Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Delaying the addition of obinutuzumab to acalabrutinib-venetoclax by one year significantly reduced the risk of infections in patients with CLL.
Who Performed the Research and Where Was it Presented:
Dr. William Wierda from the University of Texas MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
The three main classes of drugs for first-line therapy in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are Bruton tyrosine kinase inhibitors (BTKi), B-cell lymphoma 2 inhibitors (BCL2i), and monoclonal antibodies. Alone and in various combinations, a majority of people achieve years of remission with these drugs. The AMPLIFY trial showed that the BTKI acalabrutinib plus the BCL2i venetoclax was significantly better than non-targeted chemoimmunotherapy. That trial also showed that adding the monoclonal antibody obinutuzumab increased the depth and duration of the response, but this came with an increased risk of dying, especially from COVID-19. This study looked at whether the timing of adding obinutuzumab to acalabrutinib-venetoclax had any impact on the side effects experienced by patients.
Methods and Participants:
This phase 2 clinical trial began in 2020. It tested a combination of acalabrutinib and venetoclax with obinutuzumab added either at the beginning of treatment or, if needed, one year later in older or high-risk patients with treatment-naïve CLL. All patients started on acalabrutinib and venetoclax (a combination approved by the FDA in 2026). If patients still had measurable residual disease after one year of treatment, they could add 6 monthly doses of obinutuzumab regardless of whether they had already received that. Patients received up to two years of total treatment.
Results:
- A total of 84 patients enrolled in the trial, with 42 receiving early obinutuzumab and 32/42 (76%) in the second group receiving obinutuzumab in the second year.
- 24% of the early obinutuzumab group, but only 7% in the other group, could not complete two years of therapy.
- Three patients in the early obinutuzumab group died of COVID-19 during treatment.
- During the first year, most of those receiving only acalabruitib and venetoclax had diarrhea, headache, and/or nausea.
- Infections were more common in the early obinutuzumab group, with 64% of patients experiencing an infection during year one compared with 38% in the other group.
- Severe infections and severely low neutrophil counts were significantly higher in year one in the early obinutuzumab group compared with the other group.
- In year two, there were no significant differences between the groups in rates of infections of low neutrophil counts.
Both groups had at least 90% success at eradicating CLL / SLL in the bone marrow.
Conclusions:
Researchers continue to improve combinations of currently approved drugs for first-line treatment of CLL / SLL. Using three classes of drugs simultaneously at the beginning of therapy seems to have an excessive risk of infection and even death, in both this and a prior study. Initial use of acalabrutib and venetoclax for a year, followed by obinutuzumab infusions, if necessary, and then a second year of the two oral drugs, was much safer than using all three drugs at the start of therapy. Acalabrutinib and venetoclax cause GI issues and/or headache in most people. Three-drug therapy over two years has more side effects and is longer, more time-consuming, and expensive than the currently recommended two-drug time-limited protocols, but appears more effective at eradicating disease. Duration of response and long-term survival with such three-drug therapy compared to less intensive options is still unknown.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Addition of obinutuzumab after one year of combined acalabrutinib and venetoclax is safer and effective than early obinutuzumab in a randomized Phase II trial for treatment naïve CLL
