Initial Rate of BCR::ABL1 Decline for Response Prediction in Chronic Myeloid Leukemia

In this issue of the journal, Ceran et al. [1] confirm the importance of the initial rate of BCR::ABL1 transcript decline as a prognostic indicator in a cohort of 40 first-line imatinib-treated patients. Patients with the most rapid reductions, which were assessed as the number of days over which BCR::ABL1 halved after the commencement of imatinib, as well as the achievement of BCR::ABL1 international scale ratios of ≤10%, were associated with molecular response and event-free survival. The reduction ratio of BCR::ABL1, measured as the ratio of the 3-month BCR::ABL1 divided by the pre-imatinib level, also predicted responses.

A BCR::ABL1 ratio of ≤10% measured at 3 months of tyrosine kinase inhibitor (TKI) therapy, termed an early molecular response, has consistently been demonstrated to be an important prognostic indicator [2,3,4]. Nevertheless, the European LeukemiaNet recommends intervention for treatment failure only if the ratio remains above 10% upon repeat analysis within 3 months [5]. The reason is that some patients with a ratio of >10% at 3 months will have a reduction to within the optimal response category without treatment intervention by 6 months. Studies have determined that such patients can be identified by the initial rate of BCR::ABL1 reduction measured at 3 months [6,7]. Accurate identification of the patients who should switch therapy to reduce the risk of disease progression and death is critical. A single molecular test is considered insufficient to make such an important decision as a change of treatment. Imatinib is in general safe and the side effects are usually mild. The toxicity profile of second- and third-generation inhibitors is different to some degree. Several types of vascular events have been documented in patients treated with these more potent inhibitors and individual patient co-morbidities must be considered for treatment decisions [8]. Therefore, enhanced risk prediction of treatment failure is ideal.

The velocity of the initial response to TKI therapy can provide an early indication of whether a patient is responsive to targeted BCR::ABL1 inhibition. Velocity can be measured by the change in BCR::ABL1 ratio from baseline to 3 months of TKI therapy. The baseline BCR::ABL1 ratios are variable and provide no prognostic information [6]. For example, a patient with a BCR::ABL1 ratio at baseline of  10% that remains at 10% at 3 months has clearly not responded to TKI therapy and treatment failure is indicated. On the other hand, a patient with 100% BCR::ABL1 at baseline who achieves a 1-log reduction of BCR::ABL1 to 10% at 3 months has had a substantial response and treatment intervention is not warranted. Ceran et al. [1] measured the velocity of response as the ratio of the BCR::ABL1 values from baseline to 3 months [6] and defined this ratio as the “reduction ratio”. They determined that the optimal reduction ratio to predict a major molecular response was 0.04. However, the day of sample collection of the 3-month timepoint can vary from as early as 1.5 months after commencing TKI to as late as 4.5 months [9]. Therefore, the reduction ratio for a patient with a constant BCR::ABL1 decline will change over time depending on the day of the 3-month collection. Perhaps a more accurate measure of the velocity of BCR::ABL1 reduction is the BCR::ABL1 halving time. This is the number of days over which BCR::ABL1 halves on TKI therapy. Importantly, the halving time calculation takes into account the number of days between the baseline sample collection and the day of sample collection after commencing TKI therapy. The BCR::ABL1 halving time should remain constant for patients with an exponential decline, irrespective of the time lapse between baseline and the 3-month collection timepoint [7]. Ceran et al. [1] determined that the optimal BCR::ABL1 halving time to predict a major molecular response was 24 days.

Their study of 40 patients was a small cohort; however, it provides important confirmatory data on the relevance of the velocity of BCR::ABL1 transcript decline. Furthermore, the rate of decline measured from baseline to 3 months was more important for the prediction of a deep molecular response than the single BCR::ABL1 ratio measured at 3 months. Achieving a deep molecular response is a critical milestone in molecular response for patients who aim to cease therapy in an attempt to achieve treatment-free remission. The study also contributed to the growing body of evidence that measuring BCR::ABL1 transcript kinetics using a molecular method where ABL1 is the control gene is possible [10,11,12,13]. It was suggested that limitations related to the use of ABL1 for real-time quantitative PCR analysis would preclude a reliable assessment of the kinetics of response since most methods that amplify ABL1 also amplify BCR::ABL1 [6].

In conclusion, measuring BCR::ABL1 ratios at early timepoints after commencing TKI therapy remains an important prognostic indicator. Importantly, the rate of initial BCR::ABL1 decline from the baseline measurement is a better predictor than a single measurement at 3 months for some patients.