iwCLL 2023 | Recurrent genomic alterations in patients with CLL treated with venetoclax following a BCRi
Jennifer Woyach, MD, Ohio State University College of Medicine, Columbus, OH, discusses the findings of a study investigating recurrent mutations in the BCR signaling pathway and anti-apoptotic machinery in patients with chronic lymphocytic leukemia (CLL) treated with venetoclax following prior treatment with a BCR inhibitor. This study used data from a Phase II trial of venetoclax monotherapy in patients previously treated with ibrutinib or idelalisib. Paired samples collected pre-venetoclax and at time of relapse or during sustained remission allowed Dr Woyach and her team to observe how mutation acquisition and loss varied in patients as a result of venetoclax treatment. Findings suggest that BCL2 mutations were associated with venetoclax relapse which may allow patients at risk of clinical relapse to be identified in the future. This interview took place at the biennial International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2023 meeting, held in Boston, MA.
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Transcript (edited for clarity)
So we’re presenting an abstract looking at recurrent mutations, specifically those in the B-cell receptor signaling pathway and in anti-apoptotic machinery in patients treated with venetoclax after treatment with another BCR antagonist. These are actually data that come from the Phase II study of venetoclax monotherapy in patients who either were treated with ibrutinib previously or those who were treated with idelalisib previously...
So we’re presenting an abstract looking at recurrent mutations, specifically those in the B-cell receptor signaling pathway and in anti-apoptotic machinery in patients treated with venetoclax after treatment with another BCR antagonist. These are actually data that come from the Phase II study of venetoclax monotherapy in patients who either were treated with ibrutinib previously or those who were treated with idelalisib previously.
The whole study cohort includes 127 patients, 91 of which were previously treated with ibrutinib. Looking at the long term clinical data, it’s fairly similar to what has been published before with these agents. So overall, in both cohorts, we had a median progression free survival of about 33 months- longer in those patients who were previously treated with idelalisib, a little bit shorter in those previously treated with ibrutinib, there it was about almost 25 months. We don’t see any new safety signals with venetoclax monotherapy in this long-term follow up either.
One of the most interesting things that this study did is actually take paired samples pre-venetoclax and then at the time of relapse, in those patients who relapsed, or in the patients who continue to respond, many of them rolled over into an extension study and there was a sample taken at the time of rollover into an extension study. So we have a cohort of patients who are progressive venetoclax and a cohort that are still in remission. We looked at mutations in BTK, Tp53 and BCL2 in all of these patients.
Interestingly, we actually see that a couple of patients who had BTK C481S mutations prior to treatment lost it at the time of progression after venetoclax, which is really provocative information, maybe you could think that some of these patients could be re-sensitized to a BTK