Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors

Abstract

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in 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 development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two 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. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 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 seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Immune-checkpoint inhibitors: long-term implications of toxicity

“…Neurological irAEs occur in up to 5% of patients and are more common with ipilimumab-containing regimens. These events can affect the neuromuscular junction (myasthenia gravis and Lambert–Eaton myasthenic syndrome), the central nervous system (meningoencephalitis) and peripheral nerves (both sensory and motor neuropathy, including Guillain–Barré syndrome) 126 , 127 . Meningoencephalitis usually resolves with acute management (although rarely can be fatal), and whether chronic deficits occur in some patients remains unclear.…”

Movement Disorders in Oncology: From Clinical Features to Biomarkers

“…Indeed, endocrine, gastrointestinal, pulmonary, cardiac, renal, hematological, rheumatological and dermatological irAES were described [ 41 ]. The frequency of neurological irAEs (n-irAEs) varies from 1 to 12%, and both the CNS and peripheral nervous systems may be involved, the latter three times more [ 42 , 43 ]. Recently, a multi-institution group of neurologists, oncologists, and experts in irAEs developed consensus guidelines to classify the n-irAEs appropriately [ 42 ].…”

“…The frequency of neurological irAEs (n-irAEs) varies from 1 to 12%, and both the CNS and peripheral nervous systems may be involved, the latter three times more [ 42 , 43 ]. Recently, a multi-institution group of neurologists, oncologists, and experts in irAEs developed consensus guidelines to classify the n-irAEs appropriately [ 42 ]. Seven core syndromes were defined, of which four involve the CNS and three the peripheral nervous system.…”

“…Seven core syndromes were defined, of which four involve the CNS and three the peripheral nervous system. IrAEs involving the CNS include immune-related (ir)-meningitis, ir-encephalitis, ir-demyelinating diseases, and ir-vasculitis [ 42 ]. The ir-encephalitis encompasses several clinical presentations of movement disorders, namely cerebellitis, OMS, and stiff person spectrum disorders/PERM [ 42 ] ( Figure 1 ).…”

Tumortherapieassoziierte neurologische Symptome

“…Es wäre daher empfehlenswert, bereits vor dem Start der onkologischen Therapie eine neurologische und neurographische Untersuchung als Ausgangsbefund durchzuführen und diese u. U. auch im Verlauf regelmäßig zu wiederholen. Ein neu-Immuntherapieassoziierte Neuropathien: stufenweises Vorgehen nach Schwere der Symptome[5,11,12] Untersuchung, PNP-Labor (Vitamin B12, Folsäure, Diabetes und HIV-Screening), cMRT, sMRT oder Plexusdarstellung mit und ohne Kontrastmittelgabe, elektrophysiologische Diagnostik Fortführung der Immuntherapie möglich, ggf. Dosisreduktion oder Pause Immuntherapie pausieren Wie bei Grad I zusätzlich Lumbalpunktion, Lungenfunktionsprüfung Methylprednisolon 0,5-1 mg/kg Körpergewicht/Tag i.v.…”