Early Detection of Kinase Domain Mutations in Chronic Phase CML
Posted: Thursday, February 6, 2020
According to Hugues de Lavallade, MD, PhD, of King’s College, London, and colleagues, next-generation-sequencing may be able to reliably detect low levels of ABL kinase domain mutations in patients with chronic phase chronic myeloid leukemia (CML). This notable improvement in sensitivity, compared with standard Sanger sequencing, poises this assay as a potential prognostic tool in the diagnosis and treatment of CML. Findings from this study were presented at the 2019 American Society of Hematology Annual Meeting & Exposition in Orlando (Abstract 664) and published in the journal Blood.
In this ongoing phase III trial, 200 patients with newly diagnosed chronic phase CML were randomly assigned to receive first-line treatment with nilotinib or nilotinib with pegylated interferon-α2a. Of them, 96 patients were screened for kinase domain mutations.
After a median follow-up of 45 months, the researchers found 11 patients had kinase domain mutations after 12 months of treatment. Three patients had kinase domain mutations by the third month of treatment; in two of these patients, kinase domain mutations were detected by next-generation sequencing. By the 6-month time point, eight patients had kinase domain mutations, of which six were detectable by next-generation sequencing alone. Five patients had kinase domain mutations detectable by next-generation sequencing at the 6-month time point, despite achieving optimal or major molecular response. Sanger sequencing did not detect these mutations until the 18-month time point.
“The proportion of patients who develop [kinase domain] mutations by 12 months on upfront [second-generation tyrosine kinase inhibitors] should not be underestimated, as their outcome is poor. [Next-generation sequencing] may trigger early clinical intervention and prevent progression in this group, although a prospective trial is needed in this regard,” the authors concluded.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.