In CLL, Fixed-Duration Venetoclax Combos Are Equal to Continuous Ibrutinib in Head-to-Head Comparison

Fixed-duration regimens featuring the BCL2-inhibitor venetoclax (Venclexta; AbbVie/Genentech) offered patients with chronic lymphocytic leukemia (CLL) the same clinical benefit as an open-ended treatment with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica; Pharmacyclics/Janssen) in the first head-to-head trial comparing the 2 treatment strategies.

Results from CLL17 (NCT04608318), an investigator-initiated trial led by the University of Cologne in Germany, were shared early Saturday at a press conference at the 67th American Society of Hematology in Orlando, Florida, prior their public presentation in Sunday’s plenary session.

Othman Al-Sawaf, MD, PhD | Image: LinkedIn

The findings, presented by Othman Al-Sawaf, MD, PhD, of University Hospital of Cologne, showed that after 3 years, patients treated with fixed-duration regimens of venetoclax and ibrutinib as well as venetoclax and obinutuzumab (Gazyva; Genentech) a monoclonal antibody, had similar rates of progression-free survival (PFS) as those treated with a continuous regimen of ibrutinib.

Al-Sawaf noted that CLL is a common leukemia both in the US and in Europe and is most likely to affect patients older than 65 years of age. “This, of course, has a lot of implications around treatment tolerability, side effect profiles, [and] drug interactions,” he said. “So, these are clinically important considerations.” Fixed-duration regimens give these patients a break from therapy.

“The aim here is to combine and produce deep remissions and thereby allow patients to get off therapy while still remaining in remission.” Ideally, Al-Sawaf said, patients will gain “multiple years… of treatment, free intervals where they have control of their CLL, but don't require medical intervention.”

Under the study protocol, patients in the venetoclax-obinutuzumab arm received both therapies for 6 cycles (28 days each), followed by 6 more cycles of venetoclax monotherapy. Those in the venetoclax-ibrutinib arm started with the 3-cycle ibrutinib lead-in followed by 12 cycles of the combination. Patients in the ibrutinib monotherapy arm were treated continuously until progression.

Three-year PFS rates for each arm were well within the 6% range of difference that defined non-inferiority in the study:

• 81.1% in the venetoclax-obinutuzumab arm
• 81.0% in the ibrutinib arm
• 79.4% in the venetoclax-ibrutinib arm

The hazard ratio (HR) of the venetoclax-obinutuzumab arm compared with the ibrutinib arm was 0.87, type-I-error adjusted CI (98.3%) 0.54-1.41; while the HR of the venetoclax-ibrutinib arm compared with the ibrutinib arm was 0.84, type-I-error adjusted CI (98.0%) 0.53-1.32). Authors wrote that the upper limit of each adjusted CI was below the predefined noninferiority margin, “providing early evidence of noninferiority.”

Secondary end points reported by investigators included overall response rate at final staging, which was 84.2% for venetoclax-obinutuzumab, 88.5% for venetoclax-ibrutinib, and 86.0% for ibrutinib; with complete response rates of 51.5%, 46.2%, and 8.3%, respectively.

Among patients unmutated IGHV, 3-year PFS in the venetoclax-obinutuzumab arm was 75.8% (87.6% for mutated IGHV) compared with 79.7% (83.5%) in the ibrutinib arm, and 78.9% (80.0%) in the venetoclax-ibrutinib arm.

Safety. The most frequent AEs were as follows:

• infections and infestations: venetoclax-obinutuzumab, 76.3.%; venetoclax-ibrutinib, 80.2%, ibrutinib, 79.9%
• gastrointestinal disorders: venetoclax-obinutuzumab, 59.7%; venetoclax-ibrutinib, 74.3%, ibrutinib, 63.4%
• blood and lymphatic system disorders: venetoclax-obinutuzumab, 59.0%; venetoclax-ibrutinib, 42.9%, ibrutinib, 28.5%

Cardiac disorders are a known AE for ibrutinib and were highest in that arm at 34.6%; they were seen in 13.9% of the venetoclax-obinutuzumab arm and 23.8% of the venetoclax-ibrutinib arm. (Of note, second-generation BTK inhibitors have reported less cardiotoxicity than ibrutinib.)

Importance to Payers

Interest in fixed duration therapy has increased in CLL and in other blood cancers and disorders as therapeutic advances allow patients to live longer. The positive benefits of BTK inhibitors is offset by possible effects of taking the drug for multiple years; in an abstract being presented separately on Saturday at ASH, Ira Zackon, MD, of Ontada is presenting real-world data on discontinuation rates of covalent BTK inhibitors with among patients with CLL or small lymphocytic lymphoma.2 The data show discontinuation rates are higher than those seen in clinical trials and are “largely driven by toxicities,” and also associated with comorbidities, cytogenic abnormalities, and worsened performance status.

The cost of taking a drug indefinitely is a concern to payers in the US, and in other countries, to health systems. Various cost-effectiveness studies of fixed-duration therapy involving multiple drug combinations have taken place in CLL; a 2025 study from Canada found the venetoclax-obinutuzumab regimen was a cost-effective treatment option from that country’s public healthcare perspective, compared with several therapies including both first-and second-generation BTK inhibitors.3

Payers also worry about adherence to continuous regimens, and Al-Sawaf said fixed-duration plans offer benefits here as well.

“We do notice that when you discuss with patients the 2 options that most patients will prefer, of course, when they hear that there is a fixed duration option,” he said. The caveat is the bloodwork and management requirements in the ramp up phase of venetoclax to check for tumor lysis syndrome; Al-Sawaf said some frail patients are challenged by the complexity of that process and prefer the continuous dose.

“In the long run, I think for most patients, it makes much more sense to say that after a year, I do not need to come to clinic anymore,” he said. “So that's where I think these adherence points become very, very relevant.” In the ibrutinib arm of CLL17, he said, “the adherence is much poorer in the elderly, unfit patients.”

Nonetheless, he said the study supports staying with continuous use of BTK inhibitors for patients with TP53 mutation status, known to create higher risk. “Most guidelines have a conservative approach in saying these [patients] should be treated continuously with this maintenance approach.”

He noted that only 8% of the patients in the study had TP53 status. “Because the number is limited and the follow up is still limited…personally, in my clinic, it's still safer to say put patient those 8% or so patients who have TP53 alterations on continuous treatments. Other than that, we recently revised our guidelines for the German speaking parts of Europe. We say that all other groups of patients, including those with unmutated IGHV, should be considered for limited duration treatment.”

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. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL; Paper 1.
2. Zackon I, Real-world treatment patterns, factors associated with discontinuation and toxicity across covalent BTK inhibitors in first-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL; Paper 2111.
3. van de Wetering G, Owen C, Banerji V, et al. Venetoclax in combination with obinutuzumab in previously untreated fit patients with chronic lymphocytic leukemia: A Canadian cost‑utility analysis. PharmacoEconomics – Open. Published online November 7, 2025. doi:10.1007/s41669-025-00610-1