Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients

Simona Soverini, Caterina De Benedittis, Katerina Machova Polakova, Jana Linhartova, Fausto Castagnetti, Gabriele Gugliotta, Cristina Papayannidis, Manuela Mancini, Hana Klamova, Marzia Salvucci, Monica Crugnola, Alessandra Iurlo, Francesco Albano, Domenico Russo, Gianantonio Rosti, Michele Cavo, Michele Baccarani, Giovanni Martinelli

Research output: Contribution to journalArticlepeer-review

Abstract

In chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients who fail imatinib treatment, BCR-ABL1 mutation profiling by Sanger sequencing (SS) is recommended before changing therapy since detection of specific mutations influences second-generation tyrosine kinase inhibitor (2GTKI) choice. We aimed to assess i) in how many patients who relapse on secondline 2GTKI therapy next generation sequencing (NGS) may track resistant mutations back to the sample collected at the time of imatinib resistance, before 2GTKI start (switchover sample) and ii) whether low level mutations identified by NGS always undergo clonal expansion. To this purpose, we used NGS to retrospectively analyze 60 imatinib-resistant patients (CML, n = 45; Ph+ ALL, n = 15) who had failed secondline 2GTKI therapy and had acquired BCR-ABL1 mutations (Group 1) and 25 imatinibresistant patients (CML, n = 21; Ph+ ALL, n = 4) who had responded to second-line 2GTKI therapy, for comparison (Group 2). NGS uncovered that in 26 (43%) patients in Group 1, the 2GTKI-resistant mutations that triggered relapse were already detectable at low levels in the switchover sample (median mutation burden, 5%; range 1.1%-18.4%). Importantly, none of the low level mutations detected by NGS in switchover samples failed to expand whenever the patient received the 2GTKI to whom they were insensitive. In contrast, no low level mutation that was resistant to the 2GTKI the patients subsequently received was detected in the switchover samples from Group 2. NGS at the time of imatinib failure reliably identifies clinically relevant mutations, thus enabling a more effective therapeutic tailoring.

Original languageEnglish
Pages (from-to)21982-21990
Number of pages9
JournalOncotarget
Volume7
Issue number16
DOIs
Publication statusPublished - Apr 19 2016

Keywords

  • Acute lymphoblastic leukemia
  • BCR-ABL1
  • Chronic myeloid leukemia
  • Next generation sequencing
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology

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