Navigating Fixed-Duration vs Continuous Therapy Requires Strategic Sequencing in CLL

The therapeutic landscape in chronic lymphocytic leukemia (CLL) is undergoing a significant transformation, driven by advances in targeted therapies, a deeper understanding of disease biology, and a growing focus on balancing efficacy with patient quality of life and long-term tolerability.

Current strategies reflect 2 dominant paradigms in the frontline setting, according to Joanna M. Rhodes, MD, MSCE: continuous therapy with covalent BTK inhibition vs fixed-duration treatment with venetoclax (Venclexta)-based combinations. Each approach carries distinct implications for efficacy, tolerability, and long-term disease management. At the same time, evolving evidence is informing how these approaches are best sequenced in subsequent lines of therapy, where prior exposure, resistance mechanisms, and cumulative toxicities are increasingly relied upon for individualized treatment decision-making.

“In 2025 we have a lot of treatment options,” Callie C. Coombs, MD, the panel moderator, stated. “But before we treat [our patients], it’s always important to test them to better understand the biology of their disease, as it can inform our selection of therapies in the frontline setting.”

Against this backdrop, leading oncologists Callie C. Coombs, MD, Nicole Lamanna, MD, Samir A. Parikh, MBBS, Joanna M. Rhodes, MD, MSCE, and Mazyar Shadman, MD, MPH, convened for an OncLive Peer Exchange to discuss the evolving management of CLL, as informed by new data from the 2025 European Hematology Association Congress. This included navigating the selection and management of toxicities associated with fixed-duration vs continuous therapies; examining evolving strategies for sequencing BTK inhibitors in relapsed/refractory CLL; and exploring early signals and the potential future role of novel BTK degraders.

First-Line Treatment Paradigms: Fixed-Duration vs Continuous Therapy

Given the absence of head-to-head comparative data demonstrating superior efficacy of continuous treatment with second-generation covalent BTK inhibitors or fixed-duration BCL2 inhibitor–based combinations, selection between these therapeutic paradigms in frontline CLL largely depends on individual patient preferences and clinical factors, experts asserted. Before initiating any treatment for CLL, comprehensive biomarker testing is essential to understand the unique biology of each patient’s disease and to guide appropriate therapeutic selection.

Patient-specific factors also play a crucial role beyond genomic risk stratification. Treatment choice often revolves around patient lifestyle preferences, such as whether they prefer oral medication with regular clinic visits for monitoring or infusion-based therapy with more intensive upfront scheduling. Rhodes elucidated this, framing it as an investment:

“I look at their time as sort of an investment in their treatment,” she explained. “[How I approach a treatment decision often depends on] whether [patients] want to spend a lot of time upfront, investing their time to have fewer visits later on and potentially [reduce adverse] effects from being on active therapy, vs having small amounts of time that they’re investing every couple of weeks in the first few months, and then every 2 to 3 months thereafter [with] the continuous BTK inhibition.”

Specific clinical contraindications also guide treatment choice, Rhodes continued. “Patients that have a history of arrhythmias, including ventricular tachycardia and things of that nature that are very severe––maybe those are patients [whom] I would prefer to have less cardiac toxicity and place on fixed-duration venetoclax plus obinutuzumab [Gazyva].”

Fixed-Duration Regimens

Oral doublet combinations leveraging BTK inhibitors with venetoclax are a common fixed-duration approach. In the phase 2 CAPTIVATE study (NCT02910583), fixed-duration ibrutinib (Imbruvica) plus venetoclax generated durable progression-free survival (PFS) and overall survival (OS) results in patients with treatment-naive CLL/small lymphocytic lymphoma (SLL).1 Data from the final analysis presented during the 2025 American Society of Clinical Oncology Annual Meeting showed that, at a median follow-up of 68.9 months (range, 0.8-83.9), the median PFS and OS were not reached in the pooled population (n = 202). The 5.5-year PFS and OS rates were 66% (95% CI, 58%-72%) and 97% (95% CI, 93%-99%), respectively.

