What is the management for a patient who develops hyperthermia (fever over 101) on the first day of pembrolizumab (pembrolizumab, anti-PD-1 monoclonal antibody) therapy?

Management of Fever >101°F on First Day of Pembrolizumab

For a patient developing fever over 101°F on the first day of pembrolizumab, this most likely represents a Grade 1-2 infusion reaction; you should stop or slow the infusion rate, administer symptomatic treatment with antipyretics (acetaminophen) and antihistamines (diphenhydramine), and restart the infusion with close monitoring once symptoms improve. 1

Immediate Assessment and Grading

• Grade 1-2 fever (mild to moderate, <40°C): This is the most common presentation of pembrolizumab infusion reactions, occurring in approximately 3% of patients, typically manifesting as pyrexia with or without chills 1
• The fever on day one strongly suggests an infusion-related reaction rather than a delayed immune-related adverse event, as inflammatory irAEs typically present within the first 2 cycles but not during the actual infusion 1
• Rule out infection immediately with appropriate cultures and imaging, particularly if the fever persists or worsens, as bacterial infections can complicate immunotherapy 2

Acute Management Algorithm

During Active Infusion:

• Stop or slow the infusion rate immediately 1
• Administer acetaminophen and diphenhydramine as symptomatic treatment 1, 2
• Monitor vital signs closely for progression to Grade 3-4 reaction (bronchospasm, hypotension, severe symptoms) 1
• Restart infusion at slower rate once fever and symptoms resolve, with continued close monitoring 1

If Grade 3-4 Reaction Develops:

• Permanently discontinue pembrolizumab if severe infusion reaction occurs (fever >40°C with complications, bronchospasm, hemodynamic instability) 1
• Initiate aggressive symptomatic treatment including corticosteroids 1

Post-Infusion Monitoring

• Monitor for 24-48 hours for development of other immune-related symptoms that may indicate early pneumonitis, colitis, hepatitis, or other organ-specific irAEs 1, 3
• Check baseline labs including complete blood count, liver enzymes, and renal function to detect early signs of other irAEs 2
• Fever accompanied by cough and dyspnea should raise immediate concern for pneumonitis, which can present as early as 1-21 days after pembrolizumab 4

Premedication for Subsequent Doses

• Consider premedication with antipyretics and antihistamines for all subsequent pembrolizumab infusions if infusion reaction occurred 1, 2
• The ESMO guidelines specifically note that premedication with antipyretic and antihistamine may be considered for pembrolizumab to prevent recurrent infusion reactions 1
• Document the reaction thoroughly to guide management of future doses 2

Critical Pitfalls to Avoid

• Do not assume isolated fever is benign: While infusion reactions are typically mild, fever can be the first sign of serious complications including pneumonitis (which has occurred 1-21 days post-infusion), bacterial pneumonia, or hemophagocytic lymphohistiocytosis 4, 5
• Maintain high suspicion for infection: Pembrolizumab patients who develop fever may have concurrent bacterial infections that are difficult to distinguish from immune-related events, particularly if corticosteroids are initiated 4, 6
• Do not restart at full infusion rate: Always restart at a slower rate after interruption for infusion reaction 1
• Procalcitonin levels may help differentiate bacterial pneumonia from pure pneumonitis if respiratory symptoms develop 4

When to Escalate Care

• Fever persisting beyond 24 hours despite antipyretics warrants workup for infection and consideration of Grade 2 management with temporary hold of pembrolizumab 2
• Any fever accompanied by organ-specific symptoms (dyspnea, diarrhea, altered mental status, jaundice) requires immediate evaluation for immune-mediated organ toxicity 1, 3
• Consider hospitalization for Grade 3-4 fever (>40°C or with complications) with high-dose corticosteroids 2