Over the last ten years, targeted therapies such as ibrutinib and venetoclax have been introduced. They have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The GAIA (CLL13) trial is a phase 3 clinical trial of frontline time-limited venetoclax-based combination treatments vs. chemoimmunotherapy. The study began in December 2016, and it is still ongoing. When the study was designed, chemoimmunotherapy was the standard of care, and this trial continues to provide valuable information on the comparative efficacy of 4 different treatment regimens.
At the annual meeting of the American Society of Hematology (ASH) 2021, our own Dr. Brian Koffman, interviewed Dr. Stephan Stilgenbauer, Professor of Medicine at the Comprehensive Cancer Center at Ulm University in Germany. They discussed the latest results from the GAIA (CLL13) trial, which compared rates of measurable residual disease (MRD) with the different treatments.
- The GAIA (CLL13) trial is an international, multicenter, phase 3 clinical trial with 4 arms.
- FCR chemoimmunotherapy (fludarabine, cyclophosphamide, rituximab) – this was the standard of care at the time the trial was designed
- Venetoclax + rituximab
- Venetoclax + obinutuzumab
- Ventoclax + obinutuzumab + ibrutinib
- All treatments were time-limited in duration. Chemoimmunotherapy was 6 months, and venetoclax-based treatments were 1 year.
- The trial enrolled close to 1,000 treatment-naïve fit patients with CLL. “Fit” means that the patients had few concurrent illnesses/impairments unrelated to their CLL. In addition, patients had to be young and fit to tolerate FCR.
- Patients with deletion 17p were excluded because when the study was designed, it was already known that they did not do well on chemoimmunotherapy.
- The two co-primary endpoints were minimal or measurable residual disease (MRD) and progression-free survival (PFS).
- Because treatments work well now, it can take a long time to determine PFS (up to 5 years of follow-up).
- MRD can be determined more quickly and may serve as a surrogate for PFS.
- The venetoclax-based treatment regimens produced higher rates of undetectable MRD than chemoimmunotherapy.
- Obinutuzumab + venetoclax was much more effective than rituximab + venetoclax.
- The triple combination of venetoclax + obinutuzumab + ibrutinib produced slightly higher rates of undetectable MRD than venetoclax + obinutuzumab, but this difference was not statistically significant.
- Triple therapy with venetoclax + obinutuzumab + ibrutinib is feasible, but it cannot be recommended as standard therapy at this time.
- Adding ibrutinib increases toxicities by adding all the known BTK inhibitor side effects.
- The chemoimmunotherapy group had more toxicities than the targeted therapy groups.
This presentation provided an exciting look at the MRD data, but the data on PFS is still to come, and it will help to definitively say which treatment is best for patients. Thus far, combination venetoclax + obinutuzumab and a triple combination venetoclax + obinutuzumab + ibrutinib are the most effective though the triple combination has more side effects. We look forward to learning more as this study progresses. Comparative efficacy trials like this one are critical for determining the most beneficial treatments for patients.
Please enjoy this interview with Dr. Stilgenbauer from the ASH meeting, held in December 2021 in Atlanta, GA, and virtually.
You can read the actual abstract here: A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial
Take care of yourself first.
Ann Liu, PhD