Comprehensive Evaluation of Time-to-Response Parameter as a Predictor of Long-Term Outcomes Following Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia.

Early recognition of high-risk patients is important when planning further therapeutic intervention for imatinib treatment failure in patients with chronic myeloid leukemia (CML). Current guideline such as European Leukemia Network (ELN) emphasizes 3, 6, 12, and 18 months cutoff as decision point of imatinib therapy for CML. However, direct evidence of ELN guideline is still lacking. In addition, some controversy surrounds the questions: 1) which of the short-term response parameters (major cytogenetic response [MCyR], complete cytogenetic response [CCyR], or major molecular response [MMR]) is the best surrogate for long-term outcomes, 2) which time point (6, 12 or 18 months) reflect the best correlation with long-term outcomes and 3) if we exclusively use BCR/ABL quantitative PCR to monitor the response, what value for BCR/ABL levels is the best predictor for long-term outcomes.

In this comprehensive analysis, we adopted the landmark analysis method, time-dependent Cox's proportional hazard model and receiver-operating characteristics (ROC) method to analyze time-to-response parameter as predictor of long-term outcomes in 187 chronic phase (CP) CML patients receiving imatinib at least for one year at the Princess Margaret Hospital (Toronto, Canada).

Regardless of the method of analysis, we found that the earlier achievement of short-term response such as CCyR or MMR could predict the higher probability of achieving better interim outcome (such as treatment failure or loss of response), but not a long-term outcome (such as overall survival). Similar to the finding from other studies, our ROC analysis provided cutoff time range for MMR (18-36 months) and CCyR (6-12 months) that were the best predictors for CMR, LOR or treatment failure. Accordingly, the cutoffs of 12 months of CCyR or 18 months of MMR in the ELN guideline for the definition of suboptimal response could be justified based on the current result. In addition, BCR/ABL transcripts of 1.5-2.0 log reduction at 6 months and 2.0-2.5 log reduction at 12 months were better predictors of long-term outcomes following imatinib therapy in CP CML patients than the achievement of CCyR or MMR at 12 months.

The results of the current study confirm that regardless of the analytic method used (landmark analysis or time-dependent Cox's analysis), the time-to-response short-term parameter could predict the interim subsequent outcome (i.e., loss of response), but not a long-term outcome (i.e. overall survival). The ROC analysis method could provide the answer of when CML patients will be evaluated for appropriate response following imatinib therapy (i.e. MMR at 18-36 months and CCyR at 6-12 months). The current data can be a supporting evidence of ELN criteria definition of suboptimal response. In addition, the present study also suggested that the BCR/ABL transcript levels at 6 or 12 months could be an alternative early predictor of long-term outcomes.

No relevant conflicts of interest to declare.