Prognostic Impact of MMR and CCyR in CML
Both Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) are significant prognostic indicators in CML, with CCyR being the strongest predictor of long-term survival while MMR primarily predicts durability of remission and lower risk of progression. 1
Significance of CCyR
CCyR represents a critical milestone in CML treatment regardless of the therapy used:
Survival Impact: Achievement of CCyR (0% Ph+ metaphases or ≤1% BCR-ABL1 IS) within 12 months is associated with:
Timing Matters: Early achievement of CCyR (within 6-12 months) provides the best benefit-to-risk ratio by minimizing disease progression risk 3
Second-Line Therapy: For patients on second-line therapy after imatinib failure, CCyR achievement is associated with 3-year survival probability of 98% compared to 83% with partial cytogenetic response 4
Significance of MMR
MMR (≤0.1% BCR-ABL1 IS) offers additional prognostic value beyond CCyR:
Durability of Response: MMR is associated with more durable long-term cytogenetic remission 1, 2
Progression Risk: The 5-year follow-up of the IRIS trial showed that no patient who had CCyR and MMR at 12 months experienced progression to accelerated or blast phase 1
- Estimated progression-free survival rate at 24 months was 100% for patients with CCyR and MMR vs 95% for those with CCyR but no MMR 1
Event-Free Survival: The estimated event-free survival rate at 72 months was 98% for patients with MMR at 18 months compared with 89% in those without MMR 1
Comparative Value
While both responses are important, their relative significance differs:
CCyR as Primary Goal: CCyR remains the most important surrogate for long-term survival in CML 3
- Achievement of at least major cytogenetic response (MCyR) within 2 years predicts good long-term outcomes (10-year overall survival of 88% and CML-related survival of 95%) 5
MMR as Secondary Goal: MMR provides additional value but may not significantly impact overall survival in patients who have already achieved CCyR 6, 7
- In some studies with second-generation TKIs, there was no difference in event-free survival and CCyR duration between patients who achieved CCyR with and without MMR 7
Clinical Implications
Treatment Decisions: Failure to achieve CCyR by 12 months is a stronger indicator for treatment change than failure to achieve MMR 2, 3
Monitoring Strategy:
- Cytogenetic evaluation is recommended at 6 and 12 months from treatment initiation 1
- Molecular monitoring with qPCR every 3 months is recommended for all patients after initiating TKI therapy 1
- After CCyR has been achieved, molecular monitoring is recommended every 3 months for 2 years and every 3-6 months thereafter 1
Treatment-Free Remission: Achievement of sustained deep molecular response is now considered a prerequisite for attempting treatment-free remission 2, 8
Pitfalls and Caveats
Response Definitions Vary by TKI: The European LeukemiaNet response definitions based on imatinib may not be directly applicable to second-generation TKIs, which induce faster and deeper responses 7
Laboratory Standardization: Differences in techniques and internal controls make quantification of molecular responses variable across laboratories 1
Age Considerations: In older patients (≥60 years), the prognostic value of MMR may be less pronounced as mortality is often due to comorbidities unrelated to CML 5
Response Fluctuations: A minimal increase in BCR-ABL mRNA or loss of MMR predicts shorter relapse-free survival in patients with CCyR on imatinib therapy, but changes in therapy based solely on rising BCR-ABL levels should only occur in clinical trials 1
Patient Adherence: Treatment interruptions and nonadherence to TKI therapy can lead to suboptimal responses and poorer outcomes 1