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Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?

Content Provider	Semantic Scholar
Author	Branford, Susan Melo, Junia V. Hughes, Timothy P.
Copyright Year	2009
Abstract	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 with 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.
Starting Page	588
Ending Page	591
Page Count	4
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.bloodjournal.org/content/bloodjournal/114/27/5426.full.pdf?sso-checked=true
PubMed reference number	19880502v1
Alternate Webpage(s)	https://doi.org/10.1182/blood-2009-08-215939
DOI	10.1182/blood-2009-08-215939
Journal	Blood
Volume Number	114
Issue Number	27
Language	English
Access Restriction	Open
Subject Keyword	BCR gene Fusion Proteins, bcr-abl Liver Failure, Acute Mutation Myeloid Leukemia Myeloid Leukemia, Chronic Patients Protein Tyrosine Kinase Protein-tyrosine kinase inhibitor dasatinib imatinib nilotinib
Content Type	Text
Resource Type	Article

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