A recent clinical trial has found that patients with chronic lymphocytic leukemia (CLL) have similar outcomes whether they receive continuous single-agent therapy or a fixed-duration combination treatment. The study, which is the first prospective trial to directly compare these two approaches, followed 909 adult patients for a median of nearly three years.
Participants were randomly assigned to one of three treatment groups. One group received indefinite ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, unless disease progression or side effects occurred. Another group was treated for 12 cycles with venetoclax, a BCL2 inhibitor, along with obinutuzumab, a CD20 antibody, during the first six cycles. The third group received 12 cycles of venetoclax after three cycles of ibrutinib.
After a median follow-up period of 34 months, progression-free survival rates were similar across all groups: 81% in the continuous ibrutinib arm, 81.1% in the venetoclax-obinutuzumab arm, and 79.4% in the venetoclax-ibrutinib arm. These differences met the primary endpoint for non-inferiority at this time point.
Overall response rates ranged from 84.2% to 88.5%, and overall survival rates ranged from 91.5% to 96%. However, complete response rates differed by regimen: only 8.3% in the continuous ibrutinib group achieved complete response compared to over half in the fixed-duration combination arms.
None of the patients on continuous single-agent therapy reached undetectable measurable residual disease (MRD), while this status was achieved by up to 73% and 62% of patients in blood samples—and up to 62% and 40% in bone marrow samples—in the other two arms.
"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."
Side effect profiles were generally similar among all groups; infections and gastrointestinal issues were most common. Cardiovascular events were more frequent among those taking prolonged courses of ibrutinib. Obinutuzumab was linked to an increased risk of severe infections and shorter progression-free survival among patients with aggressive CLL.
The study’s ongoing follow-up will provide further insight into any longer-term differences between these treatments. Dr. Al Sawaf noted that additional research is underway to identify biomarkers that could help tailor therapy choices for individual patients.
The investigator-initiated study was sponsored by the University of Cologne with drug supply and funding support from AbbVie Inc., Janssen Pharmaceuticals, and Roche Pharmaceuticals; additional support came from the German Research Foundation.
The results were published simultaneously in NEJM.
Dr. Othman Al Sawaf from the University of Cologne is scheduled to present these findings on December 7, 2025 at the Orange County Convention Center.
