Imatinib Mesylate Determines a High Frequency of Major Molecular Responses in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia (CML) on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).

Imatinib has became the standard therapy for patients with CML. In order to determine the frequency of molecular response to imatinib and its long-term prognostic implications, we analyzed the results of molecular monitoring in 260 newly diagnosed CML Sokal low-risk patients, enrolled in a prospective clinical trial (protocol CML 023 of the GIMEMA Working Party on CML). Imatinib was given at the dose of 400 mg daily. Bone marrow samples were collected prior to therapy and every 12 months, peripheral blood samples were collected at the same check-points and at 3 months, 6 months and every 6 months thereafter. Relative BCR-ABL expression was measured by real-time quantitative PCR (TaqMan) normalized for ABL and the result was expressed as a ratio of BCR-ABL to ABL multiplied by 100. All experiments were performed in duplicate. The median follow-up time from the time treatment was started is 6 months (range, 1–18).

At the time of writing, are valuable for cytogenetic and molecular analysis at 12 months on imatinb 82 patients. At this time, complete cytogenetic remission (CCgR) was achieved in 90% of patients. Median BCR-ABL/ABL ratio before the start of imatinib was 16.1 (range, 112.6–0.004), it was 0.35 (range, 81.57–0.0006) at 3 months, 0.1 (range, 45.84–0.0002) at 6 months and 0.05 (range, 7.57–0.000001) at 12 months. Considering a major molecular response as reaching an absolute value of BCR-ABL/ABL ratio < 0.05%, we observed how after 12 months of treatment imatinib has determined a major molecular response in 52% of patients. If we were to use an absolute value of BCR-ABL/ABL ratio < 0.12 %, that has been demonstrated to be equivalent at a 3-log reduction (as referred by Hochhaus A), instead of an absolute value of 0.05%, a major molecular response would be achieved in about 70% of early chronic phase patients. BCR-ABL transcripts were undetectable at least one occasion (complete molecular response) in 4% of patient with a CCgR. Only 2 patients (2%) had no response to imatinib, in one of these we found the presence of the point mutation Y253H.

In conclusion, our results demonstrate that imatinib determines a high frequency of complete cytogenetic remission and major molecular remission in newly diagnosed CML patients. Achieving a major molecular response, particularly within the first year of therapy, could be predictive of a durable cytogenetic remission.