BTK C481 Mutations Higher Among CLL Patients With Longer BTKi Exposure

The prevalence of Bruton’s tyrosine kinase (BTK) C481 mutations, a known cause of resistance to BTK inhibitors (BTKi), might be higher in chronic lymphocytic leukemia (CLL) patients with longer BTKi exposure, according to a study presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California.

“Almost two-thirds of [patients] whose disease progresses on a covalent BTKi have a BTK C481 mutation detectable at progression. Furthermore, BTK C481 mutations have been detected up to 28 months before progression among [patients] with CLL/[small lymphocytic lymphoma (SLL)] treated with a covalent BTKi. The early identification of patients who are at risk for developing covalent BTKi resistance is critical to optimize clinical treatment of [patients] with CLL/SLL,” the researchers wrote.

In this cross-sectional study, Jennifer Prescott and colleagues assessed the prevalence of BTK C481 mutations in 130 patients with CLL/SLL. The researchers noted that DNA was assayed from blood samples collated for 6 BTK C481 mutations known to confer resistance to covalent BTKi (c.1442G>C, c.1441T>A, c.1442_1443delinsCT, c.1442G>T, c.1441T>C, and c.1442G>A). Patients were considered to have a BTK C481 mutation if any of the 6 variants showed an abnormal limit of detection.

“Because two-thirds of BTKi-experienced [patients] had <36 [months] of BTKi exposure, the prevalence of BTK C481 mutations may be higher in populations with longer BTKi exposure,” the researchers concluded. “Further analyses of the natural history of BTK C481 mutations will help identify patients who are at risk of covalent BTKi resistance.”

Reference

Prescott J, Steiniche T, Georgsen J, et al. Prevalence of resistance-associated Bruton tyrosine kinase (BTK) C481 mutations by prior treatment status among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): a real-world observational study. Abstract #4196. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.