The study also indicated that minimal residual disease (MRD) status at the end of treatment was a key predictor of long-term PFS, regardless of IGHV mutation status. However, outcomes remained suboptimal for the highest-risk genomic subgroups, such as those with TP53 disruption or complex karyotype.

Similarly, updated data from arm D of the phase 3 SEQUOIA trial (NCT03336333) showed that, at a median follow-up of 31.2 months (range, 0.4-58.0), the overall response rate (ORR) with zanubrutinib (Brukinsa) plus venetoclax was 97.4% in treatment-naive patients with CLL/SLL (n = 114).2 Respective ORRs among patients with 17p deletions and/or TP53-mutant disease (n = 66) vs those without 17p deletions and TP53-mutant disease (n = 47) were 98.5% and 95.7%.

Among patients with TP53 abnormalities, the best undetectable MRD (uMRD) rates were comparable to those with normal TP53 wild-type disease, though responses took longer to deepen, Shadman noted.

“[This study] was unique because of the inclusion of those patients with high-risk features. Although the best uMRD rates [were 59% and 60%, respectively] for both the TP53 abnormal and normal gene cohorts, it may take longer for patients to achieve [u]MRD status if they have a TP53 abnormality. What I’m learning from this is that if I want to use an all-oral doublet and avoid using an anti-CD20 antibody, it’s very doable, I just may [have to continue beyond] the 1 year of fixed duration. We need longer follow-up to see how many patients meet the criteria of stopping and what happens in terms of progression after stopping treatment.”

The optimal duration often requires individualization based on genomic risk factors rather than fixed time frames. MRD-guided approaches are accordingly vital for personalizing treatment duration based on individual response assessment, experts agreed.

In the phase 3 FLAIR study (ISRCTN01844152), which evaluated treatment with fixed-duration ibrutinib plus venetoclax, time to uMRD determined treatment duration, ranging from 2 to 6 years.3 At a median follow-up of 62.2 months, FLAIR demonstrated an OS benefit for fixed-duration ibrutinib-venetoclax compared with continuous ibrutinib monotherapy in untreated patients with CLL (HR, 0.41; 95% CI, 0.20-0.83; P < .001). At 2 years, the uMRD rate in bone marrow was 73.1% (95% CI, 67.25%-78.37%) with ibrutinib plus venetoclax vs 60.8% (95% CI, 54.65-66.71) in the chemoimmunotherapy arm and 0% (95% CI, 0.00%-1.39%) in the ibrutinib-only arm. The 5-year estimated OS rates were 95.9% (95% CI, 93.4%-98.4%), 90.5% (95% CI, 86.8%), and 86.5% (95% CI, 82.0%-91.0%) with the doublet, monotherapy, and chemoimmunotherapy, respectively.

“On the one hand, we have fixed-duration therapy for 12 cycles venetoclax and obinutuzumab that [produced] good results in our patients. On the other hand, patients [in FLAIR] may have continued treatment for up to 6 years, and we still saw good results,” Parikh stated. “Because of MRD stopping rules, a lot depends on [patients’] progression criteria and the risk of developing resistance to these agents. All of us would like to prefer to give the shortest duration of therapy to allow for a deep remission [without developing] resistance to those agents so we can potentially retreat them, and then obviously [reduce] long-term toxicity for these [patients]. [FLAIR] shows [that MRD] can be applied in the contemporary practice for CLL.

The fixed-duration, all-oral combination of venetoclax plus acalabrutinib (Calquence) is another potential regimen for previously untreated patients with CLL. Data from the phase 3 AMPLIFY trial (NCT03836261) showed that the median PFS was not calculable with either acalabrutinib plus venetoclax or acalabrutinib plus venetoclax and obinutuzumab vs 47.6 months with chemoimmunotherapy.4 This translated to a 35% reduction in the risk of disease progression or death with the doublet (HR, 0.65; 95% CI, 0.49-0.87; P = .0038) and a 58% reduction in the risk of disease progression or death with the triplet (HR, 0.42; 95% CI, 0.30-0.59; P < .0001).

