Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study

Simona Sica, Federica Sora', Simona Soverini, Luana Bavaro, Caterina De Benedittis, Margherita Martelli, Alessandra Iurlo, Nicola Orofino, Francesca Lunghi, Fabio Ciceri, Sara Galimberti, Claudia Baratè, Massimiliano Bonifacio, Luigi Scaffidi, Fausto Castagnetti, Gabriele Gugliotta, Francesco Albano, Antonella Vita Russo Rossi, Fabio Stagno, Francesco Di RaimondoMariella D'Adda, Eros Di Bona, Elisabetta Abruzzese, Gianni Binotto, Rosaria Sancetta, Marzia Salvucci, Isabella Capodanno, Mariella Girasoli, Sabrina Coluzzi, Immacolata Attolico, Caterina Musolino, Elisabetta Calistri, Mario Annunziata, Monica Bocchia, Stefania Stella, Anna Serra, Santa Errichiello, Giuseppe Saglio, Fabrizio Pane, Paolo Vigneri, Flavio Mignone, Maria Antonella Laginestra, Stefano Aldo Pileri, Antonio Percesepe, Elena Tenti, Gianantonio Rosti, Michele Baccarani, Michele Cavo, Giovanni Martinelli

Research output: Contribution to journalArticle

20 Citations (Scopus)


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 = 124) or warning (n = 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.
Original languageEnglish
Pages (from-to)534-541-541
Publication statusPublished - 2020


  • cml mutation


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