ASH 2024: Updates in the Treatment of CLL

Matthew S. Davids, MD, MMSc; Alvaro Alencar, MD; Marc S. Hoffmann, MD; Brad S. Kahl, MD; and Nicole Lamanna, MD, engage in a comprehensive discussion of frontline CLL treatment strategies, examining factors influencing the choice between fixed-duration venetoclax-based therapy and continuous BTK inhibitors, analyzing long-term SEQUOIA trial data, evaluating real-world outcomes and adverse events with covalent BTK inhibitors, and assessing emerging combination approaches including zanubrutinib plus venetoclax.

Panelists discuss how long-term SEQUOIA trial data presented at ASH 2024 inform the selection between covalent BTK inhibitors zanubrutinib and acalabrutinib in treatment-naive CLL, including considerations for combining these agents with obinutuzumab.

Panelists discuss how real-world treatment patterns with covalent BTK inhibitors differ from clinical trial experiences, particularly regarding the rates of discontinuation due to intolerance vs progression and the incidence of cardiac adverse events with acalabrutinib and zanubrutinib in clinical practice.

Panelists discuss how the combination of zanubrutinib plus venetoclax in arm D of the SEQUOIA trial contributes to understanding the potential role of BTK inhibitor and BCL2 inhibitor combinations in frontline CLL treatment.

Panelists discuss how the AMPLIFY trial evaluated acalabrutinib-venetoclax-obinutuzumab (AVO) vs acalabrutinib-venetoclax (AV) as frontline therapy options, highlighting the impressive depth of response with both regimens while noting the additional toxicity profile associated with the triplet combination.

Panelists discuss how pirtobrutinib plus venetoclax and obinutuzumab shows promise as a frontline chronic lymphocytic leukemia (CLL) treatment option, with its high selectivity and favorable safety profile potentially offering advantages over current Bruton tyrosine kinase inhibitor–based regimens, though more long-term data is needed to determine its optimal place in therapy.

Panelists discuss how patient-specific factors including age, comorbidities, genetic profile, and treatment goals guide the selection between doublet and triplet regimens in chronic lymphocytic leukemia (CLL), with considerations like Bruton tyrosine kinase inhibitor tolerability, desire for time-limited therapy, and high-risk features informing the choice between various BTK inhibitor–based combinations with venetoclax and obinutuzumab.

Panelists discuss how second-line treatment selection in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) requires careful consideration of prior therapy exposure, with noncovalent Bruton tyrosine kinase (BTK) inhibitors showing particular promise for patients with BTK resistance mutations while noting that matching-adjusted indirect comparisons (MAIC) analyses, though informative, must be interpreted cautiously in the absence of direct comparative trials.

Panelists discuss how the phase 2 study of zanubrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) demonstrated promising efficacy with deep and durable responses, suggesting this combination could be an effective option for previously treated patients while maintaining a manageable safety profile.

Panelists discuss how treatment sequencing in chronic lymphocytic leukemia (CLL) should be personalized based on prior therapy responses and resistance patterns, with emerging real-world data from ASH 2024 informing decisions about re-treatment with drug classes and treatment holidays, while considering factors like durability of previous responses and the timing of molecular resistance.

Panelists discuss how pirtobrutinib is increasingly being considered as a second-line option in relapsed/refractory chronic lymphocytic leukemia (R/R CLL), particularly for patients who have developed resistance or intolerance to covalent Bruton tyrosine kinase (BTK) inhibitors, though the optimal positioning of this noncovalent BTK inhibitor continues to evolve as more real-world experience accumulates.

Panelists discuss how the placement of chimeric antigen receptor (CAR) T-cell therapy in heavily pretreated chronic lymphocytic leukemia (CLL) continues to evolve with encouraging long-term TRANSCEND CLL-004 data from ASH 2024, while factors such as prior therapy responses, genetic profiles, and timing of progression help guide the sequencing decision between CAR T-cell therapy and pirtobrutinib in patients previously exposed to both covalent Bruton tyrosine kinase and BCL2 inhibitors.

Panelists discuss how real-world experience with pirtobrutinib generally aligns with the BRUIN study’s progression-free survival (PFS) data while sharing insights about common reasons for discontinuation and interpreting updated BRUIN CLL-321 trial results from ASH 2024 that may influence clinical decision-making regarding pirtobrutinib use in practice.

Panelists discuss how novel Bruton tyrosine kinase (BTK) degraders like NX-5948 and BGB-16673 are showing promising early clinical activity in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) based on ASH 2024 data, while bispecific antibodies such as epcoritamab from the EPCORE CLL-1 trial represent another emerging therapeutic approach, though longer follow-up is needed to fully understand their optimal role in the treatment landscape.

Panelists discuss how the remarkable evolution of chronic lymphocytic leukemia (CLL) therapy over recent years has dramatically improved patient outcomes through the development of targeted therapies like Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors while expressing excitement about emerging approaches like BTK degraders, noncovalent BTK inhibitors, and cellular therapies that promise to further advance the field in 2025 and beyond.