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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.

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