Fixed-duration regimens of venetoclax combined with obinutuzumab (VO) or ibrutinib (VI) show efficacy similar to that of continuous ibrutinib monotherapy in the first-line treatment of chronic lymphocytic leukemia (CLL), suggesting important benefits of treatment-free intervals for the typically older population of patients with CLL.

“This is the first phase 3 trial comparing the main paradigms of continuous vs fixed-duration targeted therapy of CLL,” said first author Othman Al-Sawaf, MD, PhD, in a press briefing for the study, at the American Society of Hematology (ASH) 2025 Annual Meeting.

“Many patients can achieve excellent outcomes without years of continuous Bruton tyrosine kinase (BTK) inhibitor treatment, and treatment-free intervals can now be achieved for most patients with CLL,” he said.

While BTK inhibitor monotherapy can promote durable remissions in the first-line treatment of CLL, the treatment must be administered on a continuous basis until disease progression, which can result in years of treatment and hence long-term exposure to toxicities as well as well-established cardiovascular risks.

As an alternative, the combination of a backbone of B-cell lymphoma 2 (BCL2) inhibitor venetoclax, along with a CD20 antibody such as obinutuzumab or BTK inhibitor ibrutinib, shows deeper effects and can therefore be administered on a more preferable fixed-duration basis, typically just over a year, thus providing a break from prolonged drug exposure and the risk of developing therapy resistance, not to mention costs.

“The aim here is to combine and produce deep remissions and thereby allow patients to get off therapy while still remaining in remission,” Al-Sawaf explained.

The median age of patients with CLL is between 70 and 72 years, and individuals in this age range are often taking multiple medications. Therefore, concerns about the risk of interactions with other drugs for patients with CLL makes the option to reduce treatment duration highly desirable.

CLL17 Trial

A key question, however, has been how the two approaches compare in the prevention of relapse because the efficacy of both was established primarily in their comparisons against chemotherapy.

To fill that knowledge gap, Al-Sawaf and colleagues conducted the international, prospective, phase 3 CLL17 trial, enrolling 909 patients with previously untreated CLL at 174 sites in 13 countries, between February 2021 and November 2022.

The patients were randomized to treatment with either continuous ibrutinib until disease progression (n = 301), fixed-duration treatment with VO (n = 303), or VI (n = 305), with the latter two administered over approximately 1 year.

The patients had a median age of 66 years; 67.8% were men, and their median Cumulative Illness Rating Scale (CIRS) score was 3 (range 0-18 on a scale of 1 to 56, with higher scores indicative of greater impairment in organ-system function).

Results from the prespecified interim analysis of the trial, reflecting a median follow-up of 34.2 months, showed noninferiority in the primary endpoint of progression-free survival between the three approaches, with the endpoint achieved in 81.0% of patients in the ibrutinib monotherapy group, 81.1% of patients in the VO group (hazard ratio [HR], 0.87 vs ibrutinib monotherapy), and 79.4% in the VO group (HR, 0.84 vs ibrutinib monotherapy ).

For the secondary endpoint of minimal residual disease (MRD) negativity at the end of treatment, the rate was significantly higher in the VO group (73.3%) compared with the VI group (47.2%), and the ibrutinib monotherapy group (0%).

Complete responses were observed among 51.5% of the patients in the VO group, 46.2% of those in the VI group, and just 8.3% of those in the ibrutinib group (P <.0001 for both comparisons).

There were also no significant differences in the three groups in terms of overall survival (91.5%, 96.0%, and 95.7%, respectively).

High-Risk Patient Subsets

Of note, 44.1% of the patients in the study, overall, were considered to be unfit, based on having CIRS scores > 6 or a creatinine clearance of < 70 mL/min, or both, and those patients showed the greatest benefit from the fixed-duration therapy, with 3-year progression-free survival rates of 70.4% with ibrutinib monotherapy compared with 79.6% with VO (HR, 0.58 vs ibrutinib) and 74.9% with VI (HR, 0.66 vs ibrutinib).

There were no significant differences in PFS rates between the treatment groups of fit patients.

Approximately 56% of patients in each group had unmutated immunoglobulin heavy chain variable (IGHV), a significant risk factor in CLL, and among them, the 3-year progression-free survival was similar across the treatment groups (75.8% in the VO group, 79.7% in the ibrutinib monotherapy group, and 78.9% in the VI group).

