According to a new trial, patients with chronic lymphocytic leukemia (CLL) show comparable outcomes whether they receive a single-agent treatment indefinitely or a combination treatment for a fixed period of time.

The study is the first prospective trial to directly compare these two approaches. With a median follow-up of nearly three years, the results show these approaches are essentially equivalent in terms of risk of death or disease progression.

CLL is the most common adult leukemia in which abnormal white blood cells grow out of control and build up in the bone marrow Three classes of agents have been developed that target CLL: Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and CD20 antibodies. Recommended treatment regimens for newly diagnosed CLL fall into two main categories: indefinite continuous treatment with a BTK inhibitor or a fixed-duration treatment, typically lasting about a year, using a combination of a BCL2 inhibitor and CD20 antibody or BTK inhibitor.

To compare these approaches, researchers randomly assigned 909 adult patients to one of three regimens. Those assigned to the "I" arm received continuous ibrutinib (a BTK inhibitor) indefinitely unless they experienced disease progression or unacceptable side effects. Those in the "VO" arm received 12 cycles of venetoclax (a BCL2 inhibitor) with a course of obinutuzumab (a CD20 antibody) added during the first six cycles. Those in the "VI arm" received 12 cycles of venetoclax following three cycles of ibrutinib.

At the time of analysis, the median follow-up period was 34 months, with a range of zero to 49 months. The rates of progression-free survival were 81% in the I arm, 81.1% in the VO arm, and 79.4% in the VI arm. Between-group differences fell below the pre-specified threshold for non-inferiority, meeting the study's primary endpoint for this time point.

The three arms also showed similar results in terms of overall response to treatment and overall survival, with overall response rates ranging from 84.2% to 88.5% and overall survival ranging from 91.5% to 96.0%.

The group receiving continuous ibrutinib treatment had a lower rate of complete response to treatment, an endpoint that was achieved in only 8.3% of the I arm compared with 51.5% in the VO arm and 46.2% in the VI arm. In addition, none of the patients receiving continuous ibrutinib achieved the status of undetectable measurable residual disease (MRD), a biomarker indicating that all or nearly all cancer cells have been eliminated. By contrast, undetectable MRD was achieved in 73% and 62% of patients as measured in the blood, and 62% and 40% of patients as measured in the bone marrow for the VO and VI arms, respectively.

"The secondary endpoints are surrogate parameters for us to assume long-term efficacy," said Dr. Al Sawaf. "With the fixed-duration paradigm, we see higher rates of complete response and MRD responses, and with the continuous single-agent treatment we see lower complete response and MRD responses."

Rates of side effects were overall similar across study arms, with the most common issues being infections and gastrointestinal disorders. Blood and lymphatic system disorders, cardiac disorders, and second cancers were also somewhat frequent across all arms.

Subgroup analyses showed that cardiovascular issues were more common among patients who received ibrutinib, especially among those who took ibrutinib for a longer duration. Obinutuzumab was associated with a higher risk of severe infections and with a shorter progression-free survival among patients with aggressive forms of CLL.

Researchers said that the ongoing follow-up within the trial will help strengthen the evidence for any differences in performance between the different treatment approaches. In addition, Dr. Al Sawaf said that other studies are underway to identify biomarkers that might help doctors determine which patients are most likely to benefit from each treatment strategy. 

The study was investigator-initiated under sponsorship of the University of Cologne; AbbVie Inc., Janssen Pharmaceuticals, and Roche Pharmaceuticals provided the study drugs and funding to support the trial conduct; parts of the analyses and research staff were supported by the German Research Foundation (Deutsche Forschungsgemeinschaft).

This study was simultaneously published in NEJM.

Othman Al Sawaf, MD, of the University of Cologne, will present this study on Sunday, December 7, 2025, at 2:05 p.m. Eastern time during the Plenary Scientific Session in West Hall D2 of the Orange County Convention Center.