Resistance Mutations and Treatment Selection in CLL

Dr. Jennifer J. Huang and Dr. Mazyar Shadman discuss the role of resistance mutations in treatment decision-making for relapsed/refractory chronic lymphocytic leukemia (CLL), particularly following Bruton tyrosine kinase (BTK) inhibitor therapy. Dr. Huang highlights the C481S mutation as a potential indicator of resistance to covalent BTK inhibitors, such as acalabrutinib and zanubrutinib, while noting that noncovalent BTK inhibitors, including pirtobrutinib, may retain activity in this setting. She also discusses T474I and L528W mutations, which may be associated with reduced sensitivity to pirtobrutinib. Dr. Shadman emphasizes the importance of considering variant allele frequency and the size of the resistant clone when interpreting molecular findings. The experts explain how resistance patterns may influence treatment selection, including consideration of a switch to another therapeutic class, such as a venetoclax-based regimen. They underscore that this rapidly evolving area requires individualized interpretation of molecular findings alongside clinical response and disease progression.