What are the adverse events associated with Blinatumomab (anti-CD19/CD3 bispecific monoclonal antibody) treatment?

Blinatumomab Adverse Events: Neurologic Toxicities and Cytokine Release Syndrome are the Most Significant Concerns

Blinatumomab treatment is associated with two major serious adverse events: neurologic toxicities (occurring in up to 50% of patients) and cytokine release syndrome (CRS), both of which require close monitoring and prompt intervention in a specialized cancer center with experience administering this medication. 1

Major Adverse Events

Neurologic Toxicities

• Incidence: Reported in 50% of patients
• Onset: Median onset at 7 days after starting treatment
• Severity: Grade 3 or higher neurologic toxicities occur in 15% of patients
• Manifestations:
  • Encephalopathy
  • Convulsions/seizures
  • Disorientation
  • Neurotoxicity
  • Agnosia
  • Intention tremor
  • Immune effector cell-associated neurotoxicity syndrome 2

Cytokine Release Syndrome (CRS)

• Onset: Typically occurs within first 2 days after starting blinatumomab infusion
• Manifestations:
  • Pyrexia (fever)
  • Headache
  • Nausea
  • Asthenia (weakness)
  • Hypotension
  • Increased transaminases
  • Increased total bilirubin 1
• Complications: Can progress to life-threatening hemophagocytic lymphohistiocytosis (HLH) in severe cases 3

Other Common Adverse Events

Based on clinical trials and FDA labeling:

• Hematologic:

  • Anemia (24%)
  • Neutropenia (19%)
  • Thrombocytopenia (15%)
  • Febrile neutropenia (2%) 4

• Gastrointestinal:

  • Nausea (43%)
  • Abdominal pain (13%)
  • Stomatitis (11%) 4

• General:

  • Pyrexia (76%)
  • Hypogammaglobulinemia (24%) 4

• Hepatobiliary:

  • Liver function test abnormalities (9%) 4

• Skin:

  • Rash (22%) 4

Risk Factors for Adverse Events

• For neurologic toxicity:

  • Male gender (44% of cases)
  • Younger age (18-45 years, 28.39% of cases)
  • Concomitant medications affecting:
    • Musculoskeletal system
    • Genitourinary system
    • Sexual hormones 2

• For CRS:

  • Higher disease burden
  • First cycle of treatment
  • Higher doses 1

Rare but Serious Adverse Events

• Macrophage Activation Syndrome (MAS):

  • Characterized by fever, cytopenias, elevated liver enzymes, and hyperferritinemia
  • Can occur even in patients already in remission 5

• Fatal pancreatitis when blinatumomab is used in combination with dexamethasone 4

Management Considerations

1. Prevention:

   • Administer in specialized cancer centers with experience using blinatumomab
   • Use stepwise dosing (5 mg/m²/day for first 7 days, then 15 mg/m²/day afterward in pediatric patients) 1
   • Monitor closely for early signs of toxicity

2. Intervention for neurologic toxicities:

   • Early recognition and prompt intervention
   • Dose interruption or discontinuation for severe cases
   • Supportive care

3. Intervention for CRS:

   • Early recognition and prompt intervention
   • For severe cases: tocilizumab (IL-6 receptor antagonist) has shown efficacy 3
   • Dexamethasone for severe symptoms 5

4. Special populations:

   • Pregnancy: May cause fetal harm; B-cell lymphocytopenia in infants exposed in utero
   • Breastfeeding: Avoid during treatment and for 48 hours after last dose
   • Drug interactions: Monitor closely during first 9 days of first cycle and first 2 days of second cycle in patients on concomitant CYP450 substrates 4

Monitoring Algorithm

1. Pre-treatment:

   • Assess for pre-existing neurological conditions
   • Review concomitant medications
   • Evaluate baseline liver function and blood counts

2. First 48 hours (highest risk for CRS):

   • Continuous monitoring for fever, hypotension, respiratory symptoms
   • Regular vital signs and symptom assessment

3. Days 3-14 (highest risk for neurologic toxicity):

   • Daily neurologic assessment
   • Monitor for signs of encephalopathy, seizures, or confusion
   • Be prepared to interrupt treatment if grade ≥3 toxicity occurs

4. Throughout treatment:

   • Regular monitoring of liver function tests
   • Complete blood counts
   • Assessment for signs of infection

The serious nature of these adverse events underscores the importance of receiving treatment in a specialized cancer center with experience administering blinatumomab, as early intervention can significantly reduce morbidity and mortality associated with these complications 1.