Inside the Most Anticipated CLL Abstracts: What to Expect From ASH 2025

With the upcoming 2025 ASH Annual Meeting right around the corner, OncLive® interviewed leading experts in the field of chronic lymphocytic leukemia (CLL) to gain insights into the most anticipated abstracts in the field that will be presented during the meeting.

We gathered exclusive commentary from:

• Catherine C. Coombs, MD, an associate professor in the Division of Hematology-Oncology in the Department of Medicine at the University of California Irvine School of Medicine.
• Seema A. Bhat, MD, a hematologist at The Ohio State University Comprehensive Cancer Center—James, as well as an associate professor in the Department of Internal Medicine in the Division of Hematology at The Ohio State University, both in Columbus

“The abstracts I am most looking forward to are the [phase 3] CLL17 study [NCT04608318] by the German CLL Study Group and the data from 2 phase 3 studies from the BRUIN program: BRUIN CLL-313 [NCT05023980] and BRUIN-CLL-314 [NCT05254743],” Bhat said in a statement to OncLive. “There are also interesting abstracts on newer agents [such as] lisaftoclax [APG-2575], a novel BCL-2 inhibitor, and BTK degraders [such as] bexobrutideg [NX-5948].”

How could data from CLL17 affect the CLL treatment paradigm?

Abstract 1: Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial.

Presentation time: Sunday, December 7, 2:05 pm-2:20 pm EST

Bhat: [This trial] is being presented at the plenary session. It is the first phase 3 trial directly comparing continuous ibrutinib [Imbruvica] to fixed-duration venetoclax [Venclexta]–based regimens in [patients with] untreated CLL. Both fixed-duration arms [venetoclax- obinutuzumab (Gazyva) and venetoclax-ibrutinib] achieved noninferior 3-year progression-free survival [PFS] rates compared with continuous ibrutinib, with venetoclax plus obinutuzumab producing the deepest minimal residual disease [MRD] responses and highest complete response rates. Toxicity patterns differed, with fewer cardiac events in venetoclax plus obinutuzumab or ibrutinib plus venetoclax vs ibrutinib and higher gastrointestinal/hematologic events in the venetoclax-containing arms. The field seems to be moving towards fixed-duration targeted therapy as the preferred frontline option over indefinite BTK inhibition. However, detailed data, especially for [patients with] TP53 aberrations, will be interesting.

Coombs: This is a hugely important study as it is the first trial that directly compares our ‘best’ ways of managing CLL: a continuous BTK inhibitor, ibrutinib, vs 1 of 2 time-limited treatments with novel agents, [venetoclax plus obinutuzumab or ibrutinib plus venetoclax]. The main finding of the trial is that the fixed-duration approaches are noninferior to continuous treatment with a covalent BTK inhibitor in this large trial. Time-limited approaches have a lot of benefits for patients, including less cost both financially and with respect to potential for chronic toxicities, so this is an exciting result. One caveat is that the follow-up is still short [at] only 3 years, so this is a study I will want to continue to follow as the results mature.

What data are expected to be reported from the BRUIN studies?

LBA3: Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients.

Presentation time: Tuesday, December 9, 8:00 am-8:15 am EST

Bhat: BRUIN CLL-313is a late-breaking trial comparing the noncovalent BTK inhibitor pirtobrutinib head-to-head vs chemoimmunotherapy in untreated patients with CLL without 17p deletions [del(17p)]. With 28 months [of] follow-up [for] PFS and overall survival [OS], [the findings] significantly favored pirtobrutinib compared with bendamustine plus rituximab [Rituxan]. This benefit was seen across subgroups. I believe the OS difference, despite crossover at this early follow-up, is important and positions pirtobrutinib well as a front-line choice. The current FDA approval for pirtobrutinib in CLL is as a second-line option post-covalent BTK inhibitors based on data from the [phase 3] BRUIN CLL-321 study [NCT04666038].1

Abstract 683: Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor.

Presentation time: Sunday, December 7, 5:30 pm-5:45 pm EST

Bhat: BRUIN CLL-314 is the first head-to-head randomized comparison between noncovalent and covalent BTK inhibitors in either frontline or relapsed/refractory CLL/small lymphocytic lymphoma [SLL] that showed noninferiority for efficacy (the primary end point) but better tolerability for pirtobrutinib [Jaypirca] vs ibrutinib. Pirtobrutinib had a markedly improved cardiovascular safety profile, including far lower rates of atrial fibrillation and hypertension. This could help define whether noncovalent BTK inhibition becomes preferred (especially given issues like resistance and tolerability). However, it remains to be seen how pirtobrutinib compares with acalabrutinib and zanubrutinib [Brukinsa], especially given data from the [phase 3] ALPINE trial [(NCT03734016) of zanubrutinib vs ibrutinib in relapsed/refractory CLL].

Coombs: The BRUIN CLL-314 trial compared pirtobrutinib with ibrutinib. Pirtobrutinib is a noncovalent BTK inhibitor that received its full FDA approval [on December 3, 2025], for the management of CLL after a covalent BTK inhibitor. BRUIN CLL-314 compared pirtobrutinib with ibrutinib in patients who had not had a BTK inhibitor before: some who were treatment naive and some who had received prior treatments.

Pirtobrutinib was noninferior with respect to overall response rate (the primary end point) compared with ibrutinib and looks much better from a safety standpoint, [with] much less atrial fibrillation. There was a trend toward improved PFS. These results are exciting, though I believe an important unanswered question is whether using the noncovalent BTK inhibitor pirtobrutinib before a covalent BTK inhibitor could limit future treatment options, as there is theoretical potential for cross-resistance. This may not matter for an extremely elderly patient who may not need more than 1 or 2 lines of therapy, but it would be important to consider in younger patients. More follow-up to the trial [regarding patient] response to subsequent therapies would shed light on this question.

What other notable CLL studies are being presented during ASH 2025?

Abstract 5669: Zanubrutinib + venetoclax for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D
Presentation time: Monday, December 8, 6:00 pm-8:00 pm EST

Bhat: Arm D of[the phase 3] SEQUOIA trial [NCT03336333] in treatment-naive CLL/SLL with/without del(17p) or a TP53 mutation, including high-risk patients, is a ‘time-limited/fixed-duration plus maintenance’ regimen of zanubrutinib plus venetoclax followed by zanubrutinib monotherapy. Prior data showed that, at a median follow-up of 31 months, the 24-month PFS [rate] was 92% [95% CI, 85%-96%], with a 59% undetectable MRD [rate] regardless of TP53 mutation status.2 Longer follow-up data at ASH 2025 may help define long-term efficacy and durability.

References

1. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic?utm_medium=email&utm_source=govdelivery
2. Shadman M, Munir T, Ma S, et al. Zanubrutinib and venetoclax for patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma with and without Del(17p)/TP53 mutation: SEQUOIA arm D results. J Clin Oncol. 2025;43(21):2409-2417. doi:10.1200/JCO-25-00758