HIGH BCR-ABL/GUSIS LEVELS AT DIAGNOSIS OF CHRONIC PHASE CML ARE ASSOCIATED WITH UNFAVORABLE RESPONSES TO STANDARD-DOSE IMATINIB

Purpose: 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. Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABLIS transcripts at diagnosis with the outcome - defined by the 2013 European LeukemiaNet recommendations - of 272 newly diagnosed CML patients receiving Imatinib 400 mg/daily. Applying Receiver Operating Characteristic curves we defined BCR-ABL/GUSIS and BCR-ABL/ABLIS levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS) and overall survival (OS). Results: 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%), 7 (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (p<0.001), FFS (p<0.001) and EFS (p<0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (p=0.029) but not with OS (p=0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (p=0.03), FFS (p=0.001) and EFS (p=0.005), but not with TFS (p=0.167) or OS (p=0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured employing GUS as a reference gene identify CML patients unlikely to benefit from standard dose Imatinib.

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