Can paclitaxel and pembrolizumab (Keytruda) cause high‑grade fever on day 10 after infusion in a 52‑year‑old woman with advanced FIGO grade 1 endometrioid adenocarcinoma?

Can Paclitaxel and Pembrolizumab Cause High-Grade Fever on Day 10 After Administration?

Yes, both paclitaxel and pembrolizumab can cause high-grade fever on day 10 after infusion, though the mechanisms and clinical contexts differ significantly—paclitaxel typically causes immediate infusion reactions, while pembrolizumab can trigger delayed immune-mediated adverse events including fever as part of systemic inflammatory syndromes.

Understanding the Timing and Mechanisms

Paclitaxel-Related Fever

Paclitaxel infusion reactions typically occur during the first few cycles and within the first few hours of infusion, not on day 10 1, 2. These are characterized by:

• Hot flushing, rash, cardiovascular reactions
• Respiratory or throat tightness
• Most commonly mild, but can be severe

However, delayed fever from paclitaxel alone at day 10 is uncommon and would more likely represent infection or another etiology.

Pembrolizumab-Related Fever

Pembrolizumab can cause fever through multiple mechanisms at day 10:

1. Immune-Related Adverse Events (irAEs) The FDA label explicitly warns that pembrolizumab can cause various immune-mediated toxicities that may present with fever 3. Recent case reports document:

• Hemophagocytic lymphohistiocytosis (HLH): Presents with "transient immune-related fever on day 7" followed by "recurrent high-grade fever" and splenomegaly on day 10, with highly elevated ferritin and liver dysfunction 4
• Autoimmune encephalitis: "Persistent high-grade fever one week after immunotherapy administration" with subsequent neurological deterioration 5, 6

2. Infusion Reactions While pembrolizumab infusion reactions (0.2% incidence) typically occur during or immediately after infusion 3, delayed reactions have been documented 7.

Critical Diagnostic Approach for Day 10 Fever

When evaluating high-grade fever on day 10 after carboplatin/paclitaxel/pembrolizumab, you must systematically exclude life-threatening irAEs:

Immediate Red Flags Requiring Urgent Evaluation

HLH (Highest Mortality irAE) 4:

• Recurrent high-grade fever
• Splenomegaly (check on exam and imaging)
• Ferritin >500 ng/mL (often >10,000)
• Hypertriglyceridemia
• Cytopenias
• Elevated liver enzymes
• Predisposing factors: Autoimmune disease, positive autoantibodies, EBV infection, thymic tumors

Autoimmune Encephalitis 5, 6:

• Fever with any altered mental status
• Confusion, disorientation, behavioral changes
• CSF lymphocytic pleocytosis with elevated protein
• May have concurrent hypothyroidism or other endocrinopathies

Other Immune-Mediated Syndromes 8, 3:

• Myocarditis (fever + chest pain, troponin elevation, arrhythmias)
• Pneumonitis (fever + dry cough, dyspnea)
• Colitis (fever + diarrhea, abdominal pain)

Diagnostic Algorithm

Step 1: Rule out infection first (neutropenic sepsis, pneumonia, UTI, line infection)

• Complete blood count with differential
• Blood cultures, urinalysis, chest imaging
• Broad-spectrum antibiotics if neutropenic or septic

Step 2: If infection workup negative or fever persists despite antibiotics, evaluate for irAEs:

• Laboratory: Ferritin, triglycerides, LDH, liver enzymes, troponin, TSH, cortisol
• Imaging: CT chest/abdomen/pelvis to assess for splenomegaly, lymphadenopathy
• Specialized testing based on symptoms:
  • Neurological symptoms → Brain MRI, lumbar puncture
  • Cardiac symptoms → ECG, echocardiogram
  • Respiratory symptoms → CT chest, pulmonary function tests

Step 3: Consider HLH if:

• Ferritin >500 ng/mL
• Splenomegaly present
• Two or more cytopenias
• Hypertriglyceridemia or hypofibrinogenemia
• Initiate HLH-directed therapy immediately (dexamethasone + etoposide) 4

Management Based on Etiology

If Immune-Related Fever/irAE Confirmed

For HLH 4:

• Dexamethasone + etoposide
• Permanently discontinue pembrolizumab
• Mortality is high without prompt treatment

For Autoimmune Encephalitis 5, 6:

• High-dose IV methylprednisolone (1 g daily × 3-5 days)
• Rapid response expected within 48-72 hours
• Permanently discontinue pembrolizumab

For Other Grade 3-4 irAEs 9, 8:

• High-dose corticosteroids (prednisone 1-2 mg/kg or equivalent)
• Withhold or permanently discontinue pembrolizumab depending on severity
• Refer to NCCN Guidelines for Management of Immunotherapy-Related Toxicities 9

If Infusion Reaction (Less Likely at Day 10)

Grade 3-4 infusion reactions 3, 7:

• FDA label recommends permanent discontinuation
• However, one case report showed successful rechallenge with 75% slower infusion rate plus premedication (H1/H2 blockers, acetaminophen) 7
• This approach is off-label and high-risk—only consider if pembrolizumab is critically needed and no alternatives exist

Special Considerations for This Patient Population

Advanced endometrial cancer patients receiving carboplatin/paclitaxel/pembrolizumab 9:

• This is now a Category 1 preferred regimen for stage III-IV disease
• Significant survival benefit (HR 0.30 for dMMR, 0.54 for pMMR) 9
• Grade ≥3 adverse events occur in 63-70% 10
• Most common AEs: fatigue, neuropathy, anemia, nausea—not typically high-grade fever

When fever occurs, it represents either:

1. Infection (most common, especially if neutropenic)
2. Serious irAE requiring immediate intervention
3. Rarely, delayed infusion reaction

Key Clinical Pitfalls to Avoid

1. Do not attribute day 10 fever to "expected chemotherapy side effects"—this timing is atypical and warrants full evaluation
2. Do not delay corticosteroids if HLH or autoimmune encephalitis suspected—mortality is high without prompt treatment
3. Do not rechallenge with pembrolizumab after Grade 3-4 irAE without careful risk-benefit discussion and specialist consultation
4. Do not miss splenomegaly—physical exam and imaging are critical for HLH diagnosis
5. Check ferritin in all patients with unexplained fever after immunotherapy—it's the single best screening test for HLH

Bottom Line

High-grade fever on day 10 after paclitaxel/pembrolizumab is not a typical expected side effect. While infection must be excluded first, pembrolizumab-related immune-mediated syndromes—particularly HLH and autoimmune encephalitis—are life-threatening causes that require immediate recognition and treatment. The combination of fever, splenomegaly, and markedly elevated ferritin should trigger urgent HLH evaluation and treatment 4. Early corticosteroid therapy is critical for favorable outcomes in immune-mediated toxicities 5, 6.