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Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib
Hanfstein B et al.
Leukemia, 2014 May 6 [Epub ahead of print]
Prognostic of chronic myeloid leukemia (CML) has dramatically changed since the introduction of imatinib, and further on, second generation tirosin kinase inhibitors (2GTKISs). At this current moment, we are proud to say, that most of CML patients have an overall survival (OS) similar to the healthy population. Unfortunately, there are few patients that will not achieve an optimal response with imatinib, and those patients would be in a high risk of progression to advances phases. Since most of the progressions happen in the first 2 years, it is crucial to identify patients who will not respond satisfactory to first line treatment in order to proceed to an early treatment change. Different studies have recently demonstrated how BCR-ABL level at 3 months can identify patients with a high probability of progression. Even knowing the bad prognostic of this group of patients, there are physician that advocate to wait until 6 months to make therapeutic decisions, since there are few patients who could be in optimal response after failure at 3 moths.
In this sense, the last of versions of NCCN guidelines and ESMO and European LeukemiaNet (ELN) recommendations have incorporated the PCR BCR-ABL/ABL IS level at 3 moths as an important goal to achieve. For NCCN guidelines and ESMO recommendations, patients treated with imatinib not achieving BCR-ABL/ABL <10% should received a 2GTKI, while for the ELN recommendations, this group of patients should be monitored closely due to a high risk of treatment failure in further evaluations.
In order to clarify the group of patients that could benefit the most from treatment change at 3 months, the authors have studied in 301 patients treated with imatinib front line, the velocity of the decline of BCR-ABL level during the first 3 months of treatment. To determinate the actual individual decline of transcripts, a ratio was established given by BCR-ABL/GUS at 3 months divided by BCR-ABL/GUS at diagnosis and referred to as 3-month reduction ratio. A reduction ratio of 0.35-fold was identify as the best cutoff, discriminating significantly for OS and PFS, even better than a single value at 3 months studied in the same group of patients. With this data, the authors conclude that the lack of achieving a half-log reduction at 3 months is a negative prognostic indicator and may trigger treatment intervention.
This new approach for monitoring the disease has also been studied by the Australian group, who presented their data in the last meeting of the American Society of Hematology. The Australian group has incorporated a new concept: the halving time. The authors performed an elegant analysis where patients who do not decreased by half their initial amount of transcripts had a worse prognostic compare to patients who met that endpoint.
It looks like soon, we will be monitoring our CML patients during the first months by looking the kinetic of the response. However, we have to be aware that for this purpose, GUS control should be used instead of ABL to calculate the BCR-ABL ratio.