TY - JOUR
T1 - Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients
AU - Soverini, Simona
AU - De Benedittis, Caterina
AU - Polakova, Katerina Machova
AU - Linhartova, Jana
AU - Castagnetti, Fausto
AU - Gugliotta, Gabriele
AU - Papayannidis, Cristina
AU - Mancini, Manuela
AU - Klamova, Hana
AU - Salvucci, Marzia
AU - Crugnola, Monica
AU - Iurlo, Alessandra
AU - Albano, Francesco
AU - Russo, Domenico
AU - Rosti, Gianantonio
AU - Cavo, Michele
AU - Baccarani, Michele
AU - Martinelli, Giovanni
PY - 2016/4/19
Y1 - 2016/4/19
N2 - 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.
AB - 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.
KW - Acute lymphoblastic leukemia
KW - BCR-ABL1
KW - Chronic myeloid leukemia
KW - Next generation sequencing
KW - Tyrosine kinase inhibitors
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U2 - 10.18632/oncotarget.8010
DO - 10.18632/oncotarget.8010
M3 - Article
AN - SCOPUS:84965002330
VL - 7
SP - 21982
EP - 21990
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 16
ER -