Cancer Therapy: Clinical
75% to 90% of patients treated with imatinib in early chronic phase (6, 7, 11). With standard-dose imatinib, f40% of patients have been reported to achieve at least a 3-log reduction in BCR-ABL/BCR levels, a reduction associated with an increased probability of progression-free survival (16). In these studies, 4% to 10% of patients have achieved undetectable levels of BCR-ABL (16). Studies using higher doses of imatinib have reported major molecular responses (i.e., 3-log reduction or <0.05%) in f65% of patients, and undetectable levels in 35% to 40% (9, 11). In this study, we investigated the clinical significance of these molecular responses among patients in chronic phase treated with imatinib. Among 280 patients who achieved a complete cytogenetic remission with imatinib, 174 (62%) achieved a major molecular response, and 95 (34%) had undetectable BCR-ABL transcripts at least once. It should be recognized that variations in the assay sensitivity may account for differences in the rate of patients with undetectable tran- scripts among different reports. The relevance of the sen- sitivity of the assay is further emphasized by the fact that approximately half of the patients that had undetectable transcript levels on at least one occasion later had low levels detectable. Similar results have been reported from a subset of patients from the IRIS trial. In that study, 10 of 26 (38%) patients had undetectable transcripts on at least one occasion, but only 4 (14%) had consistently undetectable levels for more than 6 months (22).
Treatment with high-dose imatinib (i.e., 800 mg) was the most significant factor associated with in increased probability of achieving a molecular response, particularly at earlier time points (i.e., 12 months). However, the overall rate of major and complete molecular response is not different between patients treated with standard versus high-dose imatinib. Because the follow-up is significantly longer for patients treated with standard dose and patients may continue to improve their cytogenetic and molecular response with continuation of therapy, further follow-up is required to determine whether there is an absolute difference in molecular response with high- dose imatinib or if it is a means of getting earlier to the same end point.
Fig. 2. Landmark analysis of duration of complete cytogenetic remission according to the molecular response at (A) 3 months, (B) 6 months, and (C) 12 months. Patients are grouped based on their BCR-ABL/ABL ratio <0.05% versus z0.05% at the specified time point. An event is considered the recurrence of any Ph-positive metaphases after achieving a complete cytogenetic remission. For this analysis, the starting point in the horizontal axis is the time when patients achieved complete cytogenetic remission.
compared with 6 of 33 (18%) of those with percentage point increments of 0.05 to 1, and 0 of 44 of those with increments of <0.05 (P = 0.0001). Again, patients with nadir levels of z0.05 had the highest probability of relapse.
Imatinib has become the standard therapy for patients with CML. A complete cytogenetic remission is achieved in
The definition of molecular responses is still evolving. For this analysis, we considered a major molecular response as reaching an absolute value of BCR-ABL/ABL ratio <0.05%, a value that has been found predictive of duration of cytogenetic response after IFN-a-based therapy by our group and others. Interestingly, it is also the median value after 12 months of therapy for the study population in this report. Other studies have reported the log decrease of BCR-ABL transcripts and considered a 3-log reduction as a major response associated with improved outcome (16). The studies have used a standardized baseline value for patients derived from the median value obtained from 30 patients studied before the start of therapy (16). Thus, it was not necessary to know the BCR-ABL level of a patient at baseline to calculate the subsequent reduction (16). The median baseline value for our patient population was 39.44. If we were to use a 3-log reduction from this value instead of an absolute ratio of <0.05% to determine a major molecular response, only five patients would not be considered to have achieved a major molecular response, and the results of the analysis would be similar.
Clin Cancer Res 2005;11(9) May 1, 2005
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