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Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: The NEXT-in-CML study
- Publication Year :
- 2020
- Publisher :
- American Society of Hematology, 2020.
-
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 = 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.
- Subjects :
- Oncology
Male
Mutation rate
bcr-abl
Drug Resistance
Fusion Proteins, bcr-abl
Gene mutation
medicine.disease_cause
Settore MED/01 - STATISTICA MEDICA
Biochemistry
Adult
Aged
Aged, 80 and over
Drug Resistance, Neoplasm
Female
High-Throughput Nucleotide Sequencing
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Middle Aged
Mutation
Mutation Rate
Prospective Studies
Protein Kinase Inhibitors
hemic and lymphatic diseases
80 and over
cml mutation
BCR-ABL mutations
Chronic
Prospective cohort study
Sanger sequencing
Leukemia
Chronic myeloid leukemia
Myeloid leukemia
Hematology
TKI
NGS
symbols
Human
medicine.medical_specialty
Immunology
symbols.namesake
CML, TKIs, BCR-ABL1
Chronic myeloid leukemia,TKI,BCR-ABL mutations,Sanger Sequencing,NGS
Internal medicine
medicine
business.industry
Fusion Proteins
Cell Biology
medicine.disease
Clinical trial
Prospective Studie
Sanger Sequencing
Neoplasm
BCR-ABL Positive
business
Myelogenous
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....5b52b7b2de8ab20d8bbbd216edc4fce7