Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM )retired), MSEd
The Bottom Line:
After patients with CLL were treated with venetoclax-obinutuzumab, their immune systems gradually recovered, but this result was slower in patients with deep responses.
Who Performed the Research and Where Was it Presented:
Dr. Stephen Opat from Monash Health in Melbourne, Australia, and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are immunocompromised, meaning they have a weakened immune system. Being immunocompromised makes patients more vulnerable to infections. The medications used for treating CLL / SLL can also suppress the immune system. For instance, chemotherapy is known to cause immunosuppression because it kills all rapidly dividing cells, including the red and white blood cells being made in the bone marrow. Rituximab and obinutuzumab are monoclonal antibodies that target CD20 found on the surface of cancerous CLL cells but also on normal B cells, so they suppress counts of both. With the introduction of many different targeted therapies for treating CLL / SLL over the past two decades, researchers wanted to learn more about how the popular combination therapy of venetoclax plus obinutuzumab impacts the immune system of CLL / SLL patients.
Methods and Participants:
This study was part of a phase 3 clinical trial comparing venetoclax-obinutuzumab with chemoimmunotherapy (either fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR)) in patients with treatment-naïve CLL. Researchers measured levels of different immune cells and immune markers.
Results:
- A total of 166 patients were randomly assigned to either venetoclax-obinutuzumab or chemoimmunotherapy (FCR / BR).
- At baseline, there were no differences in the levels of CLL cells or immune cells between the treatment groups.
- After treatment, both groups experienced a depletion in the number of CLL cells and immune cells, which was followed by a period of gradual immune system recovery.
- More patients in the venetoclax-obinutuzumab group (81%) achieved undetectable minimal residual disease (uMRD) compared with FCR / BR (55%).
- In patients receiving venetoclax-obinutuzumab, the number of CLL cells was markedly decreased at 12 months of follow-up and remained suppressed for up to 36 months.
- At 24 months of follow-up, non-malignant B cell levels were three times higher in patients who were MRD+ compared with patients who reached uMRD.
- The period of time needed for the immune system to recover was much longer in patients who had reached uMRD compared with patients who remained MRD+.
- Immunoglobulin (antibody) levels were lowest three months after venetoclax-obinutuzumab treatment, and showed signs of recovery beginning at nine months of follow-up.
Conclusions:
First, immune recovery may be delayed for years after the last medication was given, especially with combinations using obinutuzumab. Next, while venetoclax-obinutuzumab was very effective in treating CLL and produced deep responses, patients who reached uMRD required longer periods of time for immune recovery. This discovery is interesting and a somewhat surprising result. It has been postulated and suggested by some research that the CLL cells themselves have a suppressive effect on other immune cells, and their deep elimination could therefore lead to a rebound in immune health. This study teaches us that this potential benefit has to be balanced against the possibility that those who have a deeper response to therapy may have B-cells, both cancerous and healthy, that are more sensitive to the treatment drugs. There is still much to be learned, and this research reminds us we need to stop, question, and confirm any of our assumptions about any treatment’s effects on immunity. It also reminds us of the importance of getting vaccinated for diseases like influenza and COVID-19 prior to beginning treatment for CLL, and taking common-sense precautions against infections regardless of remission status.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Long-term immune reconstitution and final 1-year follow-up after fixed-duration venetoclax-obinutuzumab (VenO) in first-line (1L) chronic lymphocytic leukemia (CLL): Results from the Phase III CRISTALLO trial
