High BCR-ABL/GUS^IS Levels at Diagnosis Are Associated with Unfavorable Responses to Standard Dose Imatinib

Background

The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated a need for early molecular parameters associated with inadequate responses to Imatinib Mesylate (IM).

Objective

We correlated quantitative determination of BCR-ABL transcripts at diagnosis with the outcome (defined according to the 2013 European Leukemia Net recommendations) of 272 newly diagnosed CML patients receiving IM 400 mg/die.

Methods

BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis before patients received any pharmacological treatment using Real-Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. BCR-ABL values were then reported on the international scale (IS).

Results

With a median follow-up of 60 months, 65.4% of patients achieved an optimal response, 5.6% presented a response currently defined as "warning", 22.4% failed IM treatment and 6.6% switched to a different tyrosine kinase inhibitor because of intolerance to the drug. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We applied Receiver Operating Characteristic (ROC) curves to define BCR-ABL/GUS^IS expression levels that would separate patients likely (i.e. below the threshold) or unlikely (i.e. above the threshold) to achieve multiple endpoints, namely: optimal response (OR), failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS). Employing the specific threshold calculated for each endpoint we found that high BCR-ABL/GUS^IS levels at diagnosis were associated with inferior probabilities of OR (p<0.001), FFS (p<0.001) and EFS (p<0.001). Elevated BCR-ABL/GUS^IS levels were also associated with higher rates of disease transformation to the accelerated phase or blast crisis (p=0.029) but not with OS (p=0.132).

Conclusions

High BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from standard dose IM that should be considered for alternative forms of treatment.