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Genetic Mutations in CML and Predicting Response to TKI Therapy

By: Cordi Craig
Posted: Friday, February 14, 2020

Although BCR-ABL1 kinase domain mutations are a major cause of tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML), some patients develop resistance without this mutation. According to a molecular study presented at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 4148) and published in the journal Blood, patients who have preexisting ASXL1 mutations at diagnosis may also be more likely to be resistant to TKI therapy. Tomasz Stoklosa, MD, PhD, of the Medical University of Warsaw, Poland, and colleagues suggest that these results may be useful when assessing a patient’s risk of treatment failure.

The research team assessed the prevalence of genetic mutations in 50 patients with CML with primary (n = 26) or secondary (n = 24) resistance to TKI therapy. Most cases were resistant to imatinib (n = 49), and a single case was resistant to dasatinib.

The most frequent mutations detected at the time of resistance were ASXL1 and BCR-ABL1 kinase domain; they were present in 28% (n = 14) and 26% (n = 13) of the patient population, respectively. In 12% of patients (n = 6), both genes were mutated. Nonrecurrent genetic mutations, such as DNMT3A, were observed in individual patients (eg, DNMT3A mutations). 

The frequency of ASXL1 mutation was significantly higher among patients resistant to TKIs than among patients who were not resistant to these drugs (28% vs. 5.6%, respectively; P = .0105). All patients with ASXL1 mutation and primary or secondary resistance also carried the mutation at the time of diagnosis. There was no significant difference between patients with primary or secondary resistance in the frequency of ASXL1 or BCR-ABL1 kinase domain mutations.

Disclosure: For full disclosures of the study authors, visit ashpublications.org.



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