Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases

Abstract

BackgroundPD-1 and CTLA-4 inhibitors are associated with several adverse events including a spectrum of immune-related adverse effects (irAEs). Neurologic irAEs are uncommon occurrences with varied presentations. We describe two separate cases of ipilimumab associated meningoencephalomyelitis and demyelinating polyneuropathy with unusual presentations.Case presentationTwo melanoma patients were treated with ipilimumab in the adjuvant setting. The first patient developed a meningoencephalitis following 3 doses of ipilimumab. MRI imaging of the brain confirmed leptomeningeal enhancement although cerebrospinal fluid (CSF) analyses were negative for malignant cells consistent with meningoencephalomyelitis. Although she initially improved following treatment with steroids and intravenous immunoglobulin, she subsequently relapsed. She was successfully treated with infliximab and made a complete neurological recovery. A second patient developed progressive lower extremity weakness following two doses of ipilimumab. MRI imaging of the spine confirmed diffuse nerve root enhancement consistent with acute inflammatory demyelinating polyneuropathy (AIDP). He was treated with high dose steroids with resolution of neurological symptoms. Both patients remain disease free.ConclusionsNeurological irAEs are uncommon adverse events in the context of CTLA-4 and/or PD-1 inhibitor therapy. Care must be taken to distinguish these from leptomeningeal disease. Early recognition of neurological irAEs is critical for the initiation of specific anti-inflammatory agents to prevent and potentially reverse neurological sequelae.

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

“…only reporting the most severe or obvious cases), or over-reporting (reporting cases without a firmly established diagnosis). This study does, however, complement other detailed descriptions of these clinical syndromes [6][7][8][9][10][11]. Third, we are unable to definitively determine the incidence of each event using Vigibase, although other studies have reported incidence of neurologic toxicities in the range of 1-5% [7,8].…”

“…Neurologic toxicities have emerged as clinically relevant complications of ICI. Case series have reported limited numbers of autoimmune-like, inflammatory events including encephalitis, aseptic meningitis, myasthenia gravis, and Guillain-Barre Syndrome which may occur, in aggregate, in 1-5% of treated patients [6][7][8][9][10][11]. However, a systematic analysis of the timing, spectrum, clinical associations, and outcomes of these uncommon events has not been performed in a large number of patients.…”

<p>Decreasing Microtubule Actin Cross-Linking Factor 1 Inhibits Melanoma Metastasis by Decreasing Epithelial to Mesenchymal Transition</p>

“…3,4 Immunotherapy with immune checkpoint inhibitors (inhibitory monoclonal antibodies against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death 1 (PD-1/ PDL1) and targeted therapy (Vemurafenib and nivolumab) acted as a certain efficiency on metastatic melanoma; unfortunately, these immune-based therapies are not fully responsive in some advanced stage melanoma. 5,6 In this regard, it is desirable to adopt an efficient therapeutic strategy to overcome the shortage in successful treatment of metastatic melanoma based on immune checkpoint inhibitors and targeted therapy.…”

Advances in cancer immunotherapy 2019 – latest trends

“…Although ipilimumab was approved for the adjuvant treatment of melanoma patients by the FDA (but not by the EMA) based on a placebo-controlled phase III trial reporting superior recurrence-free and overall rates, its use was internationally disputed given the relatively high frequency of serious immune-related adverse events in patients receiving treatment with ipilimumab [33][34][35]. In Europe, nivolumab was the first checkpoint inhibitor approved for adjuvant treatment of melanoma patients, based on results of the CheckMate 238 study reported in 2017 [36].…”