What are the predictors of Major Molecular Response (MMR) vs Complete Cytogenetic Response (CCyR) in Chronic Myeloid Leukemia (CML)?

Predictors of Major Molecular Response (MMR) vs Complete Cytogenetic Response (CCyR) in Chronic Myeloid Leukemia

Early molecular response with BCR-ABL1 transcript levels ≤10% at 3 months is the strongest predictor of both MMR and CCyR, with achievement of CCyR being the most clinically significant milestone for survival outcomes in CML patients. 1

Key Predictors of Response

Early Molecular Response (EMR)

• BCR-ABL1 transcript levels ≤10% at 3 months strongly predict both subsequent CCyR and MMR achievement 1
• Rate of decline in BCR-ABL1 transcripts correlates with longer-term response:
  • BCR-ABL1 halving time <76 days with imatinib is associated with superior outcomes (4-year PFS rate 92% vs 63%) 1
  • BCR-ABL1 halving time ≤14 days with dasatinib predicts MMR by 12 months and deep molecular response by 18 months 1

Patient-Related Factors

• Sokal risk score at diagnosis significantly impacts response rates:
  • Low-risk patients have higher rates of both CCyR and MMR 1
  • High-risk patients have lower rates of both responses (e.g., in ENESTnd trial, high-risk patients had 9% progression events vs 1% in low-risk) 1

Treatment-Related Factors

• Choice of TKI influences response rates:
  • Second-generation TKIs (nilotinib, dasatinib) achieve faster and deeper responses than imatinib 2, 3
  • In the ENESTnd trial, nilotinib 300mg twice daily achieved 44% MMR at 12 months vs 22% with imatinib 2
  • CCyR rates at 12 months: 80% with nilotinib vs 65% with imatinib 2
• Treatment adherence is critical for optimal responses 1

Clinical Significance of CCyR vs MMR

CCyR as Primary Milestone

• Achievement of CCyR (0% Ph+ metaphases) or ≤1% BCR-ABL1 IS within 12 months is an established prognostic indicator of long-term survival 1
• In the IRIS study, 6-year PFS rate was 97% for patients achieving CCyR at 6 months vs 80% for those without cytogenetic response 1
• 3-year event-free survival and OS rates were 98% and 99% for patients with CCyR at 12 months vs 67% and 94% in patients without CCyR 1

MMR's Added Value

• MMR (≤0.1% BCR-ABL1 IS) is associated with:
  • Durable long-term cytogenetic remission
  • Lower rate of disease progression
  • However, MMR is not a significant predictor of superior OS in patients who are already in stable CCyR 1
• With longer follow-up, CCyR becomes an ever-stronger indicator of MMR, reducing the added prognostic value of MMR 1
• The CML IV study showed no significant differences in OS between patients who achieved MMR and those who achieved MR2.0 (≤1% BCR-ABL1 IS, corresponding to CCyR) 1

Second-Line Therapy Response Patterns

• For patients on second-line TKI therapy after imatinib failure:
  • Early molecular response (≤10% BCR-ABL1 at 3 months) predicts better PFS and OS 1
  • Achievement of CCyR with second-line TKIs is associated with 72-74% OS at 7 years vs 50-56% without CCyR 1

Clinical Implications

Treatment Decision Points

• Failure to achieve ≤10% BCR-ABL1 at 3 months should prompt consideration of treatment change, though borderline cases (e.g., 11%) may warrant reassessment at 6 months before major treatment changes 1
• Failure to achieve CCyR by 12 months is a stronger indicator for treatment change than failure to achieve MMR 1
• The absence of MMR in the presence of CCyR is not considered treatment failure 1

Common Pitfalls to Avoid

1. Overemphasizing MMR over CCyR: While MMR is important, CCyR is the more critical milestone for survival outcomes 1, 4
2. Changing therapy based solely on rising BCR-ABL levels: This should only be done in the context of clinical trials 1
3. Ignoring rate of decline: The velocity of BCR-ABL1 reduction may be more important than absolute levels at specific timepoints 1
4. Applying imatinib response criteria to second-generation TKIs: Response definitions differ for newer TKIs, with earlier response milestones expected 5

Evolving Treatment Goals

• While survival was the traditional endpoint, treatment-free remission (TFR) is now an important goal 1
• Achievement of MMR at 12 months is associated with:
  • Very low probability of subsequent response loss
  • High likelihood of achieving deep molecular response, which may facilitate TKI discontinuation 1
• For elderly patients (≥60 years), mortality is primarily due to comorbidities unrelated to CML, making CCyR a reasonable milestone even without MMR 6

In conclusion, while both CCyR and MMR are important response milestones in CML, early molecular response at 3 months is the strongest predictor of both. For long-term survival outcomes, achieving CCyR is the more critical milestone, while MMR becomes increasingly important for patients considering treatment-free remission.