The clinical outcomes of chronic myeloid leukemia patients harboring alternatively spliced BCR-ABL variants.

Objectives and importance: Tyrosine kinase inhibitors (TKIs) are indispensable for the treatment of chronic myeloid leukemia (CML). However, alternative splicing variants have been recently proposed as mechanisms of TKI resistance, although the clinical significance of these mutations remains controversial. We here present the long-term clinical courses of three CML patients harboring such unique mutations and try to assess their clinical significances. Moreover, the exon 6 frameshift presented here has been rarely reported, which may provide important information on this rare mutation. Clinical presentation: We report three cases of CML harboring an exon 7 deletion, insertion of 35 intronic nucleotides and an exon 6 frameshift, respectively. Remarkably, all patients obtained better than molecular response4.0 following administration of TKIs. Discussion and conclusion: Three CML cases highlighted an association between such splicing variants and clinical outcomes. The premature termination in the kinase domain due to these mutations likely causes conformational changes and inhibits TKI binding, but it also results in abrogating kinase activities of CML cells. Thus, the above-mentioned mutants might less affect outcomes of treatment. Noteworthy, clinically available International Scale RT-PCR system cannot distinguish kinase-active mutants from kinase-inactive mutants, which may possibly influence upon interpretation of the treatment efficacy. Clonal quantification on respective mutants could more precisely evaluate CML status in these patients. Therefore, one should realize these important splicing variants and accumulate further experiences.