Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Most resistance mutations acquired by CLL patients during zanubrutinib treatment occurred at a single site on BTK. Patients who develop resistance to covalent BTK inhibitors are likely to remain sensitive to therapies that target BTK differently.
Who Performed the Research and Where Was it Presented:
Dr. Mazyar Shadman from Fred Hutchinson Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
Bruton tyrosine kinase (BTK) inhibitors have become the backbone of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treatment. We now have second-generation covalent BTK inhibitors (acalabrutinib and zanubrutinib), which are safer than first-generation BTK inhibitor ibrutinib. However, BTK inhibitors must be taken continuously, which can eventually lead to the development of drug resistance. Researchers want to learn more about what causes patients to stop responding to next-generation covalent BTK inhibitors such as zanubrutinib.
Methods and Participants:
This study used samples for the ALPINE study, a phase 3 clinical trial comparing zanubrutinib with ibrutinib in patients with relapsed / refractory CLL or SLL. Researchers performed next-generation sequencing on samples from patients who progressed while on zanubrutinib to look for mutations in specific genes.
Results:
- Fifty-seven patients in the zanubrutinib group experienced disease progression.
- Of these, 26 patients (48%) had blood samples available from baseline and at or after disease progression for analysis by next-generation sequencing.
- Only one patient had a BTK mutation at baseline.
- Five patients acquired mutations in BTK during the study.
- Most mutations (78%) occurred at the C481 site on BTK, which is also where most ibrutinib-resistance mutations arise.
- Mutations at other sites were infrequent (13%).
Conclusions:
Most resistance mutations acquired by CLL patients during zanubrutinib treatment occurred at the C481 site on BTK. Patients who develop resistance to covalent BTK inhibitors are likely to remain sensitive to therapies that target BTK differently. In the future, learning more about acquired resistance mutations in many patients using different therapies could help guide how CLL / SLL treatments should be sequenced.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Acquired Mutations in Patients (Pts) with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) That Progressed in the ALPINE Study.
Take care of yourself first.
Ann Liu, PhD
