Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Venetoclax–obinutuzumab and ibrutinib-venetoclax-obinutuzumab produce more prolonged remissions than chemoimmunotherapy and venetoclax-rituximab in patients with CLL.
Who Performed the Research and Where Was it Presented:
Dr. Barbara Eichhorst from the University of Cologne and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
In the past decade, we have seen the introduction of very effective targeted therapies for treating chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). As time has passed, researchers have been studying different combinations of targeted therapies to drive disease levels down to undetectable measurable residual disease (uMRD) and give patients more prolonged remissions. The GAIA (CLL13) trial is a phase 3 clinical trial of frontline time-limited venetoclax-based combination treatments vs. chemoimmunotherapy, which began in December 2016. Comparative efficacy trials like this one are critical for determining the most beneficial treatments for patients. We previously reported on the MRD results of the GAIA (CLL13) trial with one year of follow-up. Now, researchers have four-year follow-up data, which includes progression-free survival results.
Methods and Participants:
The GAIA trial was a phase 3 clinical trial comparing the following treatments in fit, treatment-naïve patients with CLL:
- Chemoimmunotherapy
- Venetoclax + rituximab
- Venetoclax + obinutuzumab
- Ibrutinib + venetoclax + obinutuzumab
All treatments were limited duration. Chemoimmunotherapy (either fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) was given for approximately six months. All venetoclax-based treatments were given for approximately one year.
Results
- In total, 926 patients were assigned to one of the four treatments.
- All patients are now off treatment; the median follow-up time is just over four years.
- Progression-free survival was significantly more prolonged with venetoclax-obinutuzumab compared with venetoclax-rituximab and chemoimmunotherapy.
- Progression-free survival was significantly longer with ibrutinib-venetoclax-obinutuzumab compared with venetoclax-rituximab and chemoimmunotherapy.
- There were no significant differences in progression-free survival between venetoclax-obinutuzumab and ibrutinib-venetoclax-obinutuzumab.
- The triple combination of ibrutinib-venetoclax-obinutuzumab caused more side effects than the double combination therapies, including more cardiac side effects such as abnormal heart rhythms and high blood pressure.
- Chemoimmunotherapy caused more adverse events than the targeted therapies.
- The majority of patients treated with venetoclax-obinutuzumab (60%) or ibrutinib-venetoclax-obinutuzumab (66%) achieved uMRD at month 15 as measured by next-generation sequencing (less than one CLL cell in one million white blood cells) in the peripheral blood.
- It was more important for patients to reach uMRD than to have a complete response (the lymph nodes and spleen shrinking back to their normal size).
- Once patients came off of time-limited treatments, their quality of life improved.
Conclusion:
The combination therapies of venetoclax-obinutuzumab and ibrutinib-venetoclax-obinutuzumab produce longer remission times than chemoimmunotherapy and venetoclax-rituximab in patients with CLL. Most patients reach uMRD on these treatments, and uMRD, as measured by next-generation sequencing, appears to be an important prognostic marker of very long progression-free survival. Time-limited combination therapies are a powerful tool in treating CLL / SLL, and patients interested in these types of therapies should talk to their doctor to see if it might be the right fit for them.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract: First-Line Venetoclax Combinations in Fit Patients with CLL: 4-Year Follow-up and NGS-Based MRD Analysis from the Phase 3 GAIA/CLL13 Trial.
Take care of yourself first.
Ann Liu, PhD
