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Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response.

Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response.
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Yuda J, Miyamoto T, Odawara J, Ohkawa Y, Semba Y, Hayashi M, Miyamura K, Tanimoto M, Yamamoto K, Taniwaki M, Akashi K,


Yuda J, Miyamoto T, Odawara J, Ohkawa Y, Semba Y, Hayashi M, Miyamura K, Tanimoto M, Yamamoto K, Taniwaki M, Akashi K, (click to view)

Yuda J, Miyamoto T, Odawara J, Ohkawa Y, Semba Y, Hayashi M, Miyamura K, Tanimoto M, Yamamoto K, Taniwaki M, Akashi K,

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Cancer science 2017 08 12() doi 10.1111/cas.13353
Abstract

Treatment with tyrosine kinase inhibitors (TKIs) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional polymerase chain reaction (PCR) monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot quantify separately amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABL(I)(ns35bp) ) 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 into nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABL(I)(ns35bp) was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABL(I)(ns35bp) became undetectable in 3 patients who attained complete molecular response (CMR), whereas in remaining all 34 patients, BCR-ABL(I)(ns35bp) was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated MR in 5 patients whose BCR-ABL(I)(ns35bp) was persisted, although BCR-ABL(I)(ns35bp) does not inevitably mark TKI-resistance. Therefore, quantification of BCR-ABL(I)(ns35bp) is useful for evaluating "functional" MRD and determining effectiveness of TKIs with accuracy. This article is protected by copyright. All rights reserved.

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