| Contributors: |
Soverini, S.; Bavaro, L.; de Benedittis, C.; Martelli, M.; Iurlo, A.; Orofino, N.; Sica, S.; Sora, F.; Lunghi, F.; Ciceri, F.; Galimberti, S.; Barate, C.; Bonifacio, M.; Scaffidi, L.; Castagnetti, F.; Gugliotta, G.; Albano, F.; Rossi, A. V. R.; Stagno, F.; di Raimondo, F.; D'Adda, M.; di Bona, E.; Abruzzese, E.; Binotto, G.; Sancetta, R.; Salvucci, M.; Capodanno, I.; Girasoli, M.; Coluzzi, S.; Attolico, I.; Musolino, C.; Calistri, E.; Annunziata, M.; Bocchia, M.; Stella, S.; Serra, A.; Errichiello, S.; Saglio, G.; Pane, F.; Vigneri, P.; Mignone, F.; Laginestra, M. A.; Pileri, S. A.; Percesepe, A.; Tenti, E.; Rosti, G.; Baccarani, M.; Cavo, M.; Martinelli, G. |
| Description: |
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. |