Although fixed-duration oral doublets may be considered based on prior data, concerns exist regarding infection risks with more intensive triplet regimens, Rhodes stated.

“I think the challenge with a triplet has to do with infection risk. We see it not infrequently in trials. I’m open to it, but it’s a conversation [we must have] with patients. If we’re going to have a patient with a [TP53 abnormality] or high-risk mutations have that chance of doing a fixed-duration therapy, it’s going to be in the frontline.”

A supplemental new drug application seeking the approval of the fixed-duration, all-oral combination of venetoclax plus acalabrutinib in this patient population was submitted to the FDA in July 2025.5

Coombs noted her personal reservations about the regimen: “I personally am not too excited about acalabrutinib plus venetoclax for TP53-mutated [CLL]. I think the duration [of treatment] is probably not long enough.”

Continuous BTK Inhibition

Data from arm C of SEQUOIA trial provides crucial insights into continuous BTK inhibitor therapy outcomes for high-risk patients with TP53 disruption, as it represents the largest prospective frontline trial specifically for this population, Shadman asserted. At a median follow-up of 5 years, zanubrutinib demonstrated an estimated 5-year PFS rate of 72.2% (95% CI, 62.4%-79.8%). Moreover, the ORR was 97.3% in evaluable patients (n = 110), including a complete response (CR)/CR with incomplete hematopoietic recovery rate of 18.2%.6

“It’s nice to see that such a high-risk variable does not seem to be predicting PFS with the current follow-up,” Shadman said.

In the absence of head-to-head trials comparing all available treatment options, indirect comparison analyses are increasingly important. One matching-adjusted indirect comparison study compared continuous zanubrutinib from SEQUOIA with fixed-duration acalabrutinib plus venetoclax from AMPLIFY in treatment-naive patients without 17p deletions or TP53 mutations. At a median follow-up of 43.7 months for patients in SEQUOIA and 41.0 months for those in AMPLIFY, the population-adjusted investigator-assessed PFS favored treatment with zanubrutinib vs fixed-duration acalabrutinib plus venetoclax (HR, 0.26; 95% CI, 0.13-0.54; P < .0003).7

Shadman acknowledged the limitations of such comparisons: “It’s not a clinical trial, [so we don’t know] which [approach] is superior. We now have more treatments than head-to-head trials, and logistically, it’s not feasible to compare every single regimen in a head-to-head trial. These comparisons are basically one piece that we can use in our decision-making process.”

Navigating BTK Inhibitor–Associated Toxicities and Maintaining Tolerability

Managing adverse effects (AEs) is a critical aspect of CLL treatment, particularly given the long treatment durations and common comorbidities in patients.

Recent retrospective analyses provide important insights into the cardiovascular safety differences among BTK inhibitors. A large cohort study conducted by Lamanna and colleagues revealed that approximately 50% of patients had pre-existing hypertension across all first-line treatment groups (zanubrutinib [n = 837], acalabrutinib [n = 5071], and ibrutinib [n = 9409]).8 Moreover, second-generation BTK inhibitors like acalabrutinib and zanubrutinib were associated with lower frequencies of both new-onset and worsening hypertension vs first-generation ibrutinib.

Infectious complications represent another significant safety concern. Contrary to the assumption that infection risk would resolve after fixed-duration therapy, a retrospective analysis revealed that patients who completed venetoclax plus obinutuzumab continued to experience significant infectious complications requiring intravenous IVIG and GCSF and hospitalization for extended periods post-treatment.9 At the 18 month follow-up, infection rates were 10.1% for venetoclax plus obinutuzumab, which was higher than the 5.8% rate seen in patients on continuous BTK inhibitor therapy.

“Patients with CLL/SLL treated with venetoclax plus obinutuzumab had a significantly higher risk of serious infections and an increased usage of intravenous immunoglobulin [IVIG] and granulocyte colony-stimulating factor [GCSF] administration and hospitalization compared with those treated with zanubrutinib,” Lamanna highlighted. “However, they were at higher risk of serious infections even with prophylactic IVIG/GCSF treatment.”

