High Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.

The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. We correlated and transcripts at diagnosis with the outcome-defined by the 2013 European LeukemiaNet recommendations-of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined and levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS). With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings," 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher levels at diagnosis were associated with inferior rates of OR ( < 0.001), FFS ( < 0.001), and EFS ( < 0.001). Elevated levels were also associated with lower rates of TFS ( = 0.029) but not with OS ( = 0.132). Similarly, high levels at diagnosis were associated with inferior rates of OR ( = 0.03), FFS ( = 0.001), and EFS ( = 0.005), but not with TFS ( = 0.167) or OS ( = 0.052). However, in internal validation experiments, outperformed in samples collected at diagnosis as the latter produced 80% misclassification rates. Our data suggest that high transcripts at diagnosis measured using as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. .