Next-Generation Sequencing Detects Early Kinase Domain Mutations in Patients With CML

Next-generation sequencing (NGS) reliably and consistently detected early appearance of kinase domain mutations in patients with chronic myeloid leukemia (CML) that would not otherwise be detected, allowing for early clinical intervention (Lancet Haematol. 2019;6[5]:e276-e284).

“Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors [TKIs] in patients with [CML],” explained Aytug Kizilors, PhD, Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom, and colleagues.

“[NGS]…allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated,” they added.

This led Dr Kizilors and colleagues to conduct a population-based study examining the clinical effects of low-level kinase domain mutations identified using NGS in patients with CML.

The study included patients with newly diagnosed CML treated with first-line TKIs, as well as patients identified at the time of resistance to first-line treatment with imatinib at 6 institutions across England.

Irrespective of response to therapy, patients were screened for BCR-ABL1 kinase domain mutations using NGS. When a mutation was detected, investigators retrospectively analyzed all previous samples to establish the date of first occurrence, as well as subsequent kinetics of the mutant subclones.

The primary end points of the study were progression-free survival (PFS) and event-free survival (EFS) at 5 years.

A total of 121 patients with CML were screened for a BCR-ABL1 kinase domain mutation between February 1, 2007, and December 31, 2014. Of these patients, 99 patients were newly-diagnosed with available sequential RNA stored, and 22 were diagnosed between 1999 and 2006 and were screened at the time of resistance to first-line treatment with imatinib. First-line treatments included imatinib (n = 111), nilotinib (n = 7), and dasatinib (n = 3).

Kinase domain mutations were detected in 25 (21%) patients, 17 (68%) of whom had low-level kinase domain mutations first identified.

Among 93 patients with a complete cytogenetic response, 13 (14%) had a mutation. Of 7 patients with a clinically relevant mutation, 5 (71%) lost complete cytogenetic response versus 15 (17%) of 86 patients without a clinically relevant mutation.

Patients with a mutant clone had worse 5-year PFS than patients without a mutation (65.3% vs 86.9%, respectively; P = .0161), as well as poorer 5-year EFS (22.2% vs 62%, respectively; P <.0001).

A kinase domain mutation was identified in 4 (10%) of 41 patients with samples available at 3 months after starting first-line TKI therapy, all of which subsequently progressed to accelerated phase disease compared with 3 (8%) of 37 patients without a mutation (P <.0001).

“For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications,” Dr Kizilors and colleagues concluded.

“NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care,” they added.—Janelle Bradley