In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants

BMC Cancer

Technical Advance

Fabrizio Pane¹  Giuseppe Saglio²  Alessandra Iurlo³  Manuela Mancini⁴  Michele Cavo⁴  Gianantonio Rosti⁴  Gabriele Gugliotta⁴  Caterina De Benedittis⁴  Fausto Castagnetti⁴  Michele Baccarani⁴  Luana Bavaro⁴  Giovanni Martinelli⁴  Simona Soverini⁵  Katerina Machova Polakova⁶  Jana Linhartova⁶  Domenico Russo⁷ 

[1] Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Naples, Italy;Department of Clinical and Biological Sciences “S. Luigi Gonzaga” Hospital, University of Turin, Orbassano, Italy;Division of Haematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;Hematology “L. e A. Seràgnoli”, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy;Hematology “L. e A. Seràgnoli”, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy;Institute of Hematology “L. e A. Seràgnoli”, Via Massarenti 9, 40138, Bologna, Italy;Institute of Hematology and Blood Transfusion, Prague, Czech Republic;Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy;

关键词: BCR-ABL1;    Chronic myeloid leukemia;    Tyrosine kinase inhibitors;    Warning;    Deep sequencing;   

DOI  :  10.1186/s12885-016-2635-0

 received in 2016-01-20, accepted in 2016-07-27,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundImatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR-ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR-ABL1 KD mutants predicting for an impending relapse.Methodsa total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%IS transcript levels were used to define whether the patient had ‘optimal response’, ‘warning’ or ‘failure’ at the time of first mutation detection by DS.ResultsDS was able to backtrack dasatinib- or nilotinib-resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5–17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1–9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as ‘Warning’ (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as ‘Optimal response’ in one case, as ‘Failure’ in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with ‘warning’ at various timepoints, that later turned into optimal responders with no treatment changes.ConclusionsDS enables a larger window of detection of emerging BCR-ABL1 KD mutations predicting for an impending relapse. A ‘Warning’ response may represent a rational trigger, besides ‘Failure’, for DS-based mutation screening in CML patients undergoing second-line TKI therapy.

【 授权许可】

CC BY   
© The Author(s). 2016