What is the first-line treatment for chronic myeloid leukemia (CML)?

First-Line Treatment for Chronic Myeloid Leukemia (CML)

The standard initial treatment for newly diagnosed chronic phase CML is a tyrosine kinase inhibitor (TKI), with imatinib 400 mg daily being the most cost-effective first-line option for most patients, while second-generation TKIs (nilotinib, dasatinib, or bosutinib) are preferred for intermediate or high-risk patients. 1

Risk Stratification to Guide TKI Selection

Risk assessment is crucial for selecting the appropriate first-line TKI:

• Risk assessment tools:

  • EUTOS long-term survival (ELTS) score
  • Sokal score
  • Euro score 1

• First-line TKI options based on risk:

  • Low-risk patients: Imatinib 400 mg daily
  • Intermediate/high-risk patients: Second-generation TKIs (nilotinib, dasatinib, or bosutinib) 1

Advantages of Second-Generation TKIs

Second-generation TKIs offer several benefits over imatinib:

• Faster achievement of cytogenetic and molecular responses
• Lower risk of disease progression
• Higher rates of deep molecular response (DMR) 1

However, clinical trials with second-generation TKIs have not demonstrated survival prolongation compared to imatinib, likely due to the availability of effective salvage therapies 2

Patient-Specific Considerations for TKI Selection

When selecting a first-line TKI, consider:

1. Comorbidities:

   • Avoid dasatinib in patients with pulmonary diseases, risk of pleural effusion, or pulmonary hypertension
   • Avoid nilotinib in patients with cardiovascular diseases, diabetes, cerebrovascular diseases, or peripheral arteriopathy
   • Monitor closely patients with prolonged QT interval with any TKI 1

2. Age and treatment goals:

   • Younger patients with high-risk disease aiming for treatment-free remission may benefit more from second-generation TKIs 1, 2

3. Pregnancy planning:

   • For young female patients planning pregnancy, second-generation TKIs may be preferred due to higher chances of achieving deep molecular response 1

4. Cost considerations:

   • Imatinib is the most cost-effective option 1

Monitoring Response to First-Line Therapy

Regular monitoring is essential to assess treatment efficacy:

• Molecular monitoring: Every 3 months using quantitative PCR
• Cytogenetic monitoring: At 3,6,12, and 18 months until complete cytogenetic response is achieved 1

Key Response Milestones

Timepoint	Optimal Response	Warning/Suboptimal	Failure
3 months	BCR-ABL1 ≤10%		BCR-ABL1 >10%
6 months	BCR-ABL1 <10%	Ph+ 35%-65%	BCR-ABL1 >10%
12 months	BCR-ABL1 ≤1%		BCR-ABL1 >1%
Any time		Loss of MMR	Loss of CCgR, mutations

3, 1

Second-Line Treatment Options

For patients who fail first-line therapy:

• Alternative TKIs: Switch to a different second-generation TKI or third-generation TKI
• Consider BCR-ABL1 mutations: Patients with T315I mutation require ponatinib, asciminib, or olverembatinib 1, 2
• Allogeneic stem cell transplantation: Consider for patients who have failed at least two TKIs due to resistance 1, 2

Treatment Duration and Discontinuation

• TKI therapy should be continued indefinitely in optimal responders 1
• Patients with sustained deep molecular response (MR4 or MR4.5) for at least 2 years after ≥5 years of TKI therapy may be candidates for TKI discontinuation 1

Advanced Phase Disease

For accelerated or blast phase CML:

• Higher doses of TKIs may be required
• Allogeneic stem cell transplantation is recommended for all patients with advanced phase disease 1

By following these guidelines and considering patient-specific factors, the appropriate first-line TKI can be selected to optimize outcomes in patients with chronic myeloid leukemia.