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Updated: Jul 16, 2025
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
BCR::ABL1 kinase domain mutation testing and clinical outcome in a nationwide chronic myeloid leukemia patient
Camille Kockerols1, Peter J M Valk2, Nicole M A Blijlevens3
1Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands.
Objectives:
Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation-specific in vitro derived IC50-values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50-values, and clinical outcome of tested patients.
Methods:
Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance.
Results:
Four hundred twenty analyses were performed in 275 patients. Sixty-nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7-6.1; p < .001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50-values, but a high IC50-value did not preclude a good clinical response per se.
Conclusions:
We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50-values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance.
