What are the considerations for treatment-free remission (TFR) in patients with Chronic Myeloid Leukemia in the chronic phase (CML-cp) who have achieved a deep molecular response with Tyrosine Kinase Inhibitor (TKI) therapy?

Treatment-Free Remission in Chronic Myeloid Leukemia in Chronic Phase

Treatment-free remission (TFR) is a safe and achievable goal for carefully selected CML-CP patients who have maintained a deep molecular response for at least 2 years on TKI therapy. Approximately 40-50% of eligible patients can successfully discontinue TKI therapy without experiencing molecular relapse 1.

Patient Selection Criteria for TFR

Institutional Requirements

• High-quality internationally standardized, accurate, sensitive qRT-PCR laboratory 1
• Rapid turnaround of PCR test results (within 4 weeks) 1
• Capacity to provide PCR tests every 4-6 weeks when required 1
• Structured follow-up established to enable rapid interventions 1

Patient-Specific Criteria

• Non-high Sokal score at diagnosis 1, 2
• Typical b2a2 or b3a2 BCR-ABL1 transcripts (e14a2 transcript has better TFR outcomes than e13a2) 1, 3
• Chronic phase disease 1
• Optimal response to first-line therapy 1
• Duration of TKI therapy > 5 years 1, 2
• Achievement of MR4.5 (BCR-ABL1 ≤0.0032% IS) 1
• Duration of deep molecular response (MR4 or MR4.5) > 2 years 1

Monitoring During TFR

A strict monitoring schedule is essential after TKI discontinuation 1, 4:

• Monthly molecular monitoring during the first 6 months 1
• Every 2 months for the subsequent 6 months 1
• Every 3 months indefinitely thereafter 1

Molecular Relapse Definition and Management

• Molecular relapse is defined as loss of major molecular response (MMR; BCR-ABL1 >0.1%) 1
• Most relapses occur within the first 6 months after discontinuation 1
• Resumption of TKI therapy immediately after relapse results in regaining deep molecular response in almost all patients 1, 4
• The same TKI that was administered before discontinuation is typically recommended for reinitiation 1

TFR Success Rates

• Approximately 40-60% of patients maintain TFR after discontinuation 1, 5
• The STIM1 study showed 38% TFR rate at 60 months with imatinib 1
• Second-generation TKIs (dasatinib, nilotinib) may achieve higher rates of deep molecular response, potentially increasing TFR eligibility 1, 6
• The EURO-SKI study demonstrated that the type of first-line TKI therapy did not significantly affect molecular relapse-free survival 1

Predictive Factors for Successful TFR

The BASE-TFR score identifies factors associated with higher risk of molecular relapse 2:

• High-risk Sokal score 1, 2
• Stable deep molecular response duration before TKI suspension < 5 years 2
• Prior unstable deep molecular response 2
• e13a2 BCR-ABL transcript (associated with lower TFR success compared to e14a2) 3

TKI Withdrawal Syndrome

• Musculoskeletal symptoms (myalgia, pain in extremity, arthralgia, bone pain, spinal pain) may occur after TKI discontinuation 1, 7
• These symptoms are more frequent in the first year after discontinuation 7
• The rate generally decreases in the second year 7
• In some patients, symptoms may persist and not resolve by the end of TFR phase 7

Considerations for Pediatric CML Patients

• About 50% of children treated with at least 3 years of imatinib who maintain stable deep molecular response for at least 2 years can discontinue TKI permanently without molecular relapse 1
• TFR attempts should be limited to children in CML-CP who have not experienced previous progression, treatment failure, or warning signs 1
• The approach to TFR should be individualized and carefully addressed after discussion with parents/caregivers 1

Second TFR Attempt

• The RE-STIM study demonstrated the safety of a second TKI discontinuation after a first unsuccessful attempt 1
• TFR rate at 24 months after second TKI discontinuation was higher for patients who remained in deep molecular response within the first 3 months after the first TKI discontinuation (72% vs 32%) 1

Clinical Implications

• TFR improves quality of life by eliminating TKI-related side effects 1, 5
• Successful TFR reduces healthcare costs 1
• Regular monitoring is essential as relapses can occur even after prolonged deep molecular response 4
• All patients should be informed that TFR is a treatment goal but not a cure, and lifelong monitoring is required 1, 5