Clinical Significance of Molecular Monitoring in Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) with Imatinib Therapy.

Abstract

Most patients (pts) with CML in chronic phase treated with imatinib achieve a major cytogenetic (CG) remission, and increasing numbers of pts are achieving molecular responses. To determine the clinical significance of molecular responses in these pts, we analyzed the results of quantitative PCR monitoring among 280 pts with CML in CP who achieved a complete CG remission with imatinib therapy (117 after IFN-α failure, 163 previously untreated). Pts have been followed for a median of 31.2 mo (range, 3 to 52 mo). The median BCR-ABL/ABL ratio before the start of therapy was 37.43 (range, 0.004 to 170.53). A major molecular response (i.e., BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%) pts, and transcripts became undetectable (i.e., complete molecular response) in 95 (34%). Median time to major molecular responses was 10 mos (range, 2.8 to 46 mos) and for complete 16.7 mos (range, 3 to 48 mos) but responses have occurred as late as 48 mos with no evidence of a time after which responses do not improve any more. In a multivariate analysis, clinical characteristics associated with an increased probability of achieving a major molecular response were early chronic phase previously untreated (p=.03), no splenomegaly (p=.03), and ≤90% Ph-positive metapahases at the start of therapy (p=0.05). Only 9 of 166 (5%) patients who achieved a major molecular response and have had subsequent cytogenetic analysis have lost their cytogenetic response, compared to 25 of 68 (37%) of those who did not achieve this response (p<0.0001). Only 3 of 82 (4%) with complete molecular response have lost their cytogenetic response. Patients achieving a major molecular response 12 mos after the start of therapy have a significantly better complete cytogenetic remission duration than those not achieving this response at this time point, and similar but not statistically significant trends can be detected with earlier responses (at 3 and 6 mos). Pts with more than a 1-log-reduction in transcript levels after 3 mos of therapy have a 90% probability of achieving a 3-log reduction at 24 mos, compared to 55% for those with ≤1-log decrease (p=0.0002). We then evaluated the significance of an increasing trend in transcript levels. None of the 44 pts with an increase of <0.05 has lost the complete CG remission, compared to 6 of 33 (18%) with an absolute increase of 0.05 to 1, and 5 of 11 (45%) with an increase of >1.0 (p=0.0001). The probability of cytogenetic relapse is particularly high for patients who never achieved a major molecular remission. We conclude that achieving a major molecular response, particularly within the first year of therapy with imatinib, is predictive of a durable cytogenetic remission and should be the goal of therapy with imatinib. Increasing transcript levels after achieving a complete CG response predict for a relapse in patients who did not achieve a major molecular response.