Decoding BTK Mutations: Translating Genomics into Treatment Strategy

Resistance to Bruton tyrosine kinase (BTK) inhibitors has emerged as a major clinical challenge in the management of chronic lymphocytic leukemia (CLL), driving the need for genomically informed treatment strategies. This session will explore the evolving molecular mechanisms underlying BTK inhibitor resistance, including BTK and PLCG2 mutations, clonal evolution, and emerging resistance pathways associated with both covalent and noncovalent BTK inhibitors. Faculty will review recent clinical trial data evaluating next-generation approaches, including noncovalent BTK inhibitors, BTK degraders, and rational combination regimens designed to overcome resistance and improve durability of response. The discussion will also address the role of genomic monitoring, measurable residual disease assessment, and personalized treatment sequencing. Attendees will gain practical insights into translating genomic discoveries into evidence-based therapeutic decision-making for patients with relapsed and refractory CLL.