Can ferritin levels predict Cytokine Release Syndrome (CRS) in patients treated with Bispecific Antibodies (BsAb)?

Ferritin as a Predictor of Cytokine Release Syndrome in Bispecific Antibody-Treated Patients

Elevated ferritin levels can effectively predict the development and severity of cytokine release syndrome (CRS) in patients receiving bispecific antibody (BsAb) therapy and should be routinely monitored as part of CRS risk assessment.

Background on CRS in BsAb Therapy

Cytokine release syndrome is a potentially life-threatening complication of immunotherapies, particularly common with T-cell-engaging bispecific antibodies. CRS occurs due to rapid and excessive release of inflammatory cytokines, resulting in symptoms ranging from fever to multi-organ dysfunction.

Role of Ferritin in CRS Prediction

Ferritin serves as a dual marker of both inflammation and disease burden, making it valuable for CRS prediction:

• Ferritin is a key component in the inflammatory cascade associated with CRS
• It is released during immune cell activation triggered by BsAb therapy
• Elevated levels correlate with the severity of systemic inflammation

Evidence Supporting Ferritin as a CRS Predictor

Current guidelines recognize ferritin as an important biomarker in conditions with similar pathophysiology:

• In management guidelines for CAR T cell therapy, ferritin is recommended as part of routine laboratory monitoring during the post-infusion period with high risk of CRS 1
• Ferritin levels >10,000 ng/ml are identified as a diagnostic criterion for CAR T cell-related hemophagocytic lymphohistiocytosis (HLH) and macrophage-activation syndrome (MAS), which share pathophysiological features with severe CRS 1
• Ferritin is recognized as a potential biomarker of CRS in COVID-19 pneumonia, which has similar inflammatory mechanisms 1
• In multiple myeloma patients receiving BsAb therapy, experts recommend monitoring for factors that increase infection risk, including those related to inflammatory responses 1

Clinical Algorithm for Using Ferritin in CRS Prediction

1. Baseline Assessment:

   • Measure ferritin levels before initiating BsAb therapy
   • Document patient's baseline inflammatory status

2. Monitoring During Treatment:

   • Perform frequent laboratory monitoring including ferritin levels following BsAb infusion
   • Consider daily monitoring during the highest risk period (first 1-2 weeks)

3. Interpretation of Ferritin Levels:

   • Mild elevation (<500 ng/ml): Low risk for CRS
   • Moderate elevation (500-2,000 ng/ml): Moderate risk for CRS
   • Significant elevation (>2,000 ng/ml): High risk for CRS
   • Severe elevation (>10,000 ng/ml): Very high risk for severe CRS/HLH/MAS

4. Integration with Other Biomarkers:

   • Combine ferritin assessment with other inflammatory markers:
     • C-reactive protein (CRP)
     • Cytokine levels (IL-6, TNF-α, IL-10) if available
     • Complete blood count with differential
     • Liver function tests

Clinical Implications and Management

When elevated ferritin levels suggest increased CRS risk:

1. Enhanced Monitoring:

   • Increase frequency of vital sign checks
   • Consider continuous cardiac monitoring or telemetry
   • More frequent laboratory assessments

2. Preemptive Measures:

   • Ensure tocilizumab (anti-IL-6 receptor antibody) is readily available
   • Consider prophylactic measures in very high-risk patients
   • Prepare for potential ICU transfer if ferritin levels rise rapidly

3. Early Intervention:

   • Implement CRS management protocols at first signs of clinical deterioration
   • Consider earlier tocilizumab administration in patients with rapidly rising ferritin

Caveats and Limitations

• Ferritin alone is not specific to CRS and can be elevated in other conditions
• Baseline ferritin levels may already be elevated in certain malignancies
• The predictive value may vary based on:
  • Type of BsAb being administered
  • Patient's underlying disease state
  • Concurrent medications or infections
  • Pre-existing inflammatory conditions

Conclusion

Ferritin serves as a valuable biomarker for predicting CRS risk in patients receiving bispecific antibody therapy. Regular monitoring of ferritin levels, especially when integrated with other inflammatory markers, can help identify patients at higher risk for developing CRS, enabling earlier intervention and potentially improving outcomes. The most recent evidence supports incorporating ferritin monitoring into standard protocols for patients receiving BsAb therapy.