The Bottom Line:
The combination of ibrutinib and venetoclax is an effective first-line treatment for high-risk CLL. In this trial, nearly 2 out of 3 patients achieve undetectable minimal residual disease (uMRD) indicating remission. The results seen here are very similar to those from several other trials testing the combination of ibrutinib and venetoclax as a first-line treatment.
Who Performed the Research and Where Was it Presented:
Dr. Bill Wierda from MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology Annual Meeting in December 2022.
Background:
Most of the CLL and small lymphocytic lymphoma (SLL) research is currently looking at combination therapies that use either 2 or 3 drugs (doublets or triplets) at the same time that have different mechanisms of action. The hope is that hitting the cancer harder from multiple angles will get patients into deeper remissions faster (measured by undetectable measurable disease or uMRD) and limit the time patients need to remain on the drugs. Getting to uMRD has also been linked with more prolonged progression-free survival. Right now, one of the most studied combinations is the BTK inhibitor ibrutinib combined with the BCL2 inhibitor venetoclax.
In this video, Dr. Matthew Davids, Director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, interviewed Dr. Bill Wierda, a Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. They discussed updated results from a phase 2 clinical trial that looked at combining ibrutinib and venetoclax in those who were needing to be treated for the first time.
Methods and Participants:
This phase 2 clinical trial looked at the efficacy of ibrutinib combined with venetoclax in high-risk patients who had never been treated for their CLL. High-risk features (or biomarkers) included: deletion 17p (del17p), TP53 mutation, deletion 11q (del11q), unmutated IGHV, or those who were greater than 65 years old. Patients received a combination of ibrutinib and venetoclax for two years. The protocol was later amended to allow for one additional year of combination therapy for patients who were still MRD positive (meaning the cancer was still being detected) after two years.
Results:
- The initial results from this trial with have previously been published here.
- These newly updated results include data from 120 patients with a median follow-up time of 4 years.
- The best response rate (meaning that a patient reached uMRD at any point in the study) was 72%.
- After two years of combination therapy, 64% of patients were MRD negative (in remission), and most opted to discontinue therapy.
- Among patients who were MRD positive after two years and received an additional year of therapy, 63% of those then became MRD negative.
- More patients with unmutated IGHV reached uMRD status than patients with mutated IGHV.
- Thus far, there have been very few MRD relapses (meaning they went from undetectable disease to detectable).
- Of the 11 patients who experienced MRD relapse, ten are being actively monitored but are not requiring any additional active therapy for their CLL because they have not experienced disease progression.
- Patients who experienced relapse tended to be those who were slowest to initially respond to the treatment.
- The 4-year progression-free survival rate was 95%, and the 4-year overall survival was 97%.
Conclusions:
The combination of ibrutinib and venetoclax is very effective as a first-line treatment for those who have high-risk CLL / SLL biomarkers, with nearly 2 out of 3 patients achieving uMRD in this trial. The results seen here are very similar to those from several other trials that have tested using the combination of ibrutinib and venetoclax as a first-line treatment (GLOW and CAPTIVATE and FLAIR). This combination approach has already been approved in the European Union, and we are currently awaiting Canadian approval, but it is unlikely to be approved in the US. Both drugs are already FDA approved for use as monotherapies (used alone and not in combination with anything else) and could technically be used in combination together as an “off-label” use in the US if the patient and doctor agree that this might be the best treatment approach for them.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data
Take care of yourself first.
Ann Liu, PhD
