Research Papers:

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 and Giovanni Martinelli

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Oncotarget. 2016; 7:21982-21990. https://doi.org/10.18632/oncotarget.8010

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Simona Soverini1, Caterina De Benedittis1, Katerina Machova Polakova2, Jana Linhartova2, Fausto Castagnetti1, Gabriele Gugliotta1, Cristina Papayannidis1, Manuela Mancini1, Hana Klamova2, Marzia Salvucci3, Monica Crugnola4, Alessandra Iurlo5, Francesco Albano6, Domenico Russo7, Gianantonio Rosti1, Michele Cavo1, Michele Baccarani1, Giovanni Martinelli1

1Institute of Hematology “L. e A. Seràgnoli”, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

2Institute of Hematology and Blood Transfusion, Prague, Czech Republic

3Oncology-Hematology Department, “S. Maria delle Croci” Hospital, Ravenna, Italy

4Hematology, Parma University Hospital, Parma, Italy

5Division of Haematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

6Hematology Section, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy

7Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Correspondence to:

Simona Soverini, e-mail: [email protected]

Keywords: chronic myeloid leukemia, acute lymphoblastic leukemia, BCR-ABL1, tyrosine kinase inhibitors, Next-generation sequencing

Received: December 17, 2015     Accepted: February 23, 2016     Published: March 09, 2016


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 second-line 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 second-line 2GTKI therapy and had acquired BCR-ABL1 mutations (Group 1) and 25 imatinib-resistant 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.

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