IMPACT OF TREATMENT ADMINISTRATION ON SELECTION OF BCRABL1 KINASE DOMAIN MUTATIONS

Sborník

Background. Availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables the optimization of current therapeutic regimens; however, some patients lose their therapy responses and acquire TKIs resistance. Aims. In this study, a single center experience with monitoring of BCR-ABL1 kinase domain (KD) mutations is described and, particularly, the impact of the treatment administration on mutations selection is discussed. Methods. The CML patients treated with TKIs at our institution during the years 2003 - 2011 were included in this study. Peripheral blood and/or bone marrow samples were collected, processed and analyzed using the published procedures; detection of BCR-ABL1 KD mutations was performed by direct sequencing. Results. First, we evaluated the impact of non-TKI pretreatment on: a) spectrum of BCR-ABL1 KD mutations; b) their frequencies and c) time to mutation detection after the administration of a first-line TKI. Our data shows that pretreatment with non-specific non-TKI drugs does not preferentially select the BCR-ABL1 KD mutations, as there was no difference between the frequency of T315I or p-loop mutations compared to mutations in other KD regions (52. 7% vs. 47. 3%). In contrast, the imatinib (IMA) as first-line therapy led to clear predominance of T315I or p-loop mutations (90. 9% vs. 18. 2% of mutations located in other KD regions). In addition, median time to the detected p-loop mutations was substantially shorter in patients treated with IMA first-line compared to patients who were pretreated (16 months (3 - 41) vs. 46 months (20 - 109), p = 0. 005). Second, we analyzed the impact of administered TKIs on appearance and selection of mutations in patients that were recurrently resistant to TKIs therapy. Among the patients with initial BCR-ABL1 KD mutation, 32. 0% developed a second mutations after the change of TKIs treatment. The more potent second-line TKIs therapy caused the elimination of most of the initial IMA resistant mutations; however, several mutations resistant to secondline therapy subsequently emerged, with considerably shorter time compared to the initially detected ones (9 months (1 - 25) vs. 21 months (3 - 109), p = 0. 007). Moreover, after the therapeutic intervention with third-line TKIs, similar consequences were observed. Third, we confirm the previously described poor prognosis of CML patients with mutated BCR-ABL1 KD, since 40. 0% of our CML patients that harbored BCR-ABL1 KD mutation died during the treatment with TKIs. Moreover, 27. 8% of patients who are still on treatment have already progressed. Last, our data confirms the unique position of T315I mutation with respect to its strong resistance to the currently approved TKIs. Conclusions. Based on a “real-life”data described in this study, for some of the CML patients that harbor BCR-ABL1 KD mutations, it may seem that therapy itself consecutively leads to its failure, selecting thus the most resistant mutations under the selective pressure of applied therapy regimen (Figure 1). Note that formation and selection of mutations, that could reflect the genomic instability, is not a single process, thus all aspects must be taken into account.

Acknowledgements. Supported by The CzEch Leukemia Study Group for Life (CELL) and grants MSM0021622430 and MUNI/A/0784/2011.

Haematologica, 2012; 97(s1):  536