Neurotoxicity in patients with CNS lymphomas treated with CAR‐T cell therapy. A LOC network study

Abstract

Introduction: CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicity in CNS lymphoma patients treated with CAR-T cells. Methods: Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. Results: Thirty patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas, median of 3 previous lines) received CAR-T cells (Tisa-cel: N = 23, axi-cel, N = 7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performance Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22 and median immune effector cell-associated encephalopathy (ICE) score was 10. Twelve (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASTCT classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N = 18), motor deficit (N = 4), balance disorders (N = 8), consciousness disorders (N = 5), seizures (N = 3) and movement disorders (N = 3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2 to 4 neurotoxicity compared to other patients (243 vs. 41 pg/ml, 15 vs. 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs. secondary CNS lymphoma or type of CAR-T. Twelve patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neurotoxicity. Conclusions: The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cells, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. S. Choquet Consultant or advisory role: Kite-Gilead, Novartis