Acalabrutinib (AVO): A Promising New Triplet Treatment Option for High-Risk CLL Patients Phase 2 Study Results Matthew Davids
By Matthew Davids, MD, MMSc
This is a phase 2 investigator initiated clinical trial of a triplet regimen for the frontline treatment of CLL (chronic lymphocytic leukemia). And the 3 drugs are all FDA-approved already, including acalabrutinib. Venetoclax and Obinutuzumab, we call this the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) study. And these drugs although approved in other combinations, are not approved together. So ours is one of the first studies to look at this triplet combination. We had actually previously published a paper on an all-comer cohort of 37 patients treated with this regimen that looked very promising. And the inspiration for the study here at ASH that we presented this time is that the patients in that all comer population who had high-risk CLL (chronic lymphocytic leukemia) seemed to do very. And so here at this year’s ASH meeting, one of our fellows, Dr. Christine Ryan, presented an oral presentation on a new cohort of the study, focused specifically on the high risk patients. There were 31 new patients, and we also presented longer term follow up on the initial all-comer cohort.
What does the standard of care in this disease state and why choose to pursue the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) trial?
The trial is designed to start with an acalabrutinib lead in and then Obinutuzumab to try to debunk the patients and get rid of some of their bulky lymph node and blood disease. And then in cycle four, we start with Venetoclax, and that’s done to try to minimize the risks of tumor lysis syndrome with Venetoclax. We actually used a slightly more abbreviated ramp up schedule of Venetoclax here ramping it up over four weeks instead of 5 weeks, which we’ve found to be safe. And the patients can get about 15 months of therapy, and if they’re in the best possible response, a complete remission without any evidence of minimal residual disease (MRD), then they can stop therapy at that point. But if patients still have residual disease, then they can go on to get a second year of therapy. And then again, if patients have undetectable MRD (minimal residual disease or any side effects like atrial fibrillation, irregular heartbeat, muscle pain, vomiting blood, trouble breathing, weight gain, or flu like symptoms), they stop at the end of the 2 years. In our study, if they still have detectable disease at the end of the 2 years, then they stay on the 2 drugs, the Acalabrutinib and Venetoclax is a maintenance strategy.
Can you give us significant data from the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) trial?
Some of the key takeaways from the data in this trial. Number one, if we look at the deepest possible response after the 15 cycles of treatment, about 43% of patients achieved a complete remission with undetectable MRD (minimal residual disease) in the bone marrow, and that number was similar in the all-comer population and in the patients with high-risk disease like TP53 a variance.
The other thing is if we look at bone marrow MRD (minimal residual disease) itself, which is probably the best predictor of long-term progression-free and overall survival, that rate was in the range of about 85% of patients who achieved that milestone on the study. And again, that was irrespective of their genetic markup. So basically even the high-risk patients could do very well with this approach. Now the follow-up is still relatively short, the median is just under 3 years. We’ve only had one CLL (chronic lymphocytic leukemia) progression event so far. We have had 3 patients who’ve had transformation events, Richter’s transformation. And hodgkin’s transformation, but overall, we think the durability looks very promising. The median time off therapy right now in the patients who have electively discontinued is over a year and a half, and so we’re hoping that this time limited therapy will provide very durable benefits even for the high-risk patients with CLL (chronic lymphocytic leukemia).
What are the most common questions you get from your colleagues about this study?
So a lot of people are wondering, with our study, do we really need a triplet therapy? Would a doublet therapy be just as good, for example, with Acalabrutinib and Venetoclax without the Obinutuzumab? There are some other data that I presented at this ASH meeting in a poster showing that Acalabrutinib with Obinutuzumab was superior to Acalabrutinib alone in a couple different trials. Suggesting that there may be some benefit to adding the Obinutuzumab, and that’s in part why we wanted to explore this triplet combination. But ultimately, that question’s not gonna be answered until we have the results from another study called AMPLIFY, which is a phase 3 trial. And that actually directly compares the triplet with AVO (Acalabrutinib, Venetoclax, Obinutuzumab) to a doublet AV, and also a chemotherapy control arm. And so that eventually will answer this question, do we actually need the triplet therapy? Our study really provides the foundational evidence that led to the development of that larger study.
