Clinical, Instrumental, and Prognostic Definitions of de novo Central Nervous System Demyelinating Disorders Following Immune Checkpoint Inhibitor Therapy
stefano Masciocchi1, Antonio Malvaso1, Kevin Bihan2, Alessandro Dinoto3, Antonio Farina4, Alberto Picca5, Cristina Izquierdo Gracia6, Lorena Martín-Aguilar7, Jordi Bruna-Escuer8, Valentina Damato9, Elia Sechi10, Simone Rossi11, Nicola De Rossi12, Helena Ariño13, Alvaro Cobo-Calvo13, Sara Mariotto14, Bastien Joubert15, Enrico Marchioni16, Alberto Vogrig17, Matteo Gastaldi18
1Neuroimmunology Laboratory and Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy, 2Department of Pharmacology, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris (AP-HP), Clinical Investigation Center (CIC-1901), Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France, 3Neuroimmunology and Neuromuscular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, 4French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France, 5Neuro-Oncology Service, AP-HP, Pitié-Salpêtrière Hospital and Sorbonne Université, Paris, France, 6Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain, 7Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain., 8Neuro-Oncology Unit, Hospital Universitari de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain, 9Department of Neuroscience, University of Florence, 10University of Sassari, 11IRCCS Istituto delle Scienze Neurologiche di Bologna (S.R., R.R., M. Guarino), Italy, 12ASST-Spedali Civili di Brescia, Montichiari, Italy, 13Neurology Department, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain, 14Neurology Unit, University of Verona, 15Hospices Civils de Lyon, 16Neuroncology and Neuroinflammation Unit, IRCCS Mondino Foundation, Pavia, Italy, 17Department of Medicine (DMED), University of Udine, Udine, Italy; Clinical Neurology, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy, 18IRCCS Mondino Foundation
Objective:
We aimed to define the demographic, clinical, therapeutic and prognostic features of DEMirAEs.
Background:
Immune-related adverse events (irAEs) can occur after the administration of immune-checkpoint inhibitors (ICI). De novo demyelinating irAEs (DEMirAEs) are rare, poorly characterized and often challenging.
Design/Methods:
We conducted a multicentric retrospective study including patients with DEMirAEs consecutively seen from 2011 to 2024 in 9 neurology units in Europe. Additional cases were identified by a systematic literature review (PRISMA guidelines). Patients with a known multiple sclerosis diagnosis at ICI initiation, and patients with typical MS lesions on first brain MRI after symptoms onset were excluded. All statistical analysis were performed using Stata/SE and R version 4.0.3.
Results:
We identified 80 patients who developed de novo DEM-irAEs, comprising 15 from the present series and 65 from a literature review. Median age was 59 years (range: 9-84), with a male predominance (52/80 patients, 65%). DEMirAEs manifested after a median of 18 (range, 2-178) weeks following ICIs initiation (anti-PD1 [n=49,61%], anti-PD-L1 [n=4,5%] anti-CTLA4 [n=5,6%] and anti-PD1 + anti-CTLA4 [n=22,28%]). Clinical manifestations included: i) optic neuritis (n=17,8 bilateral); ii) myelitis (n=29,24 LETM) iii) ADEM (n=6); vi) atypical DEM-irAEs (n=7); vii) overlapping syndromes (n=21) . CSF restricted oligoclonal bands (12/50,24%) and autoantibodies against glial antigens (11/80,14% [MOG-IgG 3/51,6%; AQP4-IgG 5/53,9% and GFAP-IgG 3/35,9%]) were uncommon. Immunotherapy was administered in 93% of patients (intravenous steroids [n=61], IVIg [n=16], plasmapheresis [n=23], rituximab [n=8], and cyclophosphamide [n=8]). Among these patients 15 (24%) achieved a complete response, 25 (40%) a partial response, and 22 (35%) showed no response. Nineteen patients (17/66,26%) relapsed and 14 (18%,2 due for DEMirAEs –12 for cancer-related complications) died after a median follow-up of 7 (range 1-66) months.
Conclusions:
DEMirAEs presented as rare, heterogenous complication of ICI treatment. Long term immunosuppression should be considered in selected cases, as approximately one-quarter of patients may experience relapses.
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