Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?
Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?
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DOI：
10.1182/blood-2009-08-215939
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发表时间：
2009-12-24
期刊：
影响因子：
20.3
通讯作者：
Hughes, Timothy P.
中科院分区：
文献类型：
--
作者：
Branford, Susan;Melo, Junia V.;Hughes, Timothy P.
BCR-ABL突变对尼洛替尼或达沙替尼敏感性的临床前研究表明，大多数突变对尼洛替尼或达沙替尼敏感。相应地，最初的临床试验表明，无论突变状态如何，伊马替尼失效后CML患者的反应率相似。然而，经过更仔细的检查，临床证据表明，一些突变对尼洛替尼（Y253H， E255K/V和F359V/C）或达沙替尼（F317L和V299L）不太敏感。T315I对两者都不敏感。新型突变（F317I/V/C和T315A）对达沙替尼不敏感或不敏感。我们将这些统称为第二代抑制剂（SGI）临床相关突变。通过体外分析，其他突变赋予一定程度的不敏感性；然而，目前临床证据不足以将其定义为与SGI临床相关。在这里，我们研究了明显与SGI临床相关的突变，那些对反应影响最小的突变，以及那些需要更多数据的突变。在我们的患者系列中，在伊马替尼停止和/或尼洛替尼或达沙替尼开始时发生突变，43%的患者具有SGI临床相关突变，其中14%为T315I。SGI临床相关突变的频率取决于伊马替尼失效时的疾病阶段。临床数据表明，在伊马替尼失效后，突变通常会被检测到，有令人信服的临床证据表明，应该优先选择一种SGI。（血液。2009;114:5426-5435）
Preclinical studies of BCR-ABL mutation sensitivity to nilotinib or dasatinib suggested that the majority would be sensitive. Correspondingly, the initial clinical trials demonstrated similar response rates for CML patients after imatinib failure, irrespective of the mutation status. However, on closer examination, clinical evidence now indicates that some mutations are less sensitive to nilotinib (Y253H, E255K/V, and F359V/C) or dasatinib (F317L and V299L). T315I is insensitive to both. Novel mutations (F317I/V/C and T315A) are less sensitive/insensitive to dasatinib. We refer to these collectively as second-generation inhibitor (SGI) clinically relevant mutations. By in vitro analysis, other mutations confer a degree of insensitivity; however, clinical evidence is currently insufficient to define them as SGI clinically relevant. Here we examine the mutations that are clearly SGI clinically relevant, those with minimal impact on response, and those for which more data are needed. In our series of patients mutations at imatinib cessation and/or at nilotinib or dasatinib commencement, 43% had SGI clinically relevant mutations, including 14% with T315I. The frequency of SGI clinically relevant mutations was dependent on the disease phase at imatinib failure. The clinical data suggest that a mutation will often be detectable after imatinib failure for which there is compelling clinical evidence that one SGI should be preferred. (Blood. 2009; 114: 5426-5435)