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Case Reports
than the rest of their respective cohort (Figures 1C and F; Online Supplementary Table S2). In the serum, many cytokines were significantly elevated compared to the median of the corresponding cohort, although not consis- tently to the same extent between the two patients (Online Supplementary Figure S2; Online Supplementary Table S3). In the CSF of patient 2 at day 5, several cytokines and chemokines were elevated (Online Supplementary Figure S3; Online Supplementary Table S4). We also found a significant increase of CAR T cells and myeloid (CD66b+ and CD14+) cells in the CSF (Online Supplementary Figure S4; Online Supplementary Table S5).
The two patients described here had an atypical neuro- toxicity of severe leucoencephalomyelopathy associated with quadriparesis after CAR T-cell therapy. Clinically there appears direct anterior horn cell dysfunction in patient 1 with flaccid paralysis compared to patient 2 with upper motor neuron signs. Neither patient had a history of neurological illnesses or lymphoma in the central nervous system. It is possible that the high-tumor burden and high baseline inflammatory markers may have increased the risk of severe toxicity in patient 1 but patient 2 did not have these high-risk features. The mediastinal radiation field of patient 2 did neither explain the clinical nor the radiological presentation. In both patients, we found a massive expansion of CAR T-cells in the peripheral blood during the first week. There was increased protein level, CAR T and myeloid cells detected in CSF of patient 2 com- pared to the rest of the cohort.9 Molecules implicated in cytotoxicity (perforin, granzyme B), inflammation (SAA, ferritin, CRP), and trafficking (ICAM-1, VCAM-1, eotaxin- 3) also appeared to be extremely elevated. These observa- tions suggest mechanisms that contributed to heightened neurotoxicity in our patients including trafficking of CAR T-cells into the central nervous system, passive diffusion of cytokines, endothelial cell activation/dysfunction leading to blood-brain barrier disruption, and activation of myeloid cells, all which have been previously implicated.6– 10 Spine MRI showing reversible predominantly central spinal cord signal abnormalities in both patients seem to be unique and could represent the above described CSF abnormalities.
Prompt initiation of high-dose corticosteroids helped in reversing the acute leucoencephalomyelopathy and quadriparesis in both patients. Despite the use of high- dose corticosteroids, both patients attained a durable com- plete response, likely because they achieved peak CAR T- cell levels within the first week. This is consistent with the observation on ZUMA-1 trial that the overall response rate, complete response rate, and durability of those responses were comparable between patients who received corticosteroids versus those who did not and with the concept that high CAR T-cell levels early after infusion is associated with durable response.3,4 Collectively, these reports suggest that corticosteroids are unlikely to affect CAR T-cell efficacy when used for management of severe toxicities, their prompt initiation should be strongly con- sidered for grade 4 neurotoxicity.
Ranjit Nair,1* Gaëlle Drillet,2* Faustine Lhomme,2 Anthony Le Bras,3 Laure Michel,4 John Rossi,5 Marika Sherman,5 Allen Xue,5 Anne Kerber,5 Nutchawan Jittapiromsak,6,7 Linda Chi,6 Sudhakar Tummala,8 Sattva S. Neelapu1# and Roch Houot2#
1The University of Texas MD Anderson Cancer Center, Department of Lymphoma and Myeloma, Houston, TX, USA ; 2CHU Rennes, Department of Hematology, University of Rennes, EFS, INSERM UMR_S 1236, Rennes, France; 3CHU Rennes,
Department of Radiology, University of Rennes, Rennes, France; 4CHU Rennes, Department of Neurology, University of Rennes, INSERM CIC 1414 UMR_S 1236, Rennes, France; 5Kite (a Gilead company), Santa Monica, CA, USA; 6Department of Neuroradiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand and 8Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
*RN and GD contributed equally as co-first authors.
#SSN and RH contributed equally as co-senior authors. Correspondence: ROCH HOUOT - roch.houot@chu-rennes.fr doi:10.3324/haematol.2020.259952
Received: May 18, 2020.
Accepted: July 28, 2020.
Pre-published: July 30, 2020.
Disclosures: LM received honoraria from Merck, Novartis, Roche, Biogen and Teva; JR, MS, AX, and AK are employees and stock holders of Gilead Sciences Inc. SSN reports research support from Kite/Gilead, Merck, Bristol-Myers Squibb, Cellectis, Poseida, Karus, Acerta, and Unum Therapeutics and also serves as an advisory Board Member/Consultant for Kite/Gilead, Merck, Celgene, Bristol-Myers Squibb, Novartis, Unum Therapeutics, Pfizer, Precision Biosciences, Cell Medica, Allogene, Incyte, and Legend Biotech; RH received hon- oraria from Bristol-Myers Squibb, MSD, Gilead, Kite, Roche, Novartis, Janssen, and Celgene; NR, GD, FL, ALB, NJ, LC and ST have no conflicts of interest to disclose.
Contributions: RH and SSN designed research, analyzed data, and wrote the paper; NR, GD, FL, ALB, LM, JR, MS, AX, AK, NJ, LC, ST performed research, analyzed data, and wrote the paper.
Acknowledgments: we thank the patients who participated in this study and their families, friends, and caregivers, and the study staff and health care providers.
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