Novel BTK inhibitors and degraders for relapsed/refractory CLL/SLL: latest updates from ASH 2025 annual meeting

Although covalent and non-covalent Bruton tyrosine kinase inhibitors (BTKi) have extended clinical benefit to relapsed/refractory (R/R) and BTKi-resistant chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), there remains an unmet need for additional B-cell receptor (BCR) pathway targeted therapies for highly refractory disease. This summary highlighted latest updates from the American Society of Hematology 2025 Annual Meeting on emerging BTK-directed agents in CLL/SLL, including next-generation non-covalent BTKi, dual-kinase inhibitors, and BTK degraders. Phase 1 studies of docirbrutinib and rocbrutinib demonstrated target engagement across wild-type and resistance-associated BTK mutations with encouraging safety profiles and preliminary efficacy signals in heavily pretreated populations. Birletinib, a dual LYN/BTK inhibitor, showed a high objective response rate in patients with prior exposure to BTKi, BCL-2 inhibitors, and BTK degraders. BTK degraders, including bexobrutideg and BGB-16673, demonstrated rapid and deep responses, activity in high-risk molecular subgroups, and manageable toxicity profiles, with recommended phase 2 doses established. Collectively, these latest updates support continued clinical development of novel agents to address resistance and disease progression in R/R CLL/SLL.