What are the neurological adverse events associated with Blinatumomab (anti-CD19/CD3 bispecific monoclonal antibody) and how are they managed?

Blinatumomab-Associated Neurological Adverse Events and Management

Blinatumomab can cause serious or life-threatening neurologic toxicities in approximately 65% of patients, with grade 3 or higher neurological events occurring in about 13% of patients, requiring close monitoring and prompt intervention by experienced healthcare providers. 1

Incidence and Characteristics of Neurological Adverse Events

• Neurologic toxicities are common with blinatumomab, occurring in up to 65% of patients 1
• The median time to onset is within the first 2 weeks of treatment (typically around day 7-9) 1, 2
• Grade 3 or higher neurological toxicities occur in approximately 13% of patients 1
• Most neurological events occur during the first cycle of treatment 2

Types of Neurological Adverse Events

The most common neurological manifestations include:

• Common manifestations (≥10%):

  • Headache and tremor 1
  • Dizziness, confusional state, and encephalopathy 2

• Severe manifestations (Grade 3 or higher):

  • Encephalopathy
  • Convulsions/seizures
  • Speech disorders
  • Disturbances in consciousness
  • Confusion and disorientation
  • Coordination and balance disorders
  • Cranial nerve disorders 1

• Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS):

  • Occurs in approximately 7.5% of patients 1
  • Can occur concurrently with CRS, following resolution of CRS, or independently 1

Risk Factors for Neurological Adverse Events

Several factors increase the risk of neurological events:

• Age ≥65 years (72% vs 49% in younger patients) 2
• Race other than white (HR 2.11) 2

• 2 prior salvage therapies (HR 2.48) 2

• Prior neurological events (HR 1.65) 2
• Down syndrome (higher risk of seizures) 1
• Concurrent use of intrathecal chemotherapy 3
• Concomitant medications affecting musculoskeletal system, genitourinary system, and sexual hormones 4

Management of Neurological Adverse Events

Prevention Strategies

1. Pre-treatment assessment:

   • Evaluate pre-existing neurological conditions
   • Review concomitant medications that may increase risk 5
   • Avoid concurrent intrathecal chemotherapy if possible 3

2. Administration in specialized settings:

   • Treatment should be administered in specialized cancer centers with experience using blinatumomab 5
   • Use stepwise dosing to minimize risk 5

Monitoring

1. Neurological assessment:

   • Perform daily neurologic assessments from days 3-14 5
   • Use standardized neurological nursing assessments 6
   • Monitor for early signs of neurological toxicity 5

2. Patient education:

   • Advise outpatients to contact healthcare providers if they develop neurological symptoms 1
   • Instruct patients to refrain from driving and hazardous activities during treatment 1

Intervention for Neurological Toxicities

For management of neurological adverse events, follow this algorithm:

1. Mild to moderate toxicity (Grade 1-2):

   • Close monitoring
   • Consider temporary interruption if symptoms worsen

2. Severe toxicity (Grade 3):

   • Interrupt blinatumomab infusion
   • Administer dexamethasone
   • Resume at lower dose when resolved to Grade 1 or less 1

3. Life-threatening toxicity (Grade 4):

   • Discontinue blinatumomab permanently
   • Administer high-dose corticosteroids 1

4. For recurring neurological events:

   • Manage with infusion interruptions
   • Administer dexamethasone 2
   • Consider permanent discontinuation if events recur or persist

Relationship with Cytokine Release Syndrome (CRS)

• Neurological events may occur concurrently with CRS, following CRS resolution, or independently 1
• The highest fatality rate for neurological events occurs when they co-present with increased intracranial pressure and CRS 4
• CRS typically occurs within the first 2 days of treatment 5
• Monitor for signs of CRS including fever, headache, nausea, asthenia, hypotension, and increased liver enzymes 1

Special Considerations

• Mechanism: Evidence suggests neurological adverse events may involve T-cell adhesion to endothelial cells, followed by T-cell activation and cytokine release in the perivascular space 7
• Resolution: The majority of neurologic toxicities resolve following interruption of blinatumomab, though some result in treatment discontinuation 1
• Limited experience: There is limited experience with blinatumomab in patients with active ALL in the CNS or history of neurologic events 1

By implementing these monitoring and management strategies, healthcare providers can effectively mitigate the risk and severity of neurological adverse events associated with blinatumomab therapy while maximizing treatment benefits.