What are the failure rates and causes of dasatinib (Sprycel) and nilotinib (Tasigna)?

Failure Rates and Causes of Dasatinib and Nilotinib in Chronic Myeloid Leukemia

Both dasatinib and nilotinib have treatment failure rates of approximately 40% by 5 years, with distinct toxicity profiles being the primary cause of discontinuation rather than lack of efficacy. 1

Failure Rates

Dasatinib

• Treatment discontinuation rate: 39% within 5 years 1
• Progression-free survival at 5 years: 86% 1
• Overall survival at 5 years: 91% 1
• Failure-free survival in third-line setting: 20 months in chronic phase, 5 months in accelerated phase, 3 months in blast phase 2

Nilotinib

• Treatment discontinuation rate: 40% within 5 years, 50% within 10 years 1
• Progression-free survival at 5 years: Not explicitly stated but similar to dasatinib
• Overall survival at 5 years: 94%, 10-year OS: 87.6% 1
• Grade 3-4 adverse events: 22% (vs. 47% with dasatinib) in real-world setting 3

Primary Causes of Failure

Dasatinib Failure Causes

1. Toxicity-related discontinuation (most common):

   • Pleural effusions (up to 37% of patients) 1, 4
   • Pulmonary arterial hypertension (rare but serious) 1, 4
   • Myelosuppression and cytopenias 1
   • Bleeding tendency due to platelet dysfunction 1

2. Resistance mechanisms:

   • BCR-ABL1 kinase domain mutations (particularly T315I, F317L/V/I/C, V299L) 1
   • Clonal evolution with additional chromosomal aberrations 1
   • BCR-ABL1 independent pathways activation 1

Nilotinib Failure Causes

1. Toxicity-related discontinuation:

   • Arterio-occlusive events (5% of patients) 4
   • Hyperglycemia 1
   • Elevated serum lipase/pancreatitis 1
   • Hepatotoxicity (transaminase elevation) 1
   • Hyperbilirubinemia in patients with Gilbert's disease 1

2. Resistance mechanisms:

   • BCR-ABL1 kinase domain mutations (particularly T315I, Y253H, E255V/K, F359V/I/C) 1
   • Similar resistance patterns as dasatinib (clonal evolution, BCR-ABL1 independent pathways) 1

Comparative Efficacy in Second-Line Setting

When used as second-line therapy after imatinib failure:

• Major molecular response rates: 47% with dasatinib vs. 38% with nilotinib at 12 months 3
• Deep molecular response rates: 18.2% with dasatinib vs. 16.2% with nilotinib at 12 months 3
• Overall survival at 7 years: 72% with dasatinib vs. 85.6% with nilotinib (not statistically significant) 3

Factors Affecting Treatment Success

1. Prior TKI response: Patients who achieved cytogenetic response with prior TKI have better outcomes 1
2. Disease phase: Chronic phase has better outcomes than accelerated or blast phase 2
3. Mutation status: Specific mutations predict response to specific TKIs 1
4. Comorbidities: Pre-existing conditions affect TKI selection and tolerance 1
5. Adherence to therapy: Poor adherence is a major cause of treatment failure 1

Clinical Implications

• Treatment selection should consider comorbidities:

  • Avoid dasatinib in patients with respiratory/pulmonary conditions 1
  • Avoid nilotinib in patients with cardiovascular risk factors, diabetes, or pancreatitis 1

• Mutation testing is crucial when treatment failure occurs to guide subsequent TKI selection 1

• Third-line therapy options after failure of two TKIs can still induce responses in some patients, though these are usually less durable except in chronic phase 5, 2

• Regular monitoring is essential for early detection of resistance or intolerance 1

Pitfalls to Avoid

1. Failing to test for BCR-ABL1 mutations when resistance develops
2. Overlooking non-adherence as a cause of apparent resistance
3. Delaying treatment changes when warning signs of failure appear
4. Inappropriate dose reductions without considering alternative TKIs
5. Continuing ineffective therapy beyond recommended timeframes

Patients should be monitored closely for both efficacy and toxicity, with prompt intervention when either treatment failure or significant adverse events occur.