Dr Coombs on the Challenges in Establishing a Treatment Consensus for Relapsed CLL

"In the relapse scenario for patients who first got a covalent BTK inhibitor, assuming that the patients progressed on the BTK inhibitors as a continuous therapy. I'd say our controversy is whether a Venetoclax based approach is the best therapy, or, assuming pirtobrutinib gets a full FDA approval, is this the best option in general. I think we have evidence for both of these approaches."

Catherine C. Coombs, MD, hematologist-oncologist, associate clinical professor, Division of Hematology/Oncology, Department of Medicine, University of California Irvine Health, discusses the challenges in establishing a treatment consensus for relapsed/refractory chronic lymphocytic leukemia (CLL), particularly in patients previously treated with a covalent BTK inhibitor. With the evolving therapeutic landscape, determining the optimal sequencing of venetoclax (Venclexta)-based regimens vs noncovalent BTK inhibitors, such as pirtobrutinib (Jaypirca), remains a critical area of clinical debate.

In patients with relapsed/refractory CLL who experience disease progression on continuous covalent BTK inhibitor, venetoclax-based regimens represent a well-established option with extensive clinical experience and long-term efficacy data. Venetoclax, a selective BCL2 inhibitor, has demonstrated deep and durable responses in this setting, particularly when combined with anti-CD20 monoclonal antibodies, Coombs says. Given its time-limited treatment approach, venetoclax also offers an alternative to continuous therapy.

The recent emergence of pirtobrutinib, a next-generation noncovalent BTK inhibitor, introduces another potential option following relapse on a covalent BTK inhibitor. In December 2023, the FDA granted an accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. Although pirtobrutinib is currently indicated after a prior covalent BTK inhibitor and a venetoclax-based regimen, emerging data could help push the agent into the second-line setting after progression only on a covalent BTK inhibitor, Coombs explains. However, Coombs notes that clinical follow-up data for pirtobrutinib remain less mature compared to venetoclax-based therapies, making direct comparisons between these treatment modalities challenging. Additionally, differences in patient populations across trials further complicate treatment selection.

Establishing a consensus regarding the sequencing of these agents and regimens is essential, particularly as CLL management continues to shift toward more personalized approaches. Factors such as prior treatment history, molecular risk stratification, and patient preference play a crucial role in selecting treatment. For example, patients with high-risk disease features, such as TP53 aberrations, may benefit from a BTK inhibitor–based strategy, whereas those preferring a time-limited therapy may favor venetoclax.

Coombs underscores the need for expert-driven guidelines to navigate these therapeutic decisions, given the absence of direct comparative trials. Further prospective studies remain necessary to clarify optimal sequencing strategies, define patient populations most likely to benefit from each approach, and assess long-term outcomes.