Distinct Patterns of BTK Mutations Identified in CLL Progression on Acalabrutinib vs Ibrutinib

A recent study assessed clonal evolution in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who progressed while receiving Bruton tyrosine kinase (BTK) inhibitor therapy, identifying distinct mutation patterns associated with acalabrutinib and ibrutinib treatment. The findings suggest that while BTK C481S mutations were common in both groups, additional mutation profiles differed between the two therapies.

BTK inhibitors, such as acalabrutinib and ibrutinib, are standard treatments for CLL; however, disease progression remains a challenge, often due to the emergence of resistance mutations in the B-cell receptor pathway. Understanding the molecular mechanisms driving resistance is critical for optimizing treatment strategies and guiding next-line therapies. This study aimed to characterize clonal evolution in patients progressing on either acalabrutinib or ibrutinib, providing insights into the specific resistance mutations that arise with each agent.

Researchers analyzed paired baseline and progression peripheral blood samples from patients with relapsed/refractory CLL, including 47 patients receiving acalabrutinib and 30 receiving ibrutinib. Patients with Richter transformation were excluded. The median follow-up was 41 months. Next-generation sequencing was used to detect emergent mutations in BTK, TP53, and PLCG2, among other genes.

At the time of disease progression, 66% of patients treated with acalabrutinib and 37% of patients treated with ibrutinib developed BTK mutations (median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). The BTK C481S mutation was most common in both groups. However, unique mutations emerged based on treatment type: T474I (n = 9) and a novel E41V mutation were observed exclusively in acalabrutinib-treated patients, while L528W and A428D mutations were detected only in patients treated with ibrutinib. Preexisting TP53 mutations were present at baseline in approximately 53% of patients in both groups. Emergent TP53 mutations were detected in 13% of patients treated with acalabrutinib and 7% of those treated with ibrutinib, with a higher median VAF in the ibrutinib group (37.3% vs 6.0%). Additionally, 6 patients treated with acalabrutinib and 1 patient treated with ibrutinib developed concurrent TP53 and BTK mutations. PLCG2 mutations, another known resistance mechanism, emerged in 6% of patients treated with acalabrutinib and 20% of those treated with ibrutinib, with BTK/PLCG2 comutations occurring in 1 and 4 patients, respectively.

“Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population,” the study authors concluded.

Reference

Woyach JA, Jones D, Jurczak W, et al. Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood. 2024;144(10):1061-1068. doi:10.1182/blood.2023023659