In a 52‑year‑old woman with advanced FIGO grade 1 endometrioid adenocarcinoma who received carboplatin, paclitaxel, and pembrolizumab and developed febrile neutropenia with persistent high fevers despite broad‑spectrum antibiotics, now has a recovered neutrophil count, what should hematology‑oncology’s next management be and what is the most likely cause of the ongoing high fevers?

Management of Persistent Fever After Neutrophil Recovery

Continue empiric vancomycin and monitor closely without further antibiotic escalation, as persistent fever in a hemodynamically stable patient with recovered neutrophil counts (ANC >10,000) rarely requires antibiotic changes and is most likely drug-related from paclitaxel or pembrolizumab. 1

Most Likely Cause of High Fevers

The persistent high-grade fevers (Tmax 104.1°F) despite neutrophil recovery are most consistent with drug-induced fever from paclitaxel or pembrolizumab, though the degree is atypically high for paclitaxel alone. The combination of checkpoint inhibitor therapy adds complexity, as pembrolizumab can cause immune-related inflammatory responses that manifest as fever. 2, 3

Key supporting evidence:

• Exhaustive negative infectious workup: Blood cultures negative from two dates, negative UA, negative respiratory viral panel, CT imaging without infectious source
• Neutrophil recovery achieved: ANC increased to 10.09 K/µL, eliminating neutropenia as ongoing risk factor
• Hemodynamic stability: Patient is afebrile this morning and stable
• Elevated inflammatory markers: CRP 8.35 and ferritin jumped from 36 to 1,144, consistent with systemic inflammation rather than localized infection

The remote fungal organisms found on pelvic washing from prior to hysterectomy are appropriately dismissed by ID given subsequent surgery, lack of prolonged neutropenia, and negative imaging. 1

Immediate Hematology-Oncology Management

1. Discontinue Nivestym (G-CSF)

• ANC >10 K/µL meets stopping criteria
• Continued G-CSF may contribute to inflammatory state and bandemia 4

2. Complete Pending Viral Studies

• Await CMV, EBV, and parvovirus PCR results
• These are unlikely culprits given clinical picture but must be excluded before attributing fever to drug effect 1

3. Antibiotic Management

Do not escalate antibiotics based on fever alone. 1 The IDSA guidelines explicitly state that persistent fever in an otherwise stable patient with recovered neutrophils is rarely an indication to change antibiotics. The median time to defervescence in hematologic malignancies is 5 days, and this patient is within that window. 1

• Continue vancomycin as currently prescribed given MRSA colonization (though no confirmed infection)
• Monitor for 48-72 hours from neutrophil recovery
• Stop vancomycin after 2 days if no evidence of gram-positive infection emerges 1

4. Address Neurologic Symptoms

The worsening mental status with persistent nausea/vomiting requires urgent attention:

• Obtain MRI brain as recommended, given unremarkable CT but persistent symptoms
• Consider pembrolizumab-induced encephalitis in differential—this is a recognized immune-related adverse event that can present with encephalopathy and requires high-dose corticosteroids 5
• Evaluate for immune-related adverse events (irAEs) systematically: thyroid function (already showing hypothyroidism per ferritin context), liver enzymes, cortisol level
• The combination of neurologic symptoms + persistent fever + elevated inflammatory markers raises concern for immune-mediated toxicity from pembrolizumab 3, 5

5. Platelet Management

• Platelets improving (53K→57K) but still thrombocytopenic
• No platelet transfusion needed unless active bleeding or invasive procedures planned
• Monitor for immune-mediated thrombocytopenia (ITP) as pembrolizumab/durvalumab-related irAE, though less likely given improving trend 6

6. Hold Further Chemotherapy

Systemic treatment remains appropriately on hold until:

• Fever resolves completely
• Platelets recover to >100 K/µL 2
• Neurologic symptoms resolve or are explained
• Any immune-related adverse events are controlled

Dose reduction of 20% for subsequent paclitaxel cycles should be planned given the severe pancytopenia experienced. 2

Critical Decision Points

If Fever Recurs or Persists Beyond 48-72 Hours:

1. Reassess for occult infection:

   • Repeat imaging if new symptoms develop
   • Consider fungal coverage only if additional risk factors emerge (prolonged neutropenia >7 days, which did not occur here) 4
   • Galactomannan and beta-D-glucan if fungal infection suspected

2. Consider drug fever diagnosis of exclusion:

   • Paclitaxel can cause fever, though typically not this severe 2
   • Pembrolizumab-related systemic inflammation is increasingly likely given dMMR/MSI-H tumor biology and checkpoint inhibitor mechanism 3, 7, 8

3. Evaluate for immune-related adverse events:

   • Pembrolizumab causes irAEs in significant proportion of patients
   • Fever can be manifestation of immune-mediated colitis, hepatitis, pneumonitis, or encephalitis
   • Low threshold for corticosteroids (methylprednisolone 1-2 mg/kg/day) if irAE suspected 3, 5

If Hemodynamic Instability Develops:

Broaden antimicrobial coverage immediately to include resistant gram-negative organisms, anaerobes, and empiric antifungals. 1 This would override the conservative approach, as hemodynamic compromise changes risk stratification.

Common Pitfalls to Avoid

1. Over-treating fever in stable patients: The reflex to escalate antibiotics with persistent fever leads to unnecessary broad-spectrum coverage, increased resistance, and drug toxicity. 1

2. Missing immune-related adverse events: Pembrolizumab can cause life-threatening irAEs including encephalitis, which requires corticosteroids, not antibiotics. The neurologic symptoms here are a red flag. 5

3. Ignoring the inflammatory state: Ferritin >1,000 with elevated CRP suggests systemic inflammation beyond infection—consider drug effect or immune activation from checkpoint inhibitor. 3

4. Premature resumption of chemotherapy: Thrombocytopenia must resolve to >100 K/µL before next cycle, and any irAEs must be controlled. 2, 7

Prognosis and Treatment Context

This patient has dMMR/MSI-H endometrial cancer, which is highly responsive to pembrolizumab-based therapy. The NRG-GY018 trial showed 74% progression-free survival at 12 months in dMMR patients receiving pembrolizumab plus carboplatin/paclitaxel. 7, 8 Some patients achieve pathological complete response with this regimen. 9, 10

The priority is managing acute toxicity to enable continuation of highly effective therapy. Once fever resolves and counts recover, resumption of pembrolizumab-based treatment (with dose-reduced paclitaxel) offers excellent disease control potential in this molecular subtype.