What are the considerations for switching between dasatinib (Sprycel) and nilotinib (Tasigna) in cases of treatment failure or discontinuation?

Switching Between Dasatinib and Nilotinib: Considerations for Treatment Failure or Discontinuation

When switching between dasatinib and nilotinib due to treatment failure or discontinuation, the choice should be guided by the patient's comorbidities, side effect profile, and BCR-ABL mutation status, with careful monitoring for specific adverse events associated with each medication. 1

Reasons for Switching Between TKIs

Treatment Failure

• Hematologic failure: Switch immediately to alternative TKI 1
• Cytogenetic failure:
  • No cytogenetic response at 3 months
  • Minor or no cytogenetic response at 6 months
  • Partial cytogenetic response or less at 12 months 1
• Molecular failure: Failure to achieve major molecular response after adequate time on therapy

Intolerance/Adverse Events

• Dasatinib-specific adverse events that may necessitate switch to nilotinib:

  • Pleural effusion (occurs in 35% of patients, leading cause of discontinuation) 2
  • Pulmonary arterial hypertension 1, 3
  • Fluid retention events 1

• Nilotinib-specific adverse events that may necessitate switch to dasatinib:

  • Cardiovascular events (stroke, acute coronary syndrome) 2
  • Peripheral arterial occlusive disease 1, 4
  • QT prolongation 4
  • Hyperglycemia 4

Efficacy of Switching Between Dasatinib and Nilotinib

• After failure of one TKI, switching to another second-generation TKI (dasatinib or nilotinib) can produce responses in approximately 40% of chronic phase patients 5
• Even after failure of two prior TKIs, switching to a third TKI can still induce cytogenetic responses in about 39% of patients (32/82) 5
• Responses after two prior TKI failures are generally more durable in chronic phase than in accelerated or blast phase 6

Practical Considerations When Switching

When switching from nilotinib to dasatinib:

1. Dosing: Start dasatinib at 100 mg once daily for chronic phase or 140 mg once daily for accelerated/blast phase 1, 3
2. Monitoring:
   • Complete blood counts every 1-2 weeks for first 2 months 1
   • Monitor for pleural effusion (cough, dyspnea, chest pain) 1
   • Baseline and follow-up ECG recommended 1

When switching from dasatinib to nilotinib:

1. Dosing: Start nilotinib at 300 mg twice daily for chronic phase or 400 mg twice daily for accelerated/blast phase 1, 4
2. Monitoring:
   • Cardiovascular risk assessment before starting therapy 1
   • Monitor lipid profile and blood glucose 4
   • Administer on empty stomach (food increases absorption) 4

BCR-ABL Mutation Considerations

• Certain mutations respond better to specific TKIs
• T315I mutation is resistant to both dasatinib and nilotinib 1
• Perform mutation analysis in case of treatment failure 1

Comparative Safety Profile

Dasatinib vs. Nilotinib

• Higher rate of grade 3-4 adverse events with dasatinib (54% vs. 22% with nilotinib) 2
• More frequent dose reduction, interruption, and discontinuation with dasatinib 2
• In real-world settings, dasatinib has shorter event-free survival compared to nilotinib 2

Management of Common Adverse Events

Hematologic Toxicities (Both Drugs)

• For grade 3-4 neutropenia (ANC < 500/mm³): Hold drug until ANC ≥ 1000/mm³
• For grade 3-4 thrombocytopenia (platelets < 50,000/mm³): Hold drug until platelets ≥ 50,000/mm³
• Growth factors can be used with both TKIs for resistant neutropenia 1

Specific Management

• Dasatinib-related pleural effusion: Diuretics, dose interruption, consider short course of steroids (prednisone 20 mg/d × 3 days); reduce dose when resolved 1
• Nilotinib-related cardiovascular events: Correct cardiovascular risk factors; consider switching to alternative TKI if events are severe 1

Important Caveats

1. Low-grade adverse events matter: Even grade 2 adverse events can lead to discontinuation (80% of discontinuations due to AEs, with 50% of these being only grade 2) 2

2. Drug interactions: Both drugs interact with CYP3A4 inhibitors/inducers; dasatinib absorption is pH-dependent (avoid antacids, PPIs) 1, 3

3. Timing of discontinuation: In first-line setting, discontinuation due to adverse events occurs more rapidly than in second-line setting (2.9 vs. 15.6 months) 2

4. Consider alloHSCT: For patients who fail two or more TKIs, allogeneic hematopoietic stem cell transplantation should be considered 1

By carefully selecting the appropriate TKI based on patient characteristics and mutation profile, and with proper monitoring and management of adverse events, switching between dasatinib and nilotinib can be an effective strategy to maintain disease control while improving quality of life.