Experts Analyze 6-Year Zanubrutinib Data Across CLL/SLL Settings

In a Between the Lines program, 2 hematologic oncology specialists, Ian Flinn, MD, PhD, and Danielle Brander, MD, discussed biomarker testing and 6-year survival data exploring novel regimens for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treatment. Specifically, they analyzed frontline zanubrutinib (Brukinsa) in the phase 3 SEQUOIA trial (NCT03336333) among those untreated CLL/SLL and in the phase 3 APLINE trial (NCT03734016) for the relapsed/refractory setting.^1-3

First, they touched upon the importance of biomarker testing for CLL treatment in the community setting, foregrounded by a discussion on defining “high-risk” in the treatment of this disease. Next, they outlined the untreated CLL landscape, before breaking down key efficacy and safety data from SEQUIOA. The experts also highlighted key distinctions between zanubrutinib vs ibrutinib (Imbruvica) for the treatment of patients with relapsed/refractory disease, guided by implications for high- and low-risk populations, as well as the impact of symptom-based progression-free survival (PFS) on treatment selection for this group.

Finally, they spotlighted the impact of ongoing research in this disease space and emphasized a need for more individualized treatment approaches informed by patient characteristics and prior response to treatment.

Flinn is the chief scientific officer of Tennessee Oncology's Greco-Hainsworth Centers for Research. Brander is an assistant professor of medicine in the Hematologic Malignancies and Cellular Therapy Division at Duke Cancer Institute in Durham, North Carolina, and an editorial advisory board member for the journal ONCOLOGY.

Approaching Biomarker Testing in SLL/CLL Groups

Regarding her insights for biomarker testing for this population, Brander began by emphasizing the need to account for a patient’s individual disease, given its heterogeneity. For primary diagnoses, she explained that she uses the FISH test, which serves as a hierarchical testing method that can parse out IGHV mutational status. Furthermore, for those who are experiencing unusual progression post-diagnosis or those identified as high-risk, she turns to a patient’s karyotype, which can identify abnormalities not found with FISH, as well as TP53 mutational testing.

Flinn concurred, noting that although newer therapies are tightening differences in outcomes between patient groups, differences will still emerge, making biomarker testing crucial for these patients.

Additionally, Flinn noted that he utilizes biomarker testing regardless of the viability of treatment used, as it helps important to discern if a patient would benefit from time-limited therapy, with Brander adding that the unpredictability of emergent symptoms makes it easier to parse out potential events prior to start of treatment.

SEQUOIA Analysis: Zanubrutinib in Untreated CLL/SLL

Next, he briefly outlined available approaches in the treatment-naive space, including covalent Bruton’s tyrosine kinase (BTK) inhibitors, such as zanubrutinib and acalabrutinib (Calquence) and the BCL2 inhibitor venetoclax (Venclexta). Regarding their use of chemotherapy for these patients, Flinn expressed that he infrequently uses chemotherapy-based treatment, with Brander concurring.

Turning to the SEQUOIA analysis, Flinn highlighted the design of the trial, with patients needing to have been untreated for their CLL/SLL, symptomatic, and having measurable disease by CT scan, as well as central confirmation of 17p status. Highlighting arms A and B of the trial, he explained that patients without a 17p deletion were randomly assigned to receive zanubrutinib at 160 mg twice daily or bendamustine with rituximab (Rituxan). Flinn further explained that arm C included patients with 17p deletions as single arm, given chemoimmunotherapy was not adequate for this patient group. Additionally, he stated that the key end points were in line with prior studies apart from PFS2 and the patients were balanced between arms.

Highlighting 6-year follow-up data presented at the 2025 American Society of Hematology (ASH) Annual Meeting,he explained that even among patients with high-risk disease, robust PFS outcomes were observed.

“Those patients who were treated with bendamustine/rituximab, their PFS was less than half of what you would expect with zanubrutinib and some of the other analyses were also not as good. None of these patients had as deep a remission as perhaps when you combine with venetoclax,” Flinn explained. “The [PFS] was excellent…just speaking to the mechanism of a BTK inhibitor vs chemotherapy or even venetoclax from a safety standpoint, I didn’t think there was any real new lessons learned here.”

Next, he highlighted key safety considerations of the study, noting the prevalence of COVID-19–related infections, given it was conducted during the pandemic, as well as lower rates of atrial fibrillation and hypertension across all arms. Additionally, he identified key adverse effects (AEs) observed on the trial, including elevated rates of neutropenia with bendamustine/rituximab and elevated rates of hemorrhage with zanubrutinib. Finally, he opined upon the “excellent” outcomes of the agent for patients with 17p deletions, which build upon his increasingly high standards for BTK inhibitors in this patient group.

Brander agreed that zanubrutinib conferred favorable efficacy, adding that the size of the cohort and depth of follow-up was ideal. Furthermore, she agreed that no surprises emerged with the safety profile of the drug. She noted that patients may acquire 17p or high-risk markers in the relapsed/refractory setting, emphasizing a need to monitor patients following receipt of frontline therapy.

Regarding how the data impacts patients starting initial therapy for their CLL/SLL, Brander suggested that patients may feel reassurance given the long-term efficacy of the BTK inhibitor. However, she stressed to keep safety at top of mind for continuous administration of these agents:

“We have longer follow-up from the first-generation BTK inhibitor ibrutinib, but given some of the safety…concerns, many of us––at least for new starts––for patients moving away from that, if we're choosing a course of BTK inhibitor, [we’re] choosing a second-generation [BTK inhibitor],” Brander explained. “Though we said we weren't surprised by the safety profile. It's still important we look at not just the efficacy, but with the second-generation and these options for patients, the long-term follow up is also still helpful, especially on a continuous therapy, to know what to expect in terms of longer-term safety and making sure there's no new signals or new concerns that we didn't see before.”