What are the key takeaways from this research and data?
So I would say that we’re very excited about the results of the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) triplet therapy. But that being said, I would not consider it to be a standard of care yet at this point. I think we need to wait for longer term results and we need to wait for that comparative study. I would also encourage oncologists who are watching this to consider a different study called MAGIC, which is now accruing. This is a study comparing that doublet AV, to Venetoclax, Obinutuzumab it’s a study open around the US and actually around the world, and that’s gonna help answer the question of what’s the optimal doublet therapy with Venetoclax for frontline CLL (chronic lymphocytic leukemia)? Another very important question in the field.
About the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) Clinical Trial
In this phase 2 clinical trial, patients with chronic lymphocytic leukemia (CLL) who had not been treated in the past were given the combination of acalabrutinib, venetoclax, and obinutuzumab (AVO). The goal of the study was to determine whether or not this treatment was effective in preventing the progression of the disease. With good response rates and better progression-free survival, the most recent research findings suggest that AVO (Acalabrutinib, Venetoclax, Obinutuzumab) therapy may be a useful therapeutic choice for this patient population. Further study has to be done in order to verify these findings and determine the safety and effectiveness of AVO treatment over the long term in patients with CLL (chronic lymphocytic leukemia).
10 Key Takeaways on the AVO (Acalabrutinib, Venetoclax, Obinutuzumab) Clinical Trial
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The combination of acalabrutinib, venetoclax, and obinutuzumab (AVO) showed promising efficacy and safety in previously untreated patients with CLL (chronic lymphocytic leukemia) enriched for high-risk disease.
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High-risk CLL (chronic lymphocytic leukemia) is a subtype of the disease that is associated with poor outcomes and a higher risk of progression.
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The study enrolled a total of 78 patients with previously untreated CLL (chronic lymphocytic leukemia), 77 of whom were evaluable for response.
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The overall response rate (ORR) was 97.4%, with 57.1% of patients achieving a complete response (CR).
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The median progression-free survival (PFS) was not reached, indicating that the majority of patients had not progressed at the time of analysis.
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The combination therapy was generally well-tolerated, with a manageable safety profile through blood tests (Eg. red blood cells, white blood cells).
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Adverse events were mostly grade 1 or 2, and the most common adverse events were diarrhea, nausea, and fatigue.
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The study also evaluated minimal residual disease (MRD) negativity rates, which were high among patients achieving a CR.
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The combination of AVO (Acalabrutinib, Venetoclax, Obinutuzumab) may represent a new treatment option for previously untreated CLL (chronic lymphocytic leukemia) patients with high-risk disease.
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The results of this phase 2 study support further investigation of AVO (Acalabrutinib, Venetoclax, Obinutuzumab) in larger, randomized clinical trials.
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Matthew Davids, MD, MMSc – About The Author, Credentials, and Affiliations
Matthew Davids, MD, MMSc, got his A.B. from Harvard College in chemistry and his M.D. from Yale University School of Medicine. In New York City, he worked as an intern, resident, and assistant chief resident in internal medicine at New York-Presbyterian Weill Cornell Medical Center and Memorial Sloan-Kettering Cancer Center. He then did a residency in hematology and oncology at Dana-Farber/Partners CancerCare and got an M.M.Sc. at Harvard Medical School. As an attending physician in the Division of Lymphoma, where he is also the Director of Clinical Research and Associate Director of the CLL Center, he is also the Director of Clinical Research. He is also an Associate Professor of Medicine at Harvard Medical School and sees patients at Brigham and Women’s Hospital for hematologic malignancies.
Dr. Davids has an active translational research program on CLL and non-Hodgkin lymphoma, with a focus on studying apoptosis (especially Bcl-2 biology) in his lab and leading clinical studies to test potential therapy methods on people with CLL and other hematologic malignancies. A lot of his research has been focused on the clinical development of new therapeutic regimens for CLL using combinations of targeted inhibitors of Bcl-2, B cell receptor pathway kinases, and other new agents, as well as the use of checkpoint blockade to improve anti-tumor immunity in patients with hematologic malignancies who have relapsed after allogeneic hematopoietic cell transplantation.
