Case Study Highlights Therapeutic Potential of Tocilizumab in MOGAD With Cancer
Investigators found that in melanomas in particular, interleukin-6 blockade seems to be effective in the management of immune-related adverse events from immune checkpoint inhibitors.
Results from a case study showed that tocilizumab may be an effective treatment option for patients with myelin oligodendrocyte glycoprotein associated disease (MOGAD) with active cancer who are refractory to maintenance intravenous immunoglobulin (IVIG). All told, targeting interleukin(IL)-6 pathway with medications like tocilizumab may be beneficial in the treatment of neurologic immune-related adverse events (AEs) of immune checkpoint inhibitor (ICI) treatment in this rare patient population.
Eoin P. Flanagan, MB, BCh
Published in Neurology, the case report featured a 52-year-old man who presented with progressive encephalomyelitis that led to identification of metastatic melanoma. His characteristic core demyelinating events, strongly positive MOG-IgG in serum and cerebrospinal fluid (CSF), and absence of CSF oligoclonal bands were consistent with MOGAD, in addition to fulfilling the 2023 MOGAD diagnostic criteria.1
Leading up to the MOGAD diagnosis, a right parietal brain biopsy revealed perivascular and parenchymal chronic inflammation with CD4 T-cell predominance, activated microglia, demyelination with loss of MOG immunostaining, but absence of complement deposition and no intracranial melanoma. Repeat CSF showed pleocytosis (WBC, 58/ul, 77% lymphocytes), elevated protein (84 mg/dL), no malignant cells, and zero oligoclonal bands. The patient showed strongly positive CSF MOG-IgG levels (titer, 1:4096), and was subsequently diagnosed with MOGAD.
Led by senior author Eoin P. Flanagan, MB, BCh, a professor of neurology and chief of the Division of Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic, the patient received 1 g of intravenous methylprednisolone for 5 days with extended oral prednisone taper and 7 sessions of plasmapheresis for MOGAD encephalomyelitis. In addition, he was treated with an oral mitogen-activated protein kinase 1 and 2 inhibitor (MEK 1/2) called binimetinib and BRAF inhibitor (encorafenib) for his melanoma.
"Tumor sampling may have limited detection and MOG may be present in other tumor regions or perhaps be detected with more sophisticated testing (e.g., proteomics)," the authors noted. "Based on the paraneoplastic care score of 0 (demyelinating clinical syndrome, low risk antibody, tumor without MOG expression), he is categorized as a non-paraneoplastic neurologic syndrome.9 It is also possible that the melanoma was coincidental."
Following the use of cancer treatments, the patient improved and discharged; however, shortly after, he began to develop photosensitivity and decreased color vision with orbital MRI demonstrating bilateral optic nerve enhancement consistent with optic neuritis. Subsequently, the patient was placed on a regimen of IVIG and maintenance IVIG treatments along with a slow prednisone taper. Months later, he developed lower back pain and worsening memory, with spine MRI revealing new L2 vertebral body metastasis.
As the melanoma continued to progress, clinicians started the patient on an ICI treatment with pembrolizumab; however, this did not last long. A week after beginning treatment, he developed severe paraparesis, and spine MRI revealed multiple new cervical and thoracic T2-hyperintense and enhancing lesions consistent with MOGAD worsening despite increasing IVIG (1.2 g/kg every 3 weeks). While continuing to receive IVIG, oral prednisone and 2 more cycles of pembrolizumab, the melanoma responded “excellently” to pembrolizumab.
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Despite clinical improvements to the melanoma, the patient developed recurrent optic neuritis and thus, pembrolizumab was stopped. Tocilizumab, an IL-6 receptor blocker, was then started at a dose of 8 mg/kg IV monthly. Over time, his neurologic examination improved, and he was able to ambulate on his own. After 10 months of treatment with tocilizumab, the patient has shown no relapse of either melanoma or MOGAD, with neuroimaging results stable.
"ICI treatments targeting CTLA4, PD1, and PD-L1 have been associated with worsening of preexisting autoimmune disease or development of new autoimmunity in some patients," Flanagan et al wrote.1 "Our patient experienced worsening of MOGAD encephalomyelitis with paraparesis and optic neuritis temporally related to starting pembrolizumab. An ideal intervention for this scenario is an agent that might treat ICI immune-related adverse events but respect the anti-tumor immune response. Targeting the interleukin-6 pathway with medications such as tocilizumab, an interleukin-6 receptor blocker, has been proposed to treat MOGAD."
Prior to this study, previously published research showed that blocking IL-6 signaling may block ICI toxicity but not reduce the anti-tumor immune response. A 2019 study featured 87 patients who were treated with nivolumab for steroid refractory immune-related AEs, 34 of whom required tocilizumab. Clinical improvement was noted in 79.4% (27 of 34), with the majority of patients needing only 1 dose (52.9%). For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 during the 18-month study period.2
