How to manage Nivolumab (nivolumab)-induced fever?

Management of Nivolumab-Induced Fever

For nivolumab-induced fever, treatment should be based on severity grading, with Grade 1 fever managed with antipyretics while continuing therapy, Grade 2 fever requiring temporary withholding of nivolumab and scheduled antipyretics, and Grade 3-4 fever necessitating immediate nivolumab discontinuation and high-dose corticosteroids. 1

Clinical Presentation and Assessment

• Nivolumab-induced fever may present as an isolated symptom or with other symptoms indicating potential organ inflammation, and should be considered an important immune-related adverse event (irAE) requiring monitoring 1
• Fever may signal the onset of more serious immune-mediated reactions affecting other organ systems, including pneumonitis, nephritis, thrombocytopenia, or encephalitis 1, 2
• A thorough evaluation for concurrent irAEs affecting other organ systems is essential, as fever can be the first manifestation of a more serious immune-mediated reaction 1

Grading and Management Algorithm

Grade 1 Fever (Mild, <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 1

Grade 2 Fever (Moderate, 38.5-40°C)

• Temporarily withhold nivolumab until fever resolves 1
• Administer antipyretics on a scheduled basis 1
• Rule out infection with appropriate cultures and imaging 1
• Monitor renal function, liver enzymes, and complete blood count to detect early signs of other irAEs 1

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

• Immediately withhold nivolumab 1
• Initiate high-dose corticosteroids (e.g., methylprednisolone or equivalent) 1, 3
• Consider hospitalization for monitoring and supportive care 1
• For severe cases refractory to corticosteroids, consider additional immunosuppressive therapy such as intravenous immunoglobulin (IVIG) 3
• In cases unresponsive to steroids and IVIG, cyclosporine may be considered as a third-line therapy based on case reports of success with other immune checkpoint inhibitor-induced adverse events 4

Special Considerations

• Be vigilant for fever accompanied by specific organ-related symptoms that may indicate serious irAEs 1
• Respiratory symptoms may indicate pneumonitis, which can present with fever and cough after nivolumab administration 5
• Neurological symptoms with fever may suggest encephalitis, requiring prompt evaluation and aggressive treatment 3
• Thrombocytopenia can develop following nivolumab-induced fever and may require corticosteroid treatment 2
• Cytokine release syndrome (CRS) should be considered in patients with fever accompanied by hypotension, hypoxemia, or organ dysfunction 6

Monitoring and Follow-up

• After resolution of fever, closely monitor for recurrence when restarting nivolumab or tapering steroids 1
• Consider prophylactic antibiotics in patients requiring prolonged immunosuppression with corticosteroids 1
• Document the reaction thoroughly to guide management of future nivolumab doses 1

Management of Recurrent Fever

• Consider premedication with antipyretics for recurrent fever with subsequent nivolumab doses 1
• Evaluate for permanent discontinuation of nivolumab if fever recurs despite premedication, especially if accompanied by other significant irAEs 1
• Consider alternative treatment options in consultation with oncology specialists for patients with a history of severe fever reactions 1

Prevention and Patient Education

• Educate patients about possible immune-related side effects, including fever, and the importance of promptly reporting symptoms 7
• Healthcare providers should be aware of the spectrum of potential immune-mediated adverse events and know how to manage these adverse events 7