Expanding Options and Long-Term Data Reshape Frontline and Emerging CLL Treatment Strategies

Although targeted therapy has transformed the management of chronic lymphocytic leukemia (CLL), fundamental questions persist about how best to select among frontline regimens based on Bruton tyrosine kinase (BTK) inhibitors or venetoclax (Venclexta), how to sequence therapies across the disease course, and how to position a growing pipeline of next-generation agents, according to a panel of experts.¹

During a recent OncLive^® Peer Exchange moderated by Marc S. Hoffmann, MD, of the University of Kansas Cancer Center in Kansas City, Missouri, CLL specialists discussed evolving evidence and practical decision-making across the disease continuum, spanning frontline therapy and long-term efficacy data to combination strategies, real-world comparisons, and emerging agents.

How is frontline treatment selection in CLL being individualized?

First-line therapy selection has “gotten more complicated, but in a good way for our patients,” Catherine C. Coombs, MD, said during the discussion. She framed initial decisions around whether a patient desires continuous, treat-to-progression therapy with a covalent BTK inhibitor or values time off therapy with a fixed-duration regimen.

“I firmly believe there’s not a one-size-fits-all approach to managing CLL,” Coombs said, citing comorbidity status, concomitant medications, patient preference, and cytogenetics as factors she weighs.

Absolute contraindications are rare, she noted, although severe cardiac comorbidities, ventricular arrhythmias, or recurrent bleeding steer her away from the use of BTK inhibitors, whereas severe renal impairment complicates venetoclax use.

Patient preference is often the most important factor, Coombs added, also explaining that age-based assumptions do not always hold. Sameer A. Parikh, MBBS, added disease bulk as another consideration, pointing to an analysis from the phase 3 CLL14 trial (NCT02242942), in which patients with bulky disease (lymph nodes ≥ 5 cm) experienced inferior progression-free survival (PFS) with venetoclax plus obinutuzumab (Gazyva).²

“If there is bulky disease, potentially considering acalabrutinib, zanubrutinib, or any BTK inhibitor–based approach might be another consideration to think about,” Parikh said.

What do the CLL14 and SEQUOIA long-term follow-up data reveal about durability and high-risk disease?

Regarding the 9-year CLL14 update, Parikh framed these findings as one of the most important long-term data sets. The analysis, presented at the European Hematology Association (EHA) 2026 Congress, showed that fixed-duration venetoclax plus obinutuzumab (n = 216) maintained a median PFS advantage over chlorambucil plus obinutuzumab (n = 216), at 76.6 months with venetoclax/obinutuzumab vs 37.9 months with chlorambucil/obinutuzumab (HR, 0.50; 95% CI, 0.39-0.63; P < .001).³ Strikingly, patients with mutated IGHV achieved a median PFS of 104.9 months with venetoclax/obinutuzumab vs 64.7 months in those with unmutated IGHV treated with the same combination (HR, 2.74; 95% CI, 1.85-4.06; P < .001).

“This might be the only treatment that they require for their CLL,” Parikh said of favorable-risk, older patients. He emphasized that time to next treatment extends well beyond PFS if asymptomatic progression does not mandate immediate therapy.

For patients with mutated IGHV, she said the data make time-limited therapy “a no-brainer” for those willing to commit to the frequent early visits. The panel also cautioned against overreliance on early minimal residual disease (MRD) readouts, as patients with IGHV-mutated disease may remain well even after losing undetectable MRD status, and the discussion emphasized that there is no substitute for mature PFS data in large studies.

Mazyar Shadman, MD, MPH, reviewed 6-year follow-up findings from the phase 3 SEQUOIA trial (NCT03336333) evaluating zanubrutinib (Brukinsa) monotherapy in patients with treatment-naive CLL. The data maintained efficacy improvements vs bendamustine plus rituximab (Rituxan; BR), regardless of 17p deletion (del[17p]) status.⁴ Notably, PFS outcomes were similar for patients treated with zanubrutinib, irrespective of IGHV mutation status (HR, 1.49; P = .14). For patients harboring del(17p) in arm C, where all patients received zanubrutinib, outcomes were again similar based on IGHV mutation status (HR, 1.21; P = .0585).

Shadman also drew attention to subsequent therapy data and improvements in time to second progression with zanubrutinib, noting that most patients in the BR arm received novel agents after progression, including approximately 70% to 80% of patients who received a subsequent BTK inhibitor.

“The old argument I used to hear was, ‘Well, I’ll give BR now and rescue later,’ but it looks like that may be inferior to just starting with your best agents,” Hoffmann said.

Andrew H. Lipsky, MD, argued for disaggregating the biomarkers that are often lumped together as high risk. TP53 aberrations, including del(17p) and TP53 mutations, are the highest-risk lesions and adversely affect outcomes across therapies, but the magnitude depends on strategy, he explained.

