Key Takeaways

• All-oral doublet regimens (eg, acalabrutinib plus venetoclax) are extremely exciting to the field of chronic lymphocytic leukemia (CLL), as many patients prefer oral-only therapies. However, identifying ideal patients to receive doublet versus triplet versus continuous Bruton tyrosine kinase inhibitor (BTKi) monotherapy in the first-line setting is still evolving.
• Treatment sequencing in CLL will become increasingly more difficult with new combination regimens becoming more widely used in the first-line setting.
• The optimal sequencing of BTK inhibitors and chimeric antigen receptor T-cell therapy (CAR-T) is still being debated.
• Bispecific antibodies and BTK degraders remain exciting emerging therapies in the relapsed and/or refractory CLL population.

Session Overview & Highlights

First-Line Treatment Landscape in CLL

The faculty expressed enthusiasm for all-oral doublet regimens such as AV (acalabrutinib plus venetoclax), which have already been included in NCCN guidelines. However, distinguishing which patients would benefit most from AV versus currently available therapies like VEN+O (venetoclax plus obinutuzumab) remains difficult in the absence of data from direct comparative trials.

Clinicians continue to debate about first-line triplet therapies, as they are concerned about high infection rates and cytopenias. They were excited about the data with pirtobrutinib plus VEN+O from the American Society of Hematology (ASH) 2024 conference. Another emerging combination includes AVO (AV plus obinutuzumab) in high-risk patients from a phase two study lead by Matthew S. Davids, MD, MMSc as the AMPLIFY trial excluded patients with 17p deletion or TP53 aberration. The faculty agreed that selecting the appropriate patient for these novel combination regimens is an ongoing discussion.

Treatment Sequencing in CLL: Second-Line Treatment Options

Faculty members largely agreed that acalabrutinib and zanubrutinib are comparable in the second-line setting for those who received fixed-duration therapy in the first-line setting. The faculty largely agreed that the ideal time window of retreatment with venetoclax is still debatable, but 1 year of progression- free survival with VEN+O would be too short for such consideration. With new combination therapies (eg, AV and/or AVO) most likely getting approved soon, sequencing of therapies will be complicated, and analyzing durability of responses will be increasingly important.

Pirtobrutinib in R/R CLL

Overall, the faculty agree that pirtobrutinib is a well-tolerated agent. However, the ideal role of pirtobrutinib in R/R CLL as a second-line versus third-line treatment remains debated. There is debate on the utility of the control arm of the phase three trial that was presented at ASH 2024 (BRUIN CLL-321), with some experts no longer viewing BR (bendamustine plus rituximab) or IdelaR (idelalisib plus rituximab) as a standard of care.

Managing R/R CLL After BTKi- and Venetoclax-Containing Regimens

The discussion on R/R CLL highlighted the lack of consensus regarding optimal sequencing after receiving both covalent BTKi and venetoclax-containing regimens. Faculty members expressed mixed opinions on the efficacy of CAR-T in CLL. Some cited promising long-term remission rates; others noted the difficulty in selecting appropriate candidates, as the majority of the CLL population are elderly and may not tolerate CAR-T.

Future Directions: Emerging Therapies

Emerging treatments such as bispecific antibodies (eg, epcoritamab) and BTK degraders were highlighted as potential game-changers in CLL management. Faculty members noted that bispecific antibodies may be an alternative to CAR-T particularly given the logistical challenges of CAR-T manufacturing and administration. The faculty acknowledged that the durability of responses of these novel therapies must be understood, as those data are being gathered.

Discussion Themes and Expert Insights

The increasing treatment options available make this an exciting time for CLL treatment; however, it also is a more challenging time, since it is unclear who are the most ideal candidates for doublet or triplet therapies in the frontline setting. The faculty agree that there are multiple treatment approaches in the high-risk population. These include minimal residual disease testing to decide to discontinue or de-escalate therapy; however, this is primarily done in the clinical trial setting.

The faculty agree that the ideal role of BTK inhibitors and CAR-T must be understood further, and strategies to improve durability of responses in the relapsed and/or refractory population must be the focus.

Unmet Needs and Recommendations

Head-to-head clinical trials comparing novel combination regimens, such as AV versus Ven+O, are necessary to guide treatment selection. Furthermore, optimizing sequencing strategies after use of doublet or triplet regimens remains a gray area, as the durability of responses is unknown for this patient population. Long-term follow-up studies and real-world data for novel or investigational therapies are critical to understanding their optimal use.

Conclusion

The discussion underscores the rapidly evolving CLL landscape and the importance of continued research to refine sequencing strategies and to individualize treatment selection. The faculty largely agree on treatment strategies for a “typical” CLL patient, although differing opinions on pirtobrutinib’s role and CAR-T sequencing highlight ongoing debates in the field. As novel therapies continue to emerge, their integration into a treatment paradigm that optimizes patient outcomes while minimizing toxicity will remain a challenge.

References

1. NCCN. Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2025. Accessed February 19, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701
3. Jain N, Ferrajoli A, Swaminathan M, et al. Combined pirtobrutinib, venetoclax, and obinutuzumab as first-line treatment of chronic lymphocytic leukemia. Blood. 2024;144(suppl 1):1011. doi:10.1182/blood-2024-211454
4. Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naïve chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol. Published online December 7, 2024. doi:10.1200/JCO-24-02503
5. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886. doi:10.1182/blood-2024-198147
6. Siddiqi T, Gauthier J, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): updated follow-up of Transcend CLL 004. Blood. 2024;144(suppl 1):4633. doi:10.1182/blood-2024-200840
7. Wierda WG, Dorritie K, Gauthier J, et al. Lisocabtagene maraleucel (liso-cel) combined with ibrutinib (ibr) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): primary results from the open-label, phase 1/2 Transcend CLL 004 study. Blood. 2024;144(suppl 1):887. doi:10.1182/blood-2024-200339
8. Frost BF, Frey N, Hexner EO, et al. Curing CLL: long-term outcomes of chronic lymphocytic leukemia patients with at least one year of response to CART-19 therapy. Blood. 2024;144(suppl 1):588. doi:10.1182/blood-2024-204197
9. Danilov A, Fakhri B, Awan FT, et al. Epcoritamab monotherapy in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL): results from CLL expansion and optimization cohorts of Epcore CLL-1. Blood. 2024;144(suppl 1):883. doi:10.1182/blood-2024-199708
10. Shah NN, Omer Z, Collins GP, et al. Efficacy and safety of the Bruton's tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/b study. Blood. 2024;144(suppl 1):884. doi:10.1182/blood-2023-194839
11. Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144(suppl 1):885. doi:10.1182/blood-2024-199116