicity and its especially pathogenesis.
Nothing to declare