According to a new trial, patients with chronic lymphocytic leukemia (CLL) have comparable results whether they are treated with a single drug indefinitely or a combination therapy for a fixed period of time.
The study is the first prospective trial to directly compare these two approaches. With a mean follow-up of almost three years, the results show that these approaches are essentially equivalent in terms of risk of death or disease progression.
As clinicians, we often assume that continuous treatment will always be more effective because you simply give more treatment, but this study shows that this is not necessarily the case. The results provide the first evidence that fixed-duration treatment, which is often preferred by patients, is indeed non-inferior to continuous treatment, suggesting clinically equal efficacy.”
Othman Al Sawaf, MD, lead study author, hematologist and medical oncologist, University of Cologne, Germany
CLL is the most common adult leukemia in which abnormal white blood cells grow out of control and accumulate 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 therapy with a BTK inhibitor or fixed-duration therapy, typically lasting about one year, using a combination of a BCL2 inhibitor and a CD20 antibody or a 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 series of obinutuzumab (a CD20 antibody) added during the first six cycles. Those in “arm VI” received 12 cycles of venetoclax after three cycles of ibrotinib.
At the time of analysis, the median follow-up period was 34 months, with a range of zero to 49 months. Progression-free survival rates were 81% in arm I, 81.1% in arm VO, and 79.4% in arm VI. Between-group differences fell below the prespecified 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 treatment response and overall survival, with overall response rates ranging from 84.2% to 88.5% and overall survival from 91.5% to 96.0%.
The group receiving continuous treatment with ibrutinib had a lower complete response rate, an endpoint achieved in only 8.3% of arm I compared with 51.5% in arm VO and 46.2% in arm VI. In addition, none of the patients receiving continuous ibrutinib achieved the status of undetectable measurable residual disease (MRD), a biomarker that indicates that all or nearly all cancer cells have been eradicated. In contrast, undetectable MRD was achieved in 73% and 62% of patients as measured in blood and in 62% and 40% of patients as measured in bone marrow for the VO and VI arms, respectively.
“Secondary endpoints are surrogates to assume long-term efficacy,” Dr Al Sawaf said. “With the fixed-duration paradigm, we see higher rates of complete response and MRD responses, and with continuous single-agent therapy we see lower complete response and MRD responses.”
Adverse event rates were overall similar across study arms, with the most common problems being infections and gastrointestinal disturbances. Blood and lymphatic system disorders, heart disorders, and second cancers were also somewhat common in all arms.
Subgroup analyzes showed that cardiovascular problems were more common among patients who received ibrutinib, especially among those who received ibrutinib for longer. Obinutuzumab was associated with a higher risk of serious infections and shorter progression-free survival in patients with aggressive forms of CLL.
The researchers said continued follow-up as part of the trial will help strengthen the evidence for any differences in performance between the different treatment approaches. In addition, Dr Al Sawaf said other studies are underway to identify biomarkers that could help doctors determine which patients are most likely to benefit from each treatment strategy.
The study was initiated by the researcher under the sponsorship of the University of Cologne. AbbVie Inc., Janssen Pharmaceuticals, and Roche Pharmaceuticals provided the study drugs and funding to support the conduct of the trial. parts of the analyzes 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. time ET during the Plenary Science Session in West Room D2 of the Orange County Convention Center.
