High <i>BCR-ABL/GUS^IS</i> Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> We correlated <i>BCR-ABL/GUS^IS</i> and <i>BCR-ABL/ABL</i> 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 <i>BCR-ABL/GUS^IS</i> and <i>BCR-ABL/ABL</i> levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).<b>Results:</b> 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 <i>BCR-ABL/GUS^IS</i> levels at diagnosis were associated with inferior rates of OR (<i>P</i> < 0.001), FFS (<i>P</i> < 0.001), and EFS (<i>P</i> < 0.001). Elevated <i>BCR-ABL/GUS^IS</i> levels were also associated with lower rates of TFS (<i>P</i> = 0.029) but not with OS (<i>P</i> = 0.132). Similarly, high <i>BCR-ABL/ABL</i> levels at diagnosis were associated with inferior rates of OR (<i>P</i> = 0.03), FFS (<i>P</i> = 0.001), and EFS (<i>P</i> = 0.005), but not with TFS (<i>P</i> = 0.167) or OS (<i>P</i> = 0.052). However, in internal validation experiments, <i>GUS</i> outperformed <i>ABL</i> in samples collected at diagnosis as the latter produced 80% misclassification rates.<b>Conclusions:</b> Our data suggest that high <i>BCR-ABL</i> transcripts at diagnosis measured using <i>GUS</i> as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. <i>Clin Cancer Res; 23(23); 7189-98. ©2017 AACR</i>.