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.
Original language | English |
---|---|
Pages (from-to) | 534-541 |
Number of pages | 8 |
Journal | Blood |
Volume | 135 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2020 |
Keywords
- BCR ABL protein
- BCR ABL1 protein
- protein tyrosine kinase inhibitor
- unclassified drug
- 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