What scores predict Cytokine Release Syndrome (CRS) in bispecific therapy?

Scores That Predict Cytokine Release Syndrome (CRS) in Bispecific Therapy

The Clinical Risk Score (CRS) with a score of 0-2 indicating low risk and 3-5 indicating high risk is the most validated scoring system for predicting cytokine release syndrome in patients receiving bispecific therapy. 1

Key Predictive Scores and Risk Factors

Validated Clinical Risk Scores

• Clinical Risk Score (CRS): A 5-point scoring system where each parameter scores 1 point 1:
  1. Positive lymph nodes of primary tumor
  2. Synchronous or metachronous metastases within 12 months
  3. More than one metastatic lesion
  4. Preoperative CEA level >200 ng/mL
  5. Maximum diameter of metastatic tumor >5 cm

Neurological Assessment Tools

• CARTOX-10 Assessment Tool: For patients ≥12 years with age-appropriate cognitive abilities 1:

  • Orientation to year, month, city, hospital (4 points)
  • Naming three objects (3 points)
  • Following simple commands (1 point)
  • Writing a standard sentence (1 point)
  • Counting backward from 100 by 10 (1 point)
  • Lower scores indicate higher risk of neurotoxicity

• Cornell Assessment of Pediatric Delirium (CAPD): For patients <12 years 1:

  • CAPD score ≥9 indicates grade 3 ICANS (immune effector cell-associated neurotoxicity syndrome)
  • Increasing scores correlate with worsening severity

Baseline Predictors of CRS Risk

According to multivariable analysis, the following baseline characteristics predict CRS risk 2:

1. High marrow tumor burden
2. Lymphodepletion using cyclophosphamide and fludarabine
3. Higher CAR T-cell/bispecific antibody dose
4. Pre-existing thrombocytopenia
5. Manufacturing process factors (e.g., without selection of CD8+ central memory T cells)

Bispecific Antibody-Specific Risk Factors

Different bispecific antibodies have varying CRS incidence rates 1:

• Elranatamab-bcmm: CRS reported as common adverse event
• Talquetamab-tgvs: CRS in 77-80% of patients
• Teclistamab-cqyv: CRS in 72.1% of patients (0.6% grade 3)

Laboratory Biomarkers for CRS Prediction

• Endothelial activation markers 2:

  • Elevated angiopoietin-2
  • Increased von Willebrand factor
  • These markers may be elevated before lymphodepletion in patients who subsequently develop CRS

• Cytokine profiles 3, 4:

  • Elevated IL-6
  • Elevated IL-1
  • Increased interferon levels
  • Higher TNF-alpha levels

Monitoring and Management Approach

1. Pre-treatment assessment:

   • Evaluate baseline risk factors
   • Check endothelial activation markers if available
   • Assess tumor burden

2. Early intervention for high-risk patients 5, 6:

   • Consider prophylactic tocilizumab for high-risk patients
   • Avoid dexamethasone pre-treatment as it may impair antitumor activity

3. Regular monitoring during treatment:

   • Neurological assessments twice daily using CARTOX-10 or CAPD
   • Monitor for fever, hypotension, and respiratory symptoms
   • Track cytokine levels when possible

Common Pitfalls and Caveats

• Avoid confusing CRS with infection: Similar presentations require careful differential diagnosis 3
• Don't delay intervention: Early intervention with tocilizumab may prevent severe CRS without compromising efficacy 5
• Beware of concurrent ICANS: When CRS and ICANS occur simultaneously, management of ICANS may take precedence 1
• Recognize that CRS correlates with efficacy: Patients with higher expansion of T cells tend to have higher CRS grades but also better responses 7

Emerging Approaches

Recent data suggest that early IL-6 blockade with tocilizumab may reduce CRS severity without affecting therapeutic activity of bispecific antibodies, potentially allowing for safer application of effective doses 5, 6.