With fixed-duration venetoclax plus obinutuzumab in CLL14, patients harboring TP53-aberrant disease (n = 25) experienced a median PFS of 49.0 months vs 79.2 months for those without these aberrations (n = 24).³ Citing SEQUOIA cross-arm curves, Lipsky also noted a gap between patients with TP53 wild-type and TP53-aberrant disease.⁴

“In my practice, BTK inhibitor monotherapy, outside the context of a clinical trial, is the preferred option for patients with TP53-aberrant disease,” Lipsky said. “Cycling back to IGHV-unmutated status, this is also an adverse, predictive biomarker in certain circumstances. [However], when thinking about IGHV mutation status in the context of either in indefinite therapy with a BTK inhibitor or a time-limited treatment, the magnitude of those discrepancies is somewhat different.”

Coombs underscored a key practical distinction, noting that patients progressing on a continuous BTK inhibitor have little gap between progression and needing the next therapy and cannot be rechallenged with another covalent agent, whereas fixed-duration venetoclax-based therapy could allow for retreatment. She still favors zanubrutinib as frontline therapy for most patients harboring TP53 aberrations when the goal is the longest first remission, but she remains open to time-limited therapy for those who prioritize time off treatment.

How are fixed-duration and BTK inhibitor/BCL-2 inhibitor combinations reshaping frontline care?

Parikh pointed to the phase 3 CLL17 trial (NCT04608318) as a critical recent readout. This study compared continuous ibrutinib (Imbruvica), fixed-duration ibrutinib plus venetoclax, and fixed-duration venetoclax plus obinutuzumab.⁵ Findings presented at the 2025 American Society of Hematology Annual Meeting and Exposition showed that the 3-year PFS rate was 81.1% with fixed-duration venetoclax/obinutuzumab (n = 303), 79.4% with fixed-duration venetoclax/ibrutinib (n = 305), and 81.0% with continuous ibrutinib (n = 301; HR for venetoclax/obinutuzumab vs ibrutinib, 0.87; type-I-error adjusted 98.3% CI, 0.54-1.41; HR for venetoclax/ibrutinib vs ibrutinib, 0.84; type-I-error adjusted 98.0% CI, 0.53-1.32).

“This gives you great latitude to pick fixed-duration therapy,” he said. “It allows us to confidently state to our patients, at least with the current follow-up duration, that if you pick venetoclax plus obinutuzumab or venetoclax plus ibrutinib—which actually translates into acalabrutinib plus venetoclax for all intents and purposes in the United States—there should ideally not be a PFS decrease compared [with] continuous BTK inhibitor–based treatment.”

Shadman said that with acalabrutinib plus venetoclax, as studied in the phase 3 AMPLIFY trial (NCT03836261) that supported its February 2026 FDA approval as a first-line therapy for patients with CLL,⁶ the BTK inhibitor/BCL-2 inhibitor combination provides more flexibility on when to initiate the venetoclax compared with a regimen such as venetoclax plus obinutuzumab. When initiating venetoclax alongside acalabrutinib, he bases this timing on tumor lysis syndrome risk and patient readiness.

On triplets, Parikh explained he reserves venetoclax, acalabrutinib, and obinutuzumab for younger, fit patients with IGHV-unmutated disease, citing higher infection-related deaths in AMPLIFY and in the phase 3 Alliance A041702 trial (NCT03737981), which tested an ibrutinib-based triplet.

“A patient with CLL dying of a therapy-related complication is a fundamentally unacceptable outcome from my standpoint,” Hoffman said. “This is a disease where the vast majority of patients are going to die of other things, so if [our treatment leads to death], that’s an unacceptable outcome.”

Lipsky said he generally avoids triplets, noting that when adding a third agent such as obinutuzumab, for example, it can be difficult to weigh an added PFS benefit vs additional toxicity. He then expressed hope that combinations, such as the next-generation BCL-2 inhibitor sonrotoclax (Beqalzi) plus zanubrutinib, could obviate the need to add obinutuzumab, even in the highest-risk settings.

Real-world and indirect analyses are increasingly informing frontline treatment choices, Shadman said, framing them as valuable complements to randomized trials for questions such as choosing among second-generation BTK inhibitors. In an unanchored matching-adjusted indirect comparison presented at EHA 2026, findings showed that zanubrutinib monotherapy was associated with improved PFS and numerically favorable overall survival (OS) vs ibrutinib in patients with treatment-naive CLL.⁷

“There seems to be a signal for better efficacy for zanubrutinib, and that was [showed] in this study,” Shadman said.

Which emerging agents and combinations could change the treatment landscape?

Shadman called sonrotoclax a potential practice-changer in CLL management. The agent received its first FDA approval in May 2026 as monotherapy for the treatment of adult patients with relapsed/refractory mantle cell lymphoma.⁸

In the phase 1/1b BGB-11417-101 trial (NCT04277637), frontline sonrotoclax plus zanubrutinib produced an ORR of 100% among efficacy-evaluable patients (n = 135), including complete response rates of 51.0% for a 160-mg dose of sonrotoclax (n = 51) and 59.5% for a 320-mg dose (n = 84).⁹ Responses were consistent regardless of IGHV or TP53 status.