Interestingly, patients on continuous BTK inhibitor therapy demonstrated infection rates similar to those of untreated CLL patients, suggesting that these therapies may not significantly increase baseline infection risk.

“The comparison of patients who aren’t on treatment to those on it does emphasize one of the difficulties we have with clinical trials and attribution, where infections during treatment [are often automatically ascribed] to the therapy,” Coombs noted.

Retreatment and Sequencing Considerations With BTK and BCL2 Inhibition

The increasing use of venetoclax-based fixed-duration therapy in the frontline setting has made retreatment strategies a growing clinical consideration. The phase 2 ReVenG trial (NCT04895436) represents the first systematic study addressing venetoclax retreatment in patients who progressed more than 2 years after completing initial fixed-duration therapy.10 Initial data from the first cohort (n = 25) showed that 15 patients achieved responses with venetoclax plus obinutuzumab, including 3 CR/CRis, 2 partial responses (PRs) with radiographic CRs awaiting biopsy, and 10 PRs. Moreover, 11 of 13 patients with available samples achieved uMRD. Although longer follow-up and larger patient numbers are necessary, these early results offer reassurance when considering fixed-duration approaches, Parikh said.

“[These data] are very reassuring to me as a clinician, and I’m sure to our patients as well. [We can tell patients that we] can do fixation therapy with venetoclax plus obinutuzumab, and if there is evidence of disease progression down the road, there is certainly the ability for us to retreat.”

Sequencing after progression on oral doublet therapies like acalabrutinib-venetoclax or zanubrutinib-venetoclax remains a “data-free zone,” experts noted. Accordingly, decisions in these cases will likely involve extrapolation from venetoclax monotherapy retreatment data and resistance mutation testing to guide therapeutic choices, Rhodes highlighted.

For patients with covalent BTK inhibitor progression, the traditional developmental pathway suggests sequencing from covalent BTK inhibitors to BCL2 inhibitor therapy, followed by noncovalent BTK inhibitors like pirtobrutinib (Jaypirca), experts outlined. This approach is supported by substantial data demonstrating efficacy with venetoclax after BTK inhibitor progression, combined with evidence showing efficacy with pirtobrutinib following venetoclax treatment. However, direct progression from covalent to noncovalent BTK inhibitors like pirtobrutinib represents an alternative strategy, supported by data from the phase 3 BRUIN CLL 321 study (NCT04666038).11

“We really have to go from a covalent BTK inhibitor to either a noncovalent BTK inhibitor or directly to a venetoclax-based treatment approach,” Parikh explained. “Of course, the way these drugs were all developed, the more natural sequencing is from a covalent BTK inhibitor to a BCL2 inhibitor, and then eventually to pirtobrutinib.” He acknowledged the limited comparative data to guide optimal approaches, particularly for patients receiving modern sequencing in earlier treatment lines.

“The data that we do have are not reflective of the patients we’re seeing in our clinic,” Coombs noted. “In all these studies, these patients have had 3 to 4 prior lines of therapy and almost all had prior chemotherapy. My hope is that when we’re using [a noncovalent BTK inhibitor] in the second line where we haven’t seen much data, hopefully things look even better for both options.”

Emerging BTK and BCL2 Combinations

Emerging combination approaches are poised to significantly reshape future sequencing considerations. One notable option is the combination of zanubrutinib and the BCL2 inhibitor sonrotoclax (BGB-11417), Rhodes highlighted. Updated results from the 1/1b BGB-11417-101 trial (NCT04277637) showed that, at a median follow-up of 32.2 months, the ORR was 96.0% in evaluable patients (n = 46), including a CR rate of 52%. The median time to CR/CRi was 10.3 months (range, 5.3-42.4). Notably, 6 of the 7 response-evaluable patients who had previously received BTK inhibition achieved a PR (n = 5) or CR (n = 1). Of the 45 MRD-evaluable patients, 82% achieved uMRD at 10-4, with evidence of responses deepening over time.12

