Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma

Our plain-English summary of Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma, by A. Farina, M. Escalere, M. Dion, et al (Frontiers in Neurology, 2024).

The study

• Authors: A. Farina, M. Escalere, M. Dion, M. Moussy, A. Pegat, M. Villagrán-García, P. Devic, A. Lamiral, A. Seyve, K. Aure, A. Wang, L. Gorza, N. Streichenberger, T. Maisonobe, J. Honnorat, C. Birzu, D. Psimaras, D. Weisenburger-Lile, B. Joubert
• Journal: Frontiers in Neurology
• Published: 2024;15:1338899
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Mononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors.

Methods: Case series of three patients with mononeuritis multiplex-all with mesothelioma-identified in the databases of two French clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; OncoNeuroTox, Paris; January 2015-October 2022) set up to collect and investigate n-irAEs on a nationwide level.

Results: Three patients (male; median age 86 years; range 72-88 years) had pleural mesothelioma and received 10, 4, and 6 cycles, respectively, of first-line nivolumab plus ipilimumab combined therapy. In patient 1, the neurological symptoms involved the median nerves, and in the other two patients, there was a more diffuse distribution; the symptoms were severe (common terminology criteria for adverse events, CTCAE grade 3) in all patients. Nerve conduction studies indicated mononeuritis multiplex in all patients. Peripheral nerve biopsy demonstrated necrotizing vasculitis in patients 1 and 3 and marked IgA deposition without inflammatory lesions in patient 2. Immune checkpoint inhibitors were permanently withdrawn, and corticosteroids were administered to all patients, leading to complete symptom regression (CTCAE grade 0, patient 2) or partial improvement (CTCAE grade 2, patients 1 and 3). During steroid tapering, patient 1 experienced symptom recurrence and spreading to other nerve territories (CTCAE grade 3); he improved 3 months after rituximab and cyclophosphamide administration.

Discussion: We report the occurrence of mononeuritis multiplex, a very rare adverse event of immune checkpoint inhibitors, in the three patients with mesothelioma. Clinicians must be aware of this severe, yet treatable adverse event.

Copyright © 2024 Farina, Escalere, Dion, Moussy, Pegat, Villagrán-García, Devic, Lamiral, Seyve, Aure, Wang, Gorza, Streichenberger, Maisonobe, Honnorat, Birzu, Psimaras, Weisenburger-Lile and Joubert.

In plain English

The authors described three men with pleural mesothelioma who developed mononeuritis multiplex, a disorder of several individual nerves, after first-line nivolumab plus ipilimumab (immune checkpoint inhibitors). They were aged 72, 88 and 86 and had received 10, 4 and 6 treatment cycles. All were found in the databases of two French networks collecting neurological side effects of these drugs, January 2015 to October 2022. Symptoms were severe (grade 3) in all three, and nerve conduction tests showed mononeuritis multiplex in each. Nerve biopsies showed necrotizing vasculitis (blood-vessel inflammation) in patients 1 and 3, and IgA deposits without inflammation in patient 2. The drugs were stopped and all received corticosteroids. Patient 2 recovered fully. Patient 3 improved slightly but remained grade 3. Patient 1's symptoms returned as steroids were reduced; improvement began 3 months after cyclophosphamide and rituximab. Of 7 mesothelioma patients in the cohort of patients with these neurological side effects, 3 had definite or possible vasculitic neuropathy, which the authors saw in no other cancer type. The authors speculated about a possible association, which future studies need to confirm.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case series (three patients), with data collected retrospectively from medical charts
• Who was studied: Three male patients with pleural mesothelioma (median age 86 years, range 72 to 88; histological subtypes epithelioid, sarcomatoid, epithelioid), identified in the databases of two French clinical networks in Lyon and Paris, January 2015 to October 2022
• Exposure: First-line immune checkpoint inhibitor treatment with nivolumab plus ipilimumab: 10, 4 and 6 cycles in patients 1, 2 and 3. The article does not address asbestos exposure.
• Main results:
  • Clinical presentation was severe (CTCAE grade 3) in all three patients.
  • Nerve conduction studies showed asymmetric axonal sensory and motor mononeuritis multiplex with active denervation in all three patients.
  • Nerve biopsy showed necrotizing vasculitis in patients 1 and 3. In patient 2 it showed marked IgA deposition without inflammatory lesions or amyloid deposits.
  • In all patients, the immune checkpoint inhibitors were permanently withdrawn and corticosteroids were given.
  • Patient 2's neurological symptoms completely regressed (CTCAE grade 0).
  • Patient 3 had slight motor improvement but no substantial change in disability (CTCAE grade 3).
  • Patient 1 improved transiently. When corticosteroids were tapered, symptoms recurred and spread to other nerves (CTCAE grade 3). Patient 1 started to improve 3 months after second-line cyclophosphamide and rituximab (CTCAE grade 2).
  • At the last visit (median 8 months, range 5 to 10), all patients were stable (CTCAE grade 0 to 3). Cancer progression was documented in patients 1 and 3.
  • In the networks' database, patients with mononeuritis multiplex made up 3/183 (1.7%) of patients with neurological immune-related adverse events of CTCAE grade 2 or higher identified over more than 7 years.
  • Definite or possible vasculitic neuropathy was seen in 3 of 7 mesothelioma patients in a cohort made up of patients who had neurological immune-related adverse events. This is not a rate among all treated mesothelioma patients. The authors did not observe it in any other cancer type.
• The authors' conclusion: The authors concluded that mononeuritis multiplex may occur in patients treated with immune checkpoint inhibitors and is treatable. They speculated about a possible association between mesothelioma, these drugs and vasculitic neuropathy, which they said future studies need to confirm.
• Limitations the authors state:
  • The mechanism behind the inflammatory process remains unknown. The meaning of the IgA deposits in patient 2 is unclear.
  • In patient 3, tests to exclude a subclinical sicca (dryness) syndrome were not performed, so the relevance of that patient's anti-SSA/Ro antibodies is uncertain.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Pleural Mesothelioma, Mesothelioma, Immune-Related Adverse Events, Nivolumab (Opdivo), Ipilimumab (Yervoy), Biopsy, Deposition.

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