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Purpose <p>Recent advances in chronic lymphocytic leukemia (CLL) have established continuous Bruton tyrosine kinase (BTK) inhibition and fixed-duration venetoclax-based therapy as major frontline paradigms. Data presented at the 2025 American Society of Hematology (ASH) Annual Meeting provide direct comparative evidence and introduce next-generation BTK inhibition.</p> Patients and methods <p>Clinically relevant randomized phase&#xa0;II and&#xa0;III clinical trial abstracts presented at ASH 2025 were reviewed, with an emphasis on human clinical outcomes, prognostic subgroup analyses, minimal residual disease (MRD)-guided strategies, and treatment sequencing.</p> Results <p>The phase&#xa0;III CLL17 trial demonstrated non-inferior medium-term progression-free survival for fixed-duration venetoclax-based therapy compared with continuous ibrutinib, with higher undetectable MRD (uMRD) rates but important caveats regarding interim follow-up, overall survival (OS), infection-related mortality, TP53-aberrant disease, and the use of ibrutinib as comparator. The two phase&#xa0;III trials BRUIN CLL-313 and BRUIN CLL-314 support pirtobrutinib as a&#xa0;clinically relevant non-covalent BTK inhibitor; OS data remain immature, and the safety profile was consistent with prior trials. Infections and low-grade bleeding were the most common toxicities. Neutropenia was the most frequent treatment-related grade ≥ 3&#xa0;event, whereas class-typical cardiovascular toxicities were uncommon. Additional studies addressed optimization of combination regimens, retreatment strategies, and emerging BTK degradation.</p> Conclusion <p>Based on ASH 2025 data, treatment selection in contemporary CLL should integrate disease biology, patient preference for treatment-free intervals, cardiovascular and infection risk, MRD feasibility, and access to covalent or non-covalent BTK inhibition.</p>

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American Society of Hematology (ASH) update 2025: fixed-duration, MRD-guided, and next-generation BTK-directed therapy in chronic lymphocytic leukemia

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Victor Rathkolb,
  • Franziska Mödder,
  • Thomas Noesslinger

摘要

Purpose

Recent advances in chronic lymphocytic leukemia (CLL) have established continuous Bruton tyrosine kinase (BTK) inhibition and fixed-duration venetoclax-based therapy as major frontline paradigms. Data presented at the 2025 American Society of Hematology (ASH) Annual Meeting provide direct comparative evidence and introduce next-generation BTK inhibition.

Patients and methods

Clinically relevant randomized phase II and III clinical trial abstracts presented at ASH 2025 were reviewed, with an emphasis on human clinical outcomes, prognostic subgroup analyses, minimal residual disease (MRD)-guided strategies, and treatment sequencing.

Results

The phase III CLL17 trial demonstrated non-inferior medium-term progression-free survival for fixed-duration venetoclax-based therapy compared with continuous ibrutinib, with higher undetectable MRD (uMRD) rates but important caveats regarding interim follow-up, overall survival (OS), infection-related mortality, TP53-aberrant disease, and the use of ibrutinib as comparator. The two phase III trials BRUIN CLL-313 and BRUIN CLL-314 support pirtobrutinib as a clinically relevant non-covalent BTK inhibitor; OS data remain immature, and the safety profile was consistent with prior trials. Infections and low-grade bleeding were the most common toxicities. Neutropenia was the most frequent treatment-related grade ≥ 3 event, whereas class-typical cardiovascular toxicities were uncommon. Additional studies addressed optimization of combination regimens, retreatment strategies, and emerging BTK degradation.

Conclusion

Based on ASH 2025 data, treatment selection in contemporary CLL should integrate disease biology, patient preference for treatment-free intervals, cardiovascular and infection risk, MRD feasibility, and access to covalent or non-covalent BTK inhibition.