“We’re seeing a lot of these in development now, since they are so effective in CLL and other B-cell malignancies,” Rhodes stated. “From a safety perspective, it looked great. There were no dose-limiting toxicities. We saw a fair amount of neutropenia…but importantly, there were no tumor lysis syndrome events, which is important when we think about a BCL2 inhibitor, since that was one of the major issues with the initial understanding of how potent these medications are. I would say the combination is very effective. It’s short follow-up from a phase 1 study, but…importantly, most patients had uMRD at 10-4, which is an impressive number when we think about these fixed-duration therapies. It’s going to be interesting to see how these data mature.”

This combination is currently being evaluated in comparison with venetoclax plus obinutuzumab in patients with treatment-naive CLL in the phase 3 CELESTIAL-TNCLL study (NCT06073821), which has completed accrual, Rhodes concluded.13

References

1. Ghia P, Barr PM, Allan, JN, et al. Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. J Clin Oncol. 2025,43(suppl 16):7036. doi:10.1200/JCO.2025.43.16_suppl.7036
2. Shadman M, Munir T, Ma S, et al. Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: results in SEQUOIA arm D. J Clin Oncol. 2025;43(suppl 16):7009. doi:10.1200/JCO.2025.43.16_suppl.7009
3. Munir T, Girvan S, Cairns D, et al. Ibrutinib plus venetoclax with MRD-guided duration of treatment is superior to both continuous ibrutinib monotherapy and FCR for previously untreated CLL: report of the phase III UK FLAIR study. N Engl J Med. Published online June 15, 2025. doi: 10.1056/NEJMoa2504341
4. Fixed-duration Calquence-based regimens approved in EU for patients with chronic lymphocytic leukaemia in the 1st-line setting. News release. AstraZeneca. June 6, 2025. Accessed August 22, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/fixed-duration-calquence-approved-in-eu-for-1l-cll.html
5. AbbVie submits for U.S. FDA approval of combination treatment of Venclexta (venetoclax) and acalabrutinib for previously untreated patients with chronic lymphocytic leukemia (CLL). News release. AbbVie. July 29, 2025. Accessed August 22, 2025. https://news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL
6. Tam CSL, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1565.
7. Munir T, Yang K, Xu S, et al. Comparative efficacy of zanubrutinib (ZANU) versus fixed-duration acalabrutinib plus venetoclax (AV) for first-line treatment of chronic lymphocytic leukemia (CLL): a matching-adjusted indirect comparison (MAIC). J Clin Oncol. 2025;43(suppl 16):e19032. doi:10.1200/JCO.2025.43.16_suppl.e19032
8. Ali AK, Zhou L, Colasurdo J, et al. Risk of hypertension in patients newly diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and treated with covalent Bruton tyrosine kinase inhibitors (cBTKi): a real-world study. Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PF588.
9. Lamanna N, Colasurdo J, Zhou L, et al. Serious infections in patients with CLL/SLL treated with combination venetoclax and obinutuzumab compared with those treated with zanubrutinib: a real-world study. Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1571.
10. Davids M, Robrecht S, Tausch E, et al. Preliminary results of the ongoing multicenter, phase 2 study of retreatment with venetoclax plus obinutuzumab (ReVenG) in patients with recurrent chronic lymphocytic leukemia (CLL). Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PF575.
11. Sharman JP, Munir T, Grosicki S, 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
12. Cheah CY, Tam CS, Anderson MA, et al. Updated results from the phase 1 study of sonrotoclax (BGB-11417), a novel BCL2 inhibitor, in combination with zanubrutinib for relapsed/refractory CLL/SLL demonstrate deep and durable responses. Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract S159.
13. Shadman M, Kater AP, Woyach, JA, et al. CELESTIAL-TNCLL: an ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-naïve (TN) CLL. J Clin Oncol. 2024;42(16):TPS7087. doi:10.1200/JCO.2024.42.16_suppl.TPS7087