Symposium | BTK inhibitors in CLL: Mechanisms, clinical considerations, and unmet needs

On June 22, 2026, the Lymphoma Hub held a virtual symposium, titled Optimizing treatment for chronic lymphocytic leukemia with BTK inhibitors. During the symposium, Lymphoma Hub Steering Committee member Susan O’Brien, University of California Irvine, US, delivered a presentation on BTK inhibitors in chronic lymphocytic leukemia: Mechanisms, clinical considerations, and unmet needs.

During her presentation, O’Brien provides an overview of the discovery of Bruton’s tyrosine kinase (BTK) as a target in chronic lymphocytic leukemia (CLL), the early clinical development of BTK inhibitors (BTKi), their mechanism of action (Figure 1), and how they impacted the treatment paradigm in patients with CLL. O’Brien discusses the off-target effects of BTKi and how their selectivity impacts their safety profile, the importance of evaluating clinical factors when selecting treatment, and the long-term tolerability of and resistance to BTKi. Finally, O’Brien highlights the persistent unmet needs in patients with CLL treated with BTKi.

Key points

• Increased understanding of the role of B-cell receptor (BCR) signaling in CLL pathogenesis has led to the development of targeted therapies, such as BTKi.²
• Targeting BTK has transformed the management of patients with CLL; treatment with BTKi has significantly improved outcomes compared with traditional chemoimmunotherapy.^3,4
• While ibrutinib established BTK as a key therapeutic target in CLL, off-target effects associated with ibrutinib led to the development of more selective second-generation covalent BTKi, such as acalabrutinib and zanubrutinib, and non-covalent BTKi, such as pirtobrutinib.^5,6
  • In a study of 370 kinases, ibrutinib inhibited more off-target kinases (≥50%) vs acalabrutinib and zanubrutinib when tested at 100× their half-maximal inhibitory concentration (Figure 2).⁷
  • Pirtobrutinib is a highly selective non-covalent BTKi that inhibits fewer off-target kinases vs covalent BTKi, which may contribute to an improved safety profile (Figure 2).^8,9
• The safety profile of BTKi are closely linked to their kinase-binding patterns; BTKi are associated with an increased risk of cardiovascular toxicities, including atrial fibrillation and hypertension, and the careful evaluation of clinical factors, such as pre-existing comorbidities, is necessary.⁴
• Real-world retrospective studies have demonstrated that toxicities are a major cause of treatment discontinuation in patients receiving covalent BTKi.^10,11
• Resistance to BTKi remains a major clinical challenge, resulting in treatment failure and disease progression for a significant portion of patients.¹²
  • Several factors contribute to BTKi resistance, including genetic mutations, chromosomal aberrations, dysregulation of protein expression, tumor microenvironment, and metabolic reprogramming.¹³
• BTK C481 mutations prevent covalent BTKi binding and are the predominant mechanism of acquired resistance to covalent BTKi in patients with CLL.¹²
• Pirtobrutinib binds to BTK within the ATP-binding pocket of BTK at a location that is spatially distinct from the C481 residue, resulting in inhibitory activity even when mutations at C481 prevent covalent bond formation, addressing an unmet need in patients who are resistant to covalent BTKi.^14,15
• O’Brien concludes by highlighting persistent unmet needs in the CLL treatment landscape, including:
  • BTKi discontinuation due to toxicity or progression.¹⁶
  • Acquired resistance to BTKi.¹⁷
  • Lack of clearly defined optimal sequencing strategies.¹⁷
  • Limited treatment options for BTKi-refractory patients.¹⁷
  • Standardization and clinical validation of measurable residual disease as an actionable biomarker.^18,19
  • More durable, disease-modifying treatments for patients with high-risk CLL.²⁰ 

This educational resource is independently supported by Eli Lilly. All content is developed by SES in collaboration with an expert steering committee. Funders are allowed no influence