@article{833bf27f97a74623958d2b1eec66e84a,
title = "Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: The NEXT-in-CML study",
abstract = "In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n 5 124) or warning (n 5 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms. {\textcopyright} 2020 American Society of Hematology. All rights reserved.",
keywords = "BCR ABL protein, BCR ABL1 protein, protein tyrosine kinase inhibitor, unclassified drug, BCR-ABL1 fusion protein, human, protein kinase inhibitor, adult, aged, Article, chronic myeloid leukemia, clinical decision making, feasibility study, gene mutation, genetic screening, health care cost, high throughput sequencing, human, major clinical study, mutational analysis, priority journal, prospective study, Sanger sequencing, treatment response, turnaround time, clinical trial, drug resistance, female, genetics, male, middle aged, multicenter study, mutation, mutation rate, very elderly, Adult, Aged, Aged, 80 and over, Drug Resistance, Neoplasm, Female, Fusion Proteins, bcr-abl, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Mutation, Mutation Rate, Prospective Studies, Protein Kinase Inhibitors",
author = "S. Soverini and L. Bavaro and {de Benedittis}, C. and M. Martelli and A. Iurlo and N. Orofino and S. Sica and F. Sor{\`a} and F. Lunghi and F. Ciceri and S. Galimberti and C. Barat{\`e} and M. Bonifacio and L. Scaffidi and F. Castagnetti and G. Gugliotta and F. Albano and A.V.R. Rossi and F. Stagno and {di Raimondo}, F. and M. D'Adda and {di Bona}, E. and E. Abruzzese and G. Binotto and R. Sancetta and M. Salvucci and I. Capodanno and M. Girasoli and S. Coluzzi and I. Attolico and C. Musolino and E. Calistri and M. Annunziata and M. Bocchia and S. Stella and A. Serra and S. Errichiello and G. Saglio and F. Pane and P. Vigneri and F. Mignone and M.A. Laginestra and S.A. Pileri and A. Percesepe and E. Tenti and G. Rosti and M. Baccarani and M. Cavo and G. Martinelli",
note = "Cited By :15 Export Date: 5 March 2021 CODEN: BLOOA Correspondence Address: Soverini, S.; Institute of Hematology “L. e A. Ser{\`a}gnoli,”, Via Massarenti 9, Italy; email: simona.soverini@unibo.it Chemicals/CAS: BCR-ABL1 fusion protein, human; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors Funding details: Novartis Funding details: Teva Pharmaceutical Industries Funding details: Bristol-Myers Squibb, BMS Funding details: Pfizer Funding details: Celgene Funding text 1: Conflict-of-interest disclosure: S. Soverini received honoraria from Incyte Biosciences, Novartis, and Bristol-Myers Squibb; M. Baccarani received honoraria from Novartis, Incyte Biosciences, and Pfizer; S.G. received speaker fees from Pfizer, Novartis, and Incyte Biosciences; A.I. received honoraria from Novartis, Pfizer, and Incyte Biosciences; G.R., F. Castagnetti, G.G., F.S., and E.A. received honoraria from Novartis, Bristol-Myers Squibb, Pfizer, and Incyte Biosciences; P.V. received honoraria from Astra Zeneca, Celgene, Incyte Biosciences, Italfarmaco, Novartis, Pfizer, Tesaro, and Teva and research funding from Novartis and Pfizer. The remaining authors declare no competing financial interests. 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year = "2020",
doi = "10.1182/blood.2019002969",
language = "English",
volume = "135",
pages = "534--541",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",
}