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Pirtobrutinib, a reversible non-covalent BTK inhibitor, shows promise for CLL patients resistant to covalent BTKi therapy. Genomic analyses from the BRUIN trial reveal a complex landscape of BTK and non-BTK mutations at baseline and at progression, underscoring the dynamic clonal evolution underpinning resistance. Sensitive DNA sequencing uncovers pre-existing low-frequency mutations that may drive acquired resistance, emphasizing the need for comprehensive genomic monitoring during therapy.
