NGS Preferable for Detecting Certain Mutations in Patients With CML

Study findings point to the clinical relevance of low-level mutations in patients with chronic myeloid leukemia (CML), and support the use of next-generation sequencing (NGS) to accurately illustrates BCR-ABL1 mutation status in those who do not respond or have warning responses to tyrosine kinase inhibitor (TKI) therapy (Blood. 2020;135[8]:534-541).

“In [CML] patients, [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, [NGS] has recently been assessed in retrospective studies,” explained Simona Soverini, PhD, MSc, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy, and colleagues.

The purpose of the prospective, multi-center NEXT-in-CML study by Dr Soverini et al was to evaluate the frequency and clinical relevance of low-level mutations in patients with CML. In addition, they sought to establish the feasibility, cost, and turnaround times of routine NGS-based BCR-ABL1 mutation screenings.

A total of 236 consecutive patients with CML and no (n = 124) or warning (n = 112) responses to TKI therapy were assessed using SS and NGS at 1 of 4 reference laboratories.

All 51 patients deemed negative for mutations by SS had low-level mutations detectable via NGS, and additional low-level mutations were observed in 29 of 60 patients deemed positive for mutations by SS.

Ultimately, the investigators determined that mutations undetectable by SS were identified in 80 (34%) overall, including 42 (18%) who had low-level mutations 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,” Dr Soverini and co-investigators said.

“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,” they concluded.—Hina Porcelli