Monitoring in CLL/SLL: Optimizing Follow-Up Intervals with Continuous Therapy

Flinn pondered the optimal frequency for follow-up, considering his own tendency to see patients with CLL every 3 months, specifically for atrial fibrillation or hypertension. Brander expressed that her practice tends to follow-up with a patient more frequently during the first 6 months of zanubrutinib treatment, to assess initial tolerability and safety outcomes, changing over to a frequency of about every 3 months. She further expressed that for patients at risk for neutropenia, seeing them more frequently or having blood work done between visits may help identify when dose interruptions or modifications may be appropriate.

Next, Brander and Flinn collectively agreed that many of the treatment-related AEs observed with first-generations BTK inhibitors happen less frequently. When treatment-related AEs do emerge, Brander consults dosing guidelines. Particularly with cytopenias, if they present once at a low severity, she will usually not reduce treatment dose.

Evaluating SEQUOIA Arm D: Zanubrutinib and Venetoclax

Brander then discussed arm D of the SEQUOIA study, which evaluated the BTK inhibitor in combination with venetoclax.⁴ Highlighting that the combination was intended to be given as a fixed-duration therapy, with stopping rules in place if certain criteria were met:

“[A]l patients started with zanubrutinib monotherapy for the first 3 cycles, then added in venetoclax, which had the standard for [tumor lysis syndrome] reasons, dose ramp-up, and then that combination…continued for both a minimum amount of time and then until patients met certain undetectable measurable residual disease [MRD] stopping criteria,” she stated. “For example, before meeting the stopping criteria, patients had to [have received] a minimal of 12 cycles of venetoclax and meet the stopping rules, and a minimum of 27 cycles combined of the zanubrutinib both as monotherapy and then the combination, as well as reaching the stopping rules.”

She further highlighted key efficacy data from this arm including a 42-month PFS rate of 87% (95% CI, 78.6%-92.4%). Additionally, the undetectable MRD rate was 38% vs 36% by cycle 27 among those with or without 17p deletions. Additionally, she noted that even though the follow-up beyond fixed duration therapy was brief, most patients appeared to be maintaining undetectable MRD negativity. Finally, she highlighted that the AE profile for the combination was not surprising for this cohort.

Flinn further highlighted that fixed duration therapy may be more feasible in patients who were lower-risk, with those deemed higher risk potentially needing to undergo longer durations of therapy. Moreover, he suggested that applying the treatment regimen as outlined in the protocol may present difficulties, given that it informs when you could stop therapy through MRD testing but doesn’t inform whether you should.

Examining the ALPINE Trial Results: Zanubrutinib Utility in the Relapsed/Refractory Setting

Next, Flinn outlined the results from the ALPINE trial, which directly compared zanubrutinib and ibrutinib among patients with relapsed/refractory CLL/SLL. He explained that the study itself was “amazing,” with zanubrutinib displaying a superiority to ibrutinib in this patient population.

“When it first came out, [it] took a lot of courage to do a straight up comparison between 2 BTK inhibitors…They all had to meet International Workshop on Chronic Lymphocytic Leukemia [iwCLL] criteria for treatment, had measurable disease, and [had to be] unsuitable for fludarabine, cyclophosphamide, and rituximab [FCR],” he said. “The initial results that were presented…[showed] clearly zanubrutinib was superior to ibrutinib. We've recently seen more long-term follow-up on the zanubrutinib arm that’s been presented at ASH [2025]. Keeping with the theme that we’ve seen earlier that all the results held up over time, and we continue to see durable remissions.”

Next, he highlighted key efficacy findings from the trial, showing a median COVID-adjusted PFS of 60.3 months (95% CI, 49.7-not reached [NR]), as well as a 60-month COVID-adjusted PFS rate of 50.4% (95% CI, 44.4%-56.1%). Moreover, the complete response (CR)/CR with incomplete hematologic recovery (Cri) rate was 12.8% (95% CI, 9.4%-17.0%), with a median duration of treatment exposure of 52.5 months (range, 0.39-73.4). Furthermore, 4 patients converted to a CR/CRi after initially experiencing a partial response.

Brander iterated that the efficacy data was unsurprising but highlighted key safety considerations for this patient group with longer follow-up. Mainly, she highlighted how atrial fibrillation seemed to occur at a less frequent rate with zanubrutinib vs other BTK inhibitors, as well as how neutropenia incidence generally appeared to present in the first year of treatment before tapering off in subsequent years. She concluded by highlighting the evolving nature of this population, wondering how patients would respond with zanubrutinib monotherapy in the relapsed/refractory setting after progressing on regimens like fixed duration venetoclax.

Final Thoughts and Closing Remarks

Flinn expressed reassurance that prolonged PFS even among patients with 17p deletions was observed. Moreover, he posited that he doesn’t have the “right” answer for sequencing therapies for these patients but often relies on learning from study outcomes to inform practice.

Brander added that there was an uncertainty around head-to-head trials comparing BTK inhibition. The publication of the ALPINE trial helped to inform management of the disease for her patients, with a hope that subsequent trials will similarly compare BTK inhibitor-containing combination regimens.

References

1. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5
2. Tam C, Munir T, Robal 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
3. Tam CS, Mital A, Weinkove R, et al. Long-term results of patients receiving zanubrutinib in the phase 3 ALPINE study confirm sustained benefit in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia (R/R CLL/SLL): up to 6 years follow-up with the long-term extension (LTE1). Presented at: ASH 2025; December 6-9, 2025; Orlando, Florida. Abstract 2123.
4. 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