Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study
- 20 February 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (8), 534-541
- https://doi.org/10.1182/blood.2019002969
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 (F; n=124) or Warning (W; n=112) response to TKI therapy were analyzed in parallel by SS and by NGS in one of four reference laboratories. Fifty-one patients (22 F, 29 W) who were negative for mutations by SS had low level mutations detectable by NGS. Moreover, 29 (27F, 2W) of 60 patients who were positive for mutations by SS showed additional low level mutations. Thus, mutations undetectable by SS were identified in 80/236 (34%) patients, 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.Keywords
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