Consensus disease definitions for the spectrum of neurologic immune related adverse events.

Abstract

2647 Background: Expanding FDA-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in both therapeutic success and immune related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes evidence-based treatments and research progress. The objectives of this study were to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. Methods: A working group of 4 neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the Neuro irAE Disease Definition Panel, consisting of neurologists, oncologists, neuro-oncologists and irAE subspecialists. A modified Delphi consensus process was used, with 2 rounds of anonymous ratings by panelists and 2 virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. The working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions. Results: Twenty-seven panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for 7 core disorders: irMeningitis, irEncephalitis/Encephalomyelitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, 6 sub-classifications are described: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation and present or absent concurrent irAE. Conclusions: These disease definitions standardize irAE-N classification. They are being incorporated into a multi-institutional registry that our group has initiated to study irAEs. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.