What are the immune-mediated neurological side effects of melanoma treatment?

From the Guidelines

Immune-mediated neurological side effects of melanoma treatment are a significant concern and require prompt management to prevent long-term morbidity and mortality, with the most recent consensus recommendations suggesting holding immunotherapy and initiating corticosteroids as the first line of treatment 1.

Introduction to Immune-Mediated Neurological Side Effects

Immune checkpoint inhibitors (ICIs) like pembrolizumab, nivolumab, and ipilimumab have revolutionized the treatment of melanoma, but they can also cause significant immune-mediated neurological side effects, including:

• Peripheral neuropathy
• Myasthenia gravis
• Guillain-Barré syndrome
• Encephalitis
• Aseptic meningitis
• Transverse myelitis These side effects occur because ICIs enhance T-cell activity against cancer cells but can also trigger autoimmune responses against neural tissues.

Management of Neurological Side Effects

Management of these side effects typically begins with:

• Holding the immunotherapy
• Initiating corticosteroids, usually methylprednisolone 1-2 mg/kg/day or prednisone 1-2 mg/kg/day For severe cases (grade 3-4 toxicities), additional treatments may be necessary, such as:
• Intravenous immunoglobulin (IVIG) at 2 g/kg divided over 5 days
• Plasma exchange Neurological symptoms should be promptly reported to healthcare providers, as early intervention improves outcomes 1.

Risk Factors and Timing of Neurological Side Effects

The risk of neurological side effects varies by agent, with combination therapy carrying a higher risk than monotherapy 1. Most neurological toxicities develop within the first 3 months of treatment, though they can appear later. Regular neurological assessments during melanoma treatment are essential for early detection and intervention.

Key Recommendations

The most recent consensus recommendations emphasize the importance of prompt recognition and management of immune-mediated neurological side effects, with a focus on holding immunotherapy and initiating corticosteroids as the first line of treatment 1. Additionally, healthcare providers should:

• Monitor patients closely for neurological symptoms
• Report any symptoms promptly
• Consider additional treatments, such as IVIG or plasma exchange, for severe cases By following these recommendations, healthcare providers can help minimize the risk of long-term morbidity and mortality associated with immune-mediated neurological side effects of melanoma treatment.

From the FDA Drug Label

Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections New or Reactivated Viral Infections Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil.

The immune-mediated neurological side effects of mycophenolate mofetil include:

• Progressive multifocal leukoencephalopathy (PML), which can be fatal and presents with symptoms such as hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia 2
• Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, which can lead to serious outcomes including deteriorating renal function and renal graft loss 2 It is essential to monitor patients for neurological symptoms and consider consultation with a neurologist as clinically indicated.

From the Research

Immune-Mediated Neurological Side Effects of Melanoma Treatment

• Immune checkpoint inhibitors, such as anti-PD1 antibodies, have become a standard treatment for melanoma, but they can cause immune-mediated adverse events (irAEs), including neurological side effects 3, 4.
• A study found that 58 patients developed neurological adverse effects while being treated with PD1 antibodies, alone or in combination with ipilimumab, with a median time of 7 weeks from treatment initiation to development of neurological adverse effects 3.
• The most common neurological toxicities affected the peripheral nervous system (64%), and 86% of patients were treated with corticosteroids, with 37% requiring further immunomodulation 3.
• Another study found that baseline corticosteroid use did not affect the efficacy of immunotherapy in patients with advanced melanoma, but a higher dose of baseline prednisone-equivalent was associated with poor overall survival 5.
• The use of immune checkpoint inhibitors can lead to a unique constellation of side effects, distinct from other cancer therapies, collectively termed immune-mediated adverse events (irAEs) 4.
• Immune checkpoint inhibitor-based immunotherapy is dramatically changing the management of melanoma, but the success of ICI-based therapy is limited by the development of escape mechanisms, which allow melanoma cells to avoid recognition and destruction by immune cells 6.
• A recent study found that high corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival in patients with melanoma 7.

Management of Neurological Side Effects

• Management of neurological adverse effects may require immunomodulation beyond corticosteroids, including intravenous immunoglobulin, plasmapheresis, mycophenolate mofetil, cyclophosphamide, and rituximab 3.
• Clinicians should weigh the possible detrimental effects of immunosuppression on survival against the potential disadvantages of undertreatment 7.
• Further studies are needed to confirm the efficacy of therapies that combine different classes of ICIs as well as ICIs with other types of therapies, and to identify novel and more effective predictive biomarkers to better stratify melanoma patients 6.