Why is a patient with metastatic renal cell carcinoma (RCC) on lenvatinib (lenvatinib) and previously given pembrolizumab (pembrolizumab) experiencing persistent neutropenia?

Persistent Neutropenia in a Patient with Metastatic Renal Cell Carcinoma on Lenvatinib and Prior Pembrolizumab

The persistent neutropenia in this patient is most likely due to lenvatinib therapy, which has a significant adverse event profile including hematological toxicities, and requires dose modification or temporary interruption based on the severity of neutropenia.

Mechanism of Neutropenia

• Lenvatinib is associated with hematological adverse events including lymphopenia (54% all grades, 9% grade 3-4) and neutropenia (31% all grades, 4% grade 3-4) as documented in clinical trials 1
• The combination of lenvatinib with pembrolizumab has shown higher rates of grade 3-4 adverse events (82.4%) compared to sunitinib monotherapy (71.8%) 2
• Previous exposure to pembrolizumab may have primed the immune system, potentially exacerbating the myelosuppressive effects when lenvatinib was added 2

Clinical Significance

• Neutropenia increases the risk of serious infections, which can lead to treatment interruptions, dose reductions, or discontinuation of therapy 1
• In the CLEAR trial, adverse events led to discontinuation of lenvatinib in 25.6% of patients and required dose reductions in 68.8% of patients receiving lenvatinib plus pembrolizumab 2
• Persistent neutropenia may negatively impact survival outcomes by necessitating treatment interruptions that compromise antitumor efficacy 3

Management Algorithm

1. Assess severity of neutropenia:

   • Grade 1-2: Monitor closely but continue treatment 3
   • Grade 3: Interrupt lenvatinib until resolved to Grade 0-1, then resume at reduced dose 1
   • Grade 4 or febrile neutropenia: Interrupt treatment immediately and consider hospitalization 1

2. Lenvatinib dose modifications:

   • First reduction: Decrease from 20mg to 14mg daily 1
   • Second reduction: Further decrease to 10mg daily if neutropenia persists 1
   • Third reduction: Consider 8mg daily as final dose reduction 1

3. Supportive measures:

   • Consider granulocyte colony-stimulating factor (G-CSF) for severe neutropenia 3
   • Prophylactic antibiotics may be warranted if neutropenia is prolonged 3
   • Regular monitoring of complete blood counts (every 1-2 weeks initially) 1

Important Considerations

• Benefit-risk assessment: Despite adverse events, the lenvatinib-pembrolizumab combination showed significant survival benefit in the CLEAR trial (median PFS 23.9 months vs 9.2 months with sunitinib) 2, 4
• Treatment goals: Maintaining the highest tolerable dose of lenvatinib is important for maximizing efficacy while managing toxicity 3
• Alternative regimens: If neutropenia remains unmanageable, consider switching to alternative regimens such as nivolumab plus cabozantinib or axitinib plus pembrolizumab 2

Common Pitfalls to Avoid

• Premature discontinuation: Don't discontinue therapy without attempting dose modifications first, as even reduced doses may provide clinical benefit 3
• Overlooking other causes: Rule out other potential causes of neutropenia such as bone marrow infiltration by cancer or other medications 3
• Inadequate monitoring: Regular blood count monitoring is essential, especially after dose modifications 1
• Delayed intervention: Early intervention for neutropenia can prevent more serious complications and allow continued treatment 3

By following this structured approach to managing neutropenia in this patient with metastatic renal cell carcinoma, you can optimize the balance between treatment efficacy and toxicity, potentially improving both quality of life and survival outcomes.