Open AccessPersistent detection of alternatively spliced BCR ‐ ABL variant results in a failure to achieve deep molecular response
Author(s) -
Yuda Junichiro,
Miyamoto Toshihiro,
Odawara Jun,
Ohkawa Yasuyuki,
Semba Yuichiro,
Hayashi Masayasu,
Miyamura Koichi,
Tanimoto Mitsune,
Yamamoto Kazuhito,
Taniwaki Masafumi,
Akashi Koichi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13353
Subject(s) - nilotinib , breakpoint cluster region , imatinib , tyrosine kinase , cancer research , myeloid leukemia , minimal residual disease , dasatinib , medicine , abl , biology , leukemia , immunology , receptor
Treatment with tyrosine kinase inhibitors ( TKI ) may sequentially induce TKI ‐resistant BCR ‐ ABL mutants in chronic myeloid leukemia ( CML ). Conventional PCR monitoring of BCR ‐ ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR ‐ ABL and its mutants, including alternatively spliced BCR ‐ ABL with an insertion of 35 intronic nucleotides ( BCR ‐ ABL Ins35bp ) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR ‐ ABL mutants, we performed deep sequencing analysis of BCR ‐ ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI ‐resistant mutations were documented in 3 patients, whereas BCR ‐ ABL Ins35bp was detected in all patients. After switching to nilotinib, both BCR ‐ ABL and BCR ‐ ABL Ins35bp became undetectable in 3 patients who attained complete molecular response ( CMR ), whereas in the remaining all 34 patients, BCR ‐ ABL Ins35bp was persistently detected, and minimal residual disease ( MRD ) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR ‐ ABL Ins35bp was persisted, although BCR ‐ ABL Ins35bp does not definitively mark TKI resistance. Therefore, quantification of BCR ‐ ABL Ins35bp is useful for evaluating “functional” MRD and determining the effectiveness of TKI with accuracy.