“Overall, in looking at the hazard ratios, we can conclude for patients with unmutated IGHV, that fixed-duration options are noninferior to continuous treatments,” Al-Sawaf said.

The corresponding progression-free survival rates among patients with also higher-risk 17p deletion or TP53 mutations were 62% in the VO group, 79.4% in the ibrutinib monotherapy group, and 69% in the VI group. But Al-Sawaf cautioned that the relatively low numbers of those patients (< 8% of study participants) limits conclusions.

“Ongoing follow-up and correlative analyses are needed to clarify whether persons with high-risk biologic features such as TP53 alterations or complex karyotypes derive greater benefit from venetoclax-ibrutinib than from venetoclax-obinutuzumab or from extended-duration treatment,” he said.

Infections

Consistent with the known risks for infection in CLL, nearly 80% of patients in the study had at least one infection, which was partly high, because the study took place during the COVID pandemic, however, “there were many infections beyond COVID,” Al-Sawaf noted.

The infection rates were similar between the three treatment groups, however, severe and fatal infection rates were more common in the VO group (12 deaths due to infection vs seven in the VI group and three in the ibrutinib monotherapy group).

Cytopenias were more common in the combination groups, with more than half of the patients in the VO group (52.5%) and 36.3% in the VI group experiencing neutropenia.

Cardiac toxicities were notable in the ibrutinib monotherapy group, consistent with the drug’s known risks, with 16.8% of those patients experiencing atrial fibrillation compared with 3.7% with VO and 12.5% with VI.

“The safety comparisons highlight that infections remain a major challenge in CLL, and that particularly in the context of anti-CD20 antibodies, we need to be especially cautious about the risk of severe infections,” Al-Sawaf added.

Newer BTK Choices?

The more recent availability in the US of newer BTK inhibitors acalabrutinib and zanubrutinib have further improved cardiovascular safety while providing similar and in some regards greater efficacy as ibrutinib, Al-Sawaf said. But evidence is still lacking on whether the results from the CLL17 trial may also apply to those agents, he added.

“We definitely need to be careful with the extrapolation of these results to other agents,” he said in response to a question on the issue from the audience.

“This study focuses on ibrutinib, and importantly, the findings that we observe and the efficacy outcomes that we see are very similar to what we have also seen in the first-line studies of acalabrutinib and zanubrutinib.”

However, so far, all of the improvements of those drugs have been observed in the relapse setting, he noted.

“In the first-line setting, we don’t have data yet on the superiority of those over ibrutinib.”

Fixed-Duration ‘Should be Preferred’

Overall, “we can now conclude that fixed-duration therapies are indeed noninferior to continuous BTK inhibition with respect to progression-free survival, but ongoing follow-up will help us clarify whether there are distinct subgroups that have different efficacy outcomes,” Al-Sawaf said.

However, “for patients, these findings mean that fixed-duration treatment options should be preferred over continuous therapies in most contexts and for most patients with CLL.”

In an introduction of the study at the meeting, Kerry A. Rogers, MD, an associate professor in the Division of Hematologyat The Ohio State University, in Columbus, Ohio, underscored that “it is critical to understand differences in the adverse event profiles of these regimens with a randomized comparison.”

“The [CLL17] trial begins to answer some of these questions as a randomized phase 3 study comparing the three types of regimens,” she said. “The initial results are already very informative and I’m confident that extended follow-up of this study over the next several years will continue to add to what we know about these regimens.”

Further commenting to Medscape Medical News, Wendy Stock, MD, who is the co-leader of the Clinical and Experimental Therapeutics research program at the University of Chicago, Chicago, added that “the take-home message in this well-done study [is that] the fixed duration treatment arms were noninferior, and this is exciting since this could be a big win for patient quality of life with fixed duration treatment and less long term financial toxicity.”

This study was simultaneously published in The New England Journal of Medicine.

Al-Sawaf’s disclosures included relationships with AbbVie, Janssen, Roche, BeiGene, Genmab, Lilly, and AstraZeneca. Rogers’ disclosures included consulting and/or other relationships with AbbVie Inc, Genentech, Novartis; Alpine Immune Science; BeiGene Ltd, Janssen Biotech Inc, and Loxo Oncology Inc. Stock had no disclosures to report.