Sonrotoclax plus zanubrutinib is now being tested against 2 fixed-duration standards: venetoclax plus obinutuzumab in the phase 3 CELESTIAL-TNCLL trial (NCT06073821), which is fully accrued, and acalabrutinib plus venetoclax in the phase 3 CELESTIAL-TNCLL-2 trial (NCT07277231), which is accruing.

Lipsky offered a framework for interpreting those eventual readouts. Against venetoclax plus obinutuzumab, comparable MRD outcomes would be notable because obinutuzumab “does a lot of the heavy lifting,” and the oral doublet’s ease of administration lowers the bar. Against acalabrutinib plus venetoclax, he would scrutinize the numbers more closely, wanting the phase 1 signal to hold.

On BTK degraders, Parikh explained the rationale of destroying the BTK protein rather than inhibiting it, enabling activity beyond covalent and noncovalent BTK inhibitor failure. BTK degraders under development and being evaluated in clinical trials have driven responses as single agents in heavily pretreated patients, although more mature data will provide key information regarding durability. Shadman stressed that longer follow-up is needed to characterize safety, given the field’s low threshold for harm, and saw potential to move degraders into earlier lines.

On resistance testing, Lipsky said he orders it to build a knowledge base but does not yet act on it, favoring actionable benchmarks over resistance panels. Coombs voiced a caution about moving the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) earlier because of possible shared resistance pathways, contrasting it with venetoclax, which she moves freely relative to covalent BTK inhibitors.

Shadman closed by calling for trial end points that capture efficacy, safety, and quality of life together, arguing that traditional PFS and OS “may not be relevant to our day-to-day discussions” when comparing continuous and fixed-duration strategies. Parikh noted that CLL outcomes increasingly approach those of an age- and sex-matched general population, shifting the focus toward helping patients live “not only as long as we’d like for them to but also as well [as we would like them to].”

About the Faculty

Marc S. Hoffmann, MD, is an associate professor of hematologic malignancies and cellular therapeutics, medical director of lean and quality improvement, and medical director of the Lymphoma Program at the University of Kansas Cancer Center in Kansas City, Missouri.

Catherine C. Coombs, MD, is an associate professor in the Division of Hematology/Oncology in the Department of Medicine at the University of California, Irvine.

Andrew H. Lipsky, MD, is an assistant professor of medicine at Columbia University Medical Center in New York, New York.

Sameer A. Parikh, MBBS, is an associate professor of medicine and a consultant in the Division of Hematology at Mayo Clinic in Rochester, Minnesota.

Mazyar Shadman, MD, MPH, is a professor in the Division of Clinical Research and deputy chief medical officer at Fred Hutch Cancer Center, where he also serves as medical director of cellular immunotherapy at the Bezos Family Immunotherapy Clinic. He is a member of the Immunotherapy Integrated Research Center and an affiliate investigator in the Division of Translational Science and Therapeutics at Fred Hutch, as well as a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

References

1. Hoffmann MS, Coombs CC, Lipsky AH, Parikh SA, Shadman M. Novel treatment approaches in CLL. OncLive Peer Exchange. 2026
2. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-1935. doi:10.1182/blood.2024024631
3. Fischer K, Al-Sawaf O, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: final analysis of the randomized phase 3 CLL14 study. Presented at: EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S146.
4. Tam C, Munir T, Robak T, et al. Sustained efficacy of zanubrutinib (zanu) vs bendamustine + rituximab (BR) in treatment (tx)-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients (pts) with del(17p): 6-year follow-up in the phase 3 SEQUOIA study. Blood. 2025;146(suppl 1):2129. doi:10.1182/blood-2025-2129
5. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: results from the randomized CLL17 trial. Blood. 2025;146(suppl 1):1. doi:10.1182/blood-2025-1
6. Calquence plus venetoclax approved in the US as first all-oral, fixed-duration combination for patients with chronic lymphocytic leukaemia in the 1st-line setting. News release. AstraZeneca. February 20, 2026. Accessed August 4, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/fixed-duration-calquence-combo-approved-in-us.html
7. Munir T, Jurczak W, Mohseninejad L, et al. Zanubrutinib vs ibrutinib in treatment-naive chronic lymphocytic leukemia: implications for interpreting fixed-duration outcomes from CLL17. Presented at: EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PS1718.
8. FDA grants accelerated approval to sonrotoclax for relapsed or refractory mantle cell lymphoma. FDA. May 13, 2026. Accessed August 4, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sonrotoclax-relapsed-or-refractory-mantle-cell-lymphoma
9. Tam CSL, Opat S, Lasica M, et al. Effect of first-line treatment of CLL/SLL with the all-oral combination of sonrotoclax (sonro) and zanubrutinib (zanu) on minimal residual disease (uMRD) rates, including in patients with del(17p)/TP53. J Clin Oncol. 2026;44(suppl 16):7043. doi:10.1200/JCO.2026.44.16_suppl.7043