Fixed-Duration Venetoclax Regimens Yield Noninferior CLL PFS to Ibrutinib

Fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) or ibrutinib (Imbruvica) yielded noninferior progression-free survival (PFS) compared with continuous ibrutinib monotherapy in treatment-naive patients with chronic lymphocytic leukemia (CLL), according to prospective data from the phase 3 CLL17 trial (NCT04608318) presented in a press briefing at the 2025 American Society of Hematology Annual Meeting and Exposition.¹

Findings showed that the 3-year PFS rates were 81.1% with fixed-duration venetoclax/obinutuzumab, 79.4% with fixed-duration venetoclax/ibrutinib, and 81.0% with continuous ibrutinib. The HR for venetoclax/obinutuzumab vs ibrutinib was 0.87 (type-I-error adjusted 98.3% CI, 0.54-1.41) and 0.84 for venetoclax/ibrutinib vs ibrutinib (type-I-error adjusted 98.0% CI, 0.53-1.32).

Three-year overall survival rates across the 3 arms were 91.5%, 96.0%, and 95.7%, respectively.

“Fixed-duration treatments with both venetoclax/obinutuzumab and venetoclax/ibrutinib, when administered over 1 year, are equally effective to continuous indefinite therapy. We see more deep remissions with the combination therapies,” lead study author Othman Al-Sawaf, MD, hematologist and medical oncologist in the Department of Hematology and Oncology of the University Hospital of Cologne in Cologne, Germany said in an oral presentation at the press briefing. “For us, the findings mean that, nowadays, most patients with previously untreated CLL should be considered for a fixed-duration treatment to enable these treatment-free intervals. Of course, longer follow-up will substantiate our findings further.”

Data also showed that the objective response rates (ORRs) in the venetoclax/obinutuzumab, venetoclax/ibrutinib, and ibrutinib arms were 84.2%, 88.5%, and 86.0%, respectively. In the venetoclax/obinutuzumab arm, this comprised a 32.7% partial response (PR) rate and a 51.5% complete response (CR) rate; in the venetoclax/ibrutinib arm, these rates were 42.3% and 46.2%. In the continuous ibrutinib arm, 77.7% of patients had PRs, and 8.3% of patients had CRs.

“Response to therapy was very high … but only the combination therapies were able to produce meaningful CRs, which we do not see with single-agent therapy,” Al-Sawaf said.

Fixed-duration targeted therapy is defined as time-limited treatment that is generally 12 to 15 months and combines venetoclax with obinutuzumab or a BTK inhibitor. The goal, Al-Sawaf said, is to achieve deep remissions and allow patients a treatment-free interval.

Continuous therapy involves long-term daily treatment with a BTK inhibitor, which is continued until disease progression or intolerance.

In the open-label, multicenter, phase 3 CLL17 trial, investigators evaluated continuous ibrutinib compared with venetoclax plus obinutuzumab and ibrutinib plus venetoclax in 909 patients with previously untreated CLL. In the continuous ibrutinib arm, the oral BTK inhibitor was given at 420 mg daily until disease progression or intolerance. In the venetoclax/obinutuzumab arm, venetoclax was given orally at 400 mg daily starting on day 22 of cycle 1 until day 28 in cycle 12, while obinutuzumab was given at 1000 mg intravenously starting on days 1, 8, and 15 of cycle 1, and day 1 on cycles 2 through 6. In the ibrutinib/venetoclax arm, ibrutinib was given at 420 mg daily on day 1 of cycle 1 through cycle 15 in 28-day cycles, and venetoclax was given at 400 mg daily on day 1 of cycle 4 through cycle 15 in 28-day cycles.

Patients, who were enrolled from February 2021 to November 2022, were randomly assigned 1:1:1 to each of the 3 arms. Those with 17p deletion (del17p) and TP53 mutations were permitted, as well as both fit and unfit patients.

The primary end point was PFS. The median observation time was 34.2 months (IQR, 30.3-39.3). Specifically, investigators independently tested the PFS noninferiority of fixed-duration venetoclax/obinutuzumab vs continuous ibrutinib and fixed-duration venetoclax/ibrutinib vs continuous ibrutinib.

Baseline characteristics in the venetoclax/obinutuzumab (n = 303), venetoclax/ibrutinib (n = 305), and ibrutinib (n = 301) arms showed that 71.3%, 66.9%, and 65.1% of patients were male; the median age was 66 years (range, 40-90), 66 years (range, 37-83), and 65 years (range, 34-85); and 51.2%, 51.8%, and 48.5% were 65 years or older. The median CIRS across the 3 arms was 3 (range, 0-18), and 44.5%, 44.6%, and 43.2% of patients across the 3 arms were deemed unfit. A total of 56.4%, 56.4%, and 56.8% of patients had unmutated IGHV; 7.6%, 8.2%, and 7.0% had TP53 mutations/del17p; and 5.6%, 6.9%, and 7.0% of patients had very high CLL-International Prognostic Index. The complex karyotype was 3 or higher in 15.8%, 20.0%, and 21.9% in the venetoclax/obinutuzumab, venetoclax/ibrutinib, and ibrutinib arms, respectively.

Additional response data showed that undetectable minimal residual disease rates below 10^-4 in the peripheral blood and bone marrow, respectively, were 73.3% and 62% with venetoclax/obinutuzumab, 47.2% and 40% with venetoclax/ibrutinib, and 0% each with ibrutinib.

Regarding safety, any-grade adverse events occurring in at least 15% of patients in the venetoclax/obinutuzumab, venetoclax/ibrutinib, and ibrutinib arms, respectively, were blood and lymphatic system disorders (59.0%; 42.9%; 28.5%), gastrointestinal disorders (59.7%; 74.3%; 63.4%), diarrhea (27.1%; 47.2%; 34.9%), fatigue (25.4%; 25.4%; 19.1%), infections and infestations (76.3%; 80.2%; 79.9%), metabolism and nutrition disorders (30.5%; 24.8%; 24.2%), musculoskeletal and connective tissue disorders (37.6%; 49.2%; 56.7%), nervous system disorders (34.9%; 37.0%; 34.6%), respiratory/thoracic/mediastinal disorders (27.8%; 32.7%; 37.6%), skin and subcutaneous tissue disorders (29.5%; 55.8; 55.7%), and vascular disorders (20.3%; 33.7%; 41.6%).

Grade 3 to 5 infections of interest in the venetoclax/obinutuzumab, venetoclax/ibrutinib, and ibrutinib arms, respectively, included infections and infestations (34.9%; 25.1%; 24.8%), comprising COVID-19 (15.9%; 8.6%; 6.7%) and pneumonia (9.8%; 7.3%; 7.4%). Data also showed grade 3 to 5 cardiac disorders (4.4%; 7.3%; and 11.4%), including atrial fibrillation (0.7%; 3.6%; 4.0%).

The FDA approved venetoclax in combination with obinutuzumab as a fixed-duration regimen in May 2019 for the treatment of patients with previously untreated CLL or small lymphocytic leukemia based on findings from the CLL14 trial (NCT02242942).²

Disclosures: Al-Sawaf cited consultancy and research funding from AbbVie, Janssen, Roche, BeiGene, Lilly, and AstraZeneca.

References

1. 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(supplement 1):1. doi:10.1182/blood-2025-1.
2. FDA approves new fixed-duration treatment option for previously untreated chronic lymphocytic leukemia. News release. Genentech. May 15, 2019. Accessed December 6, 2025. https://tinyurl.com/ywdmz7v4