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

Pritika Sharma1, Heng Jiang2, Delong Liu3

  • 1Division of Hematology and Oncology, Westchester Medical Center and New York Medical College, Valhalla, NY, 10595, USA.

Journal of Hematology & Oncology
|June 7, 2026
PubMed

Insights

New Bruton tyrosine kinase (BTK) inhibitors and BTK degraders show promise for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), addressing resistance and unmet needs.

Area of Science:

  • Hematology
  • Oncology
  • Pharmacology

Background:

  • Covalent and non-covalent Bruton tyrosine kinase inhibitors (BTKi) offer clinical benefits for relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • A significant unmet need persists for novel B-cell receptor (BCR) pathway targeted therapies in highly refractory CLL/SLL, particularly for patients with BTKi resistance.
  • Emerging BTK-directed agents represent a critical area of research for overcoming treatment resistance in CLL/SLL.

Purpose of the Study:

  • To summarize the latest advancements in emerging BTK-directed agents for CLL/SLL presented at the American Society of Hematology (ASH) 2025 Annual Meeting.
  • To highlight the potential of next-generation non-covalent BTKi, dual-kinase inhibitors, and BTK degraders in managing R/R and BTKi-resistant CLL/SLL.
  • To assess the preliminary efficacy, safety, and target engagement of novel agents in heavily pretreated CLL/SLL populations.

Main Methods:

  • Review of clinical trial data from emerging BTK-directed agents presented at ASH 2025.
  • Analysis of Phase 1 study results for docirbrutinib and rocbrutinib, evaluating target engagement across BTK mutations.
  • Assessment of efficacy and safety data for birletinib (dual LYN/BTK inhibitor) and BTK degraders (bexobrutideg, BGB-16673) in pretreated CLL/SLL patients.

Main Results:

  • Docirbrutinib and rocbrutinib demonstrated target engagement in wild-type and resistant BTK mutations, with encouraging safety and preliminary efficacy in heavily pretreated patients.
  • Birletinib achieved a high objective response rate in patients previously treated with BTKi, BCL-2 inhibitors, and BTK degraders.
  • BTK degraders (bexobrutideg, BGB-16673) showed rapid, deep responses, activity in high-risk subgroups, and manageable toxicity, with established Phase 2 doses.

Conclusions:

  • Novel BTK-directed agents, including next-generation inhibitors and degraders, show significant promise for R/R CLL/SLL.
  • These emerging therapies demonstrate efficacy in challenging patient populations, including those with resistance to prior treatments.
  • Continued clinical development of these agents is crucial to address disease progression and resistance in CLL/SLL.

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