How to manage fever induced by Nivolumab (nivolumab, an anti-programmed death-1 (PD-1) antibody)?

Management of Nivolumab-Induced Fever

For nivolumab-induced fever, management should be based on fever severity, with mild cases (<38.5°C) treated with antipyretics while continuing therapy, moderate cases (38.5-40°C) requiring temporary treatment interruption, and severe cases (>40°C) necessitating immediate nivolumab discontinuation and corticosteroid therapy. 1

Clinical Presentation and Assessment

• Nivolumab-induced fever typically presents as an isolated symptom or may be accompanied by other symptoms indicating potential organ inflammation, and should be considered an important immune-related adverse event (irAE) requiring monitoring 1
• Fever may develop within hours to days after nivolumab administration, as demonstrated in case reports of patients developing high fever within several hours after the first administration 2, 3
• Fever can be the first sign of a more serious immune-mediated reaction, including cytokine release syndrome (CRS), which requires prompt recognition and management 4
• Always evaluate patients for potential concurrent irAEs affecting other organ systems, as fever may signal the onset of conditions such as immune-mediated nephritis, thrombocytopenia, or encephalitis 2, 3, 5

Grading and Management Algorithm

Grade 1 (Mild Fever <38.5°C)

• Continue nivolumab therapy with close monitoring 1
• Administer antipyretics such as acetaminophen as needed 1
• Monitor for development of other immune-related symptoms 6

Grade 2 (Moderate Fever 38.5-40°C)

• Consider temporarily withholding nivolumab until fever resolves 1
• Administer antipyretics on a scheduled basis rather than as needed 1
• Rule out infection with appropriate cultures and imaging 6
• Monitor renal function, liver enzymes, and complete blood count to detect early signs of other irAEs 2, 3

Grade 3-4 (Severe Fever >40°C or Fever with Complications)

• Immediately withhold nivolumab 1
• Initiate high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day or equivalent) 1, 4
• Consider hospitalization for monitoring and supportive care 1
• Evaluate for cytokine release syndrome, which may require intensive care management if accompanied by hypotension, hypoxemia, or organ dysfunction 4
• For suspected CRS that is severe, consider adding specialized treatments such as IL-6 inhibitors in consultation with specialists 4

Special Considerations

• Be vigilant for fever accompanied by specific organ-related symptoms that may indicate serious irAEs 1:

  • Respiratory symptoms: potential pneumonitis
  • Gastrointestinal symptoms: potential colitis
  • Neurological symptoms: potential encephalitis 5
  • Joint pain with morning stiffness: potential polymyalgia rheumatica 7
  • Acute kidney injury: monitor creatinine levels daily if fever develops after nivolumab administration 2

• Patients with pre-existing autoimmune conditions may be at higher risk for developing fever and other irAEs 1

Monitoring and Follow-up

• After resolution of fever, closely monitor for recurrence when restarting nivolumab or tapering steroids 1
• For patients requiring prolonged immunosuppression with corticosteroids, consider prophylactic antibiotics to prevent opportunistic infections 1
• The incidence of infusion reactions with PD-1/PD-L1 inhibitors is low (<1% of adverse events in phase III studies), but can increase significantly when combined with other therapies 6
• Document the reaction thoroughly to guide management of future nivolumab doses 6

Management of Recurrent Fever

• For recurrent fever with subsequent nivolumab doses, consider premedication with antipyretics 6
• If fever recurs despite premedication, evaluate for permanent discontinuation of nivolumab, especially if accompanied by other significant irAEs 6
• For patients with a history of severe fever reactions, consider alternative treatment options in consultation with oncology specialists 6