Neurological management and work-up of neurotoxicity associated with CAR T cell therapy

Abstract

Introduction: Treatment with CD19 chimeric antigen receptor (CAR) T cells is an innovative therapeutic approach for patients with relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL) and B-lineage acute lymphoblastic leukemia (r/rALL). However, convincing therapeutic response rates can be accompanied by cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS).

Methods: Single center, prospective observational study of fifteen consecutive r/r DLBCL patients treated with Tisagenlecleucel within 1 year at Hannover Medical School. Extensive neurological work-up prior to CAR T cell infusion included clinical examination, cognitive testing (Montreal-Cognitive-Assessment), brain MRI, electroencephalogram, electroneurography, and analysis of cerebrospinal fluid. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Afterwards, all patients were assessed at least once a week.

Results: ICANS occurred in 4/15 patients (27%) within 6 days (4-6 days) after CAR T cell infusion. Patients with ICANS grade 2 (n = 3) exhibited similar neurological symptoms including apraxia, expressive aphasia, disorientation, and hallucinations, while brain MRI was inconspicuous in either case. Treatment with dexamethasone rapidly resolved the clinical symptoms in all three patients. Regarding baseline parameters prior to CAR T cell treatment, patients with and without ICANS did not differ.

Conclusions: In our cohort, ICANS occurred in only every fourth patient and rather low grade neurotoxicity was found during daily examination. Our results demonstrate that a structured neurological baseline examination and close monitoring are helpful to detect CAR T cell related neurotoxicity already at an early stage and to potentially prevent higher grade neurotoxicity.

Keywords: Autoimmunity; Chimeric Antigen Receptors; Immunotherapy; Neurotoxicity; T-Lymphocytes.

Fig. 1

Hannover cohort neurological examination and monitoring before, during and after CAR T cell treatment. CSF: cerebrospinal fluid; EEG: electroencephalography; MoCA: Montreal Cognitive Assessment; MRI: magnetic resonance imaging

Fig. 2

MoCA test results during 10 days monitoring period. All 15 patients were treated with CAR T cell therapy. Except for patient 4 and patient 15 all patients were subjected to a daily MoCA test until the 10th day after therapy. MoCA: Montreal Cognitive Assessment. Pat: patient. *Patient 4 was intubated due to severe CRS on day 8, no further testing; # Patient 15 was transferred to palliative care unit on day 7, no further testing

Fig. 3

Typical ICANS symptoms independent of ICANS grading. Symptoms occurring in the cases described above are printed in bold and blue. Severity of symptoms increases from left to right

Fig. 4

IL-6 levels and MoCA scores of two exemplary ICANS patients compared with all patients that neither had ICANS nor CRS Day 0: day of CAR T cell therapy. Patients 7 and 11 developed immune effector cell-associated neurotoxicity syndrome (ICANS) grade 2. MoCA: Montreal Cognitive Assessment