Driving Outcomes in CLL: Treatment Sequencing Strategies

On September 10, 2025, a panel of hematologists and oncologists participated in a virtual workshop to examine the evolving treatment landscape in chronic lymphocytic leukemia (CLL). Moderated by Tara Graff, DO, the session covered first-line treatment options, sequencing strategies in the relapsed/refractory (R/R) setting, approaches in the post–covalent BTKi setting, and considerations for patients exposed to both BTKi and venetoclax. The discussion also highlighted themes of shared decision-making, unmet needs, and emerging therapies aimed at improving outcomes in CLL. 

Session Overview and Highlights 

First-Line Treatment Landscape in CLL 

Dr Graff emphasized that both continuous BTKi therapy and fixed-duration venetoclax-based regimens remain central to frontline management of CLL. Enthusiasm has grown for all-oral, fixed-duration doublets such as acalabrutinib plus venetoclax (AV), which have demonstrated promising efficacy in the AMPLIFY trial and are now included in the NCCN guidelines.1,2 However, determining how AV compares with venetoclax plus obinutuzumab (VEN+O) in practice remains a challenge. 

Dr Graff also expressed caution regarding first-line triplet approaches and shared concerns over increased infection risk and cytopenias. While adding obinutuzumab to AV (AVO) may improve responses, its role remains uncertain. Dr Graff also highlighted that the AMPLIFY trial excluded patients with high-risk disease features such as TP53 or deletions in the short arm of chromosome 17.2 Participants agreed that patient selection is critical, with the general consensus being that most patients tend to prefer the fixed-duration regimens. 

Treatment Sequencing in CLL: Second-Line Treatment Options 

The participants agreed that sequencing decisions in R/R CLL depend on multiple factors, including prior therapy and the reason for discontinuation. Patients who relapse after VEN+O and maintain remission for several years may be considered for retreatment, whereas early progression within 1 year often requires switching to a BTKi. The panel also discussed distinguishing intolerance from resistance; intolerance may justify switching to another covalent BTKis, while resistance usually requires a different class of medication. With newer, more tolerable agents, clinicians are increasingly willing to switch earlier, and retesting for cytogenetic changes remains key to guiding therapy. 

Treatment Decisions in the Post–Covalent BTKi Setting  

Dr Graff noted that covalent BTKi(eg, ibrutinib, acalabrutinib, and zanubrutinib) often face resistance through BTK C481 mutations.3 Pirtobrutinib overcomes this limitation; it provided encouraging results with longer progression-free survival in the phase 3 BRUIN CLL-321 trial.4 In discussing where pirtobrutinib optimally fits in treatment sequencing, some panelists favored reserving it for double-exposed patients, whereas others reported success using it earlier in second-line therapy, especially when patients became refractory to a covalent BTKi. Experts agreed that pirtobrutinib is better tolerated than covalent BTKi and remains a promising option. However, questions remain regarding its optimal timing and positioning in therapy, including whether it should be used as monotherapy, in combination with other agents, or as a bridge to CAR-T. 

R/R CLL After Double Exposure (BTKi and Venetoclax) 

The discussion highlighted the limited treatment options for patients whose disease progresses after BTKi- and venetoclax-based regimens. Panelists expressed differing views on CAR-T, acknowledging that some patients achieve durable remissions, but modest response rates, toxicity, and logistical barriers limit its use in practice. Pirtobrutinib was often preferred for older or less fit patients, whereas CAR-T may still be considered for select younger individuals with aggressive disease. The role of minimal residual disease (MRD) testing was also raised, with experts noting its value in predicting long-term outcomes; however, it is not being used consistently to guide therapy in current practice. Looking ahead, novel approaches (eg, BTK degraders, second-generation BCL2 inhibitors, and bispecific antibodies) were viewed as promising options to improve outcomes in this setting. 

Final Thoughts and Key Takeaways 

The workshop reinforced that sequencing decisions in CLL are becoming more complex, with new agents continuing to expand therapeutic options. Pirtobrutinib stood out as a therapy that may move earlier into the treatment paradigm, although its ideal placement remains under discussion. Looking ahead, BTK degraders, bispecific antibodies, and next-generation BCL2 inhibitors may provide new options, especially for double-exposed patients. At the same time, access issues like insurance approvals were recognized as persistent barriers that may limit the adoption of novel therapies. 

Discussion Themes and Expert Insights 

Panelists agreed that both continuous BTKi therapy and fixed-duration venetoclax-based regimens remain central in frontline CLL treatment. Enthusiasm is growing for all-oral doublets that include AV; still, comparisons with VEN+O remain unclear. Triplet regimens raised concern about added toxicity, highlighting the need for careful patient selection. 

In the R/R setting, sequencing depends on various factors, with prior therapy being a key consideration. Pirtobrutinib was highlighted as an important option post–covalent BTKi, but opinions differed on whether to use it in the second line or later. For double-exposed patients, CAR-T offers potential but limited efficacy in CLL compared to other lymphomas, making clinical trials, BTK degraders, and bispecific antibodies key areas of research. Patient preference and shared decision-making were emphasized throughout. 

Unmet Needs and Recommendations 

The panelists agreed that several gaps persist in optimizing CLL care. Head-to-head trials are needed to define the role of AV versus VEN+O and clarify the benefit of adding obinutuzumab to AV. Sequencing remains an open question, especially in double-exposed patients. Dr Graff noted that broader use of MRD testing could help guide treatment decisions, but its role in practice remains inconsistent. Long-term follow-up for agents like pirtobrutinib, along with access challenges such as insurance approvals, were identified as barriers. 

Conclusion 

This workshop, led by Dr Graff, highlighted both the progress and complexity of CLL management. Frontline options are expanding, but sequencing strategies remain unsettled, especially for high-risk and double-exposed patients. Pirtobrutinib, degraders, and bispecific antibodies are promising additions, although their placement in therapy is still debated. Looking ahead, the panelists agreed that continued research, broader use of MRD testing, and greater attention to patient preferences will be key to refining treatment and improving long-term outcomes in CLL. 

References 

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2025. Accessed September 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf 
2. Brown JR, et al; AMPLIFY Investigators. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia.NewEngl J Med. 2025;92(8): 748-762. doi:10.1056/NEJMoa2409804
3. Thompson PA, Tam CS. Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Blood. 2023;141(26):3137-3142. doi:10.1182/blood.2023020240
4. Sharman JP et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166

This article was supported in part by Eli Lilly. Content independently developed and published by OncLive.