Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
Mol Diagn Ther. 2012 Aug 1;16(4):251-9. doi: 10.1007/BF03262214.
The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection.
Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study. A total number of 100 patients who did not achieve an optimal therapy response or who lost their therapy response were screened for the presence of BCR-ABL1 KD mutations, using direct sequencing.
Our data show that pretreatment with non-specific non-TKI drugs prior to TKI therapy does not preferentially select for initial BCR-ABL1 KD mutations, in contrast to first-line imatinib therapy, which shows a clear predominance of T315I or P-loop mutations compared with mutations located in other KD regions. In addition, the median time to detection of P-loop mutations was substantially shorter in patients treated with first-line imatinib than in those pretreated with non-TKI drugs. Furthermore, analysis of CML patients who had recurrent resistance to TKI therapy revealed possible therapy-driven selection of BCR-ABL1 KD mutations. Finally, we confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 KD, since 40.0% of our CML patients who harbored a BCR-ABL1 KD mutation died from CML while receiving TKI treatment. Moreover, among the patients who are still on treatment, 27.8% have already progressed. Our data also confirm the unique position of the T315I mutation with respect to its strong resistance to currently approved TKIs.
On the basis of the 'real-life' data described in this study, it is possible that the therapy itself results in its failure and selects the most resistant mutations under the selective pressure of the applied therapy regimen in some CML patients who harbor BCR-ABL1 KD mutations.
不同的酪氨酸激酶抑制剂（TKI）具有不同的抗白血病效力，这使得目前的治疗方案得以优化；然而，一些患者会失去治疗反应并产生 TKI 耐药性。在本研究中，我们描述了一个单中心监测 BCR-ABL1 激酶结构域（KD）突变的经验，并讨论了治疗对突变选择的影响。
本研究纳入了 2003 年至 2011 年在马萨里克大学和布尔诺大学医院内科-血液学和肿瘤学系接受 TKI 治疗的慢性髓系白血病（CML）患者。共有 100 名未达到最佳治疗反应或失去治疗反应的患者接受了 BCR-ABL1 KD 突变的检测，使用直接测序法。
我们的数据表明，与一线伊马替尼治疗相比，TKI 治疗前使用非特异性非 TKI 药物预处理不会优先选择初始 BCR-ABL1 KD 突变，而一线伊马替尼治疗则明显优先选择 T315I 或 P 环突变，而不是其他 KD 区域的突变。此外，与非 TKI 药物预处理的患者相比，一线伊马替尼治疗的患者检测到 P 环突变的中位时间明显缩短。此外，对 TKI 治疗复发耐药的 CML 患者的分析显示，BCR-ABL1 KD 突变可能是治疗驱动的选择。最后，我们证实了先前描述的 CML 患者 BCR-ABL1 KD 突变的不良预后，因为我们的 40.0%的 CML 患者携带 BCR-ABL1 KD 突变，在接受 TKI 治疗时死于 CML。此外，仍在接受治疗的患者中，有 27.8%已经进展。我们的数据还证实了 T315I 突变的独特地位，因为它对目前批准的 TKI 具有很强的耐药性。
基于本研究中描述的“真实世界”数据，在一些携带 BCR-ABL1 KD 突变的 CML 患者中，治疗本身可能会导致其失败，并在应用治疗方案的选择性压力下选择最耐药的突变。
