Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM, retired, MSEd
The Bottom Line:
In patients being treated with BTK inhibitors, mutations in BTK are relatively rare (2 in 100 patients). When patients do develop mutations, it most commonly occurs at the binding site of covalent BTK inhibitors.
Who Performed the Research and Where Was it Presented:
Dr. Alan Skarbnik from Novant Health Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2024.
Background:
Bruton tyrosine kinase inhibitors (BTKi) revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) when they were introduced over ten years ago. Now, we have four approved BTKis, including irreversible, covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) and reversible noncovalent BTKi (pirtobrutinib). All are very effective for treating CLL / SLL, but they have traditionally been taken continuously. Over time, patients can develop mutations in the BTKi binding site, which causes resistance to these drugs. This study looked at how common BTK mutations are in a real-world population.
Methods and Participants:
This was a retrospective study of patients with CLL who had a BTK mutational panel performed by NeoGenomics Laboratories between 2018 and 2023. Only patients who had been treated with BTKi for more than one year were included in the analysis.
Results:
- Nearly 14,000 patients had samples processed, but only 238 patients (1.7%) had BTK mutations, suggesting that these mutations are relatively rare.
- 81% of patients received BTKi as a first-line treatment, and 19% received BTKi as a second or later line of therapy.
- The most common BTK mutation was C481 (94%), which is the binding site for covalent BTKi such as ibrutinib, acalabrutinib, and zanubrutinib.
- The T474 mutation only occurred in 4% of patients with BTK mutations.
- Interestingly, no L528 mutations were seen in this study.
- Almost half of the patients with BTK mutations also had mutations in TP53, which is higher than the general CLL population.
Conclusions:
In patients being treated with BTK inhibitors, mutations in BTK are relatively rare (2 in 100 patients). This suggests that if BTKi were used for a limited duration, significant resistance could be avoided, and the BTKi could be used again in case of relapse. Trials are studying this possibility now. When patients do develop mutations, it most commonly occurs at C481, the binding site of covalent BTK inhibitors. Not surprisingly, BTK mutations commonly occur alongside other mutations such as TP53 mutations.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Mutations in the Bruton Tyrosine Kinase (BTK) Gene in Patients with Chronic Lymphocytic Leukemia (CLL) Receiving BTK Inhibitors (BTKis)
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