How to manage neuropathy in patients taking Keytruda (pembrolizumab)?

Management of Neuropathy in Patients Taking Keytruda (Pembrolizumab)

For patients experiencing neuropathy while on Keytruda (pembrolizumab), immediately grade the severity and hold or discontinue Keytruda based on the grade, with Grade 2 requiring temporary hold and Grade 3-4 requiring permanent discontinuation, while initiating appropriate immunosuppressive therapy.

Grading and Initial Assessment of Neuropathy

Neuropathy associated with Keytruda is an immune-related adverse event (irAE) that requires prompt recognition and management. The first step is to grade the severity:

• Grade 1: Mild symptoms with no interference with function
• Grade 2: Moderate symptoms with some interference with activities of daily living (ADLs)
• Grade 3-4: Severe symptoms limiting self-care, requiring aids, or causing weakness limiting walking, dysphagia, facial weakness, or respiratory muscle weakness

Diagnostic Workup

For suspected Keytruda-related neuropathy, perform:

1. Neurological consultation (all grades)

2. Laboratory testing:

   • Screen for reversible causes: HbA1c, vitamin B12, folate, TSH, vitamin B6, serum protein electrophoresis, immunofixation, CPK 1
   • Consider autoimmune workup: ANA, ESR, CRP, ANCA, anti-smooth muscle antibodies, SSA/SSB, RNP, anti-dsDNA 1
   • Paraneoplastic antibody testing (anti-ganglioside antibodies, anti-MAG, anti-Hu/ANNA-1) 1

3. Imaging and other tests:

   • MRI spine with/without contrast (Grade 2 or higher) 1
   • MRI brain if cranial nerve involvement 1
   • Electrodiagnostic studies (NCS/EMG) to evaluate polyneuropathy 1
   • Consider lumbar puncture for CSF analysis 1
   • Pulmonary function testing if respiratory symptoms present 1

Management Algorithm Based on Severity

Grade 1 (Mild)

• Low threshold to hold Keytruda and monitor symptoms for a week 1
• If continuing treatment, monitor very closely for progression 1
• Consider gabapentin, pregabalin, or duloxetine for pain management 1

Grade 2 (Moderate)

• Hold Keytruda and resume only once symptoms return to Grade 1 1
• Consider prednisone 0.5-1 mg/kg/day (especially if progressing from mild) 1
• Initiate pain management with gabapentin, pregabalin, or duloxetine 1
• Neurology consultation 1

Grade 3-4 (Severe)

• Permanently discontinue Keytruda 1
• Hospital admission 1
• Urgent neurology consultation 1
• For suspected Guillain-Barré syndrome (GBS)-like presentation:
  • Start IVIG (0.4 g/kg/day for 5 days) or plasmapheresis 1
  • Initiate methylprednisolone 2-4 mg/kg/day or pulse dosing (1g daily for 5 days) 1
  • Frequent neurological checks and pulmonary function monitoring 1
  • Monitor for autonomic dysfunction 1
• For non-GBS severe neuropathy:
  • Initiate methylprednisolone 1g daily for 3 days followed by oral corticosteroid taper 1

Pain Management for Neuropathic Pain

For painful neuropathy, follow a stepwise approach:

1. First-line options:

   • Calcium channel α2-δ ligands: gabapentin (300-2400 mg/day) or pregabalin (150-600 mg/day) 1
   • SSNRIs: duloxetine (30-60 mg/day) or venlafaxine 1
   • Secondary-amine TCAs: nortriptyline or desipramine (start low, titrate slowly) 1

2. For inadequate response:

   • Try alternative first-line medication or add a second agent from a different class 1
   • For refractory pain, consider opioid analgesics or tramadol for short-term relief 1

Special Considerations and Monitoring

• Perform frequent neurological checks, especially with severe presentations 1
• Monitor for concurrent autonomic dysfunction (orthostatic hypotension, GI issues, urinary problems) 1
• For patients with peripheral neuropathy, consider non-pharmacological measures:
  • Wear loose-fitting shoes and cotton socks 1
  • Avoid bedding that presses on toes 1
  • Moderate walking to help circulation 1
  • Cold water soaks for temporary pain relief 1

Rechallenge Considerations

• Extreme caution with rechallenging after severe cases 1
• Only consider rechallenge after complete resolution of symptoms and tapering off immunosuppression 1
• For Grade 3-4 neuropathy, permanent discontinuation is generally recommended 1

Pitfalls and Caveats

1. Don't mistake immune-related neuropathies for typical Guillain-Barré syndrome - they often have different CSF profiles (lymphocytic rather than albuminocytologic dissociation) and may respond differently to treatment 2

2. Unlike idiopathic GBS where steroids are not typically recommended, corticosteroids are beneficial in Keytruda-induced neuropathy 1, 2

3. Pembrolizumab can cause isolated cranial neuropathies that may respond to IVIG 3

4. Early recognition and intervention are critical - delayed treatment may lead to irreversible neurological damage or death 2

5. Peripheral neuropathy is reported in approximately 1.7% of patients receiving Keytruda 4, but severe cases can be life-threatening

By following this structured approach to grading, diagnosis, and management, clinicians can effectively address neuropathy in patients receiving Keytruda while optimizing patient outcomes regarding morbidity, mortality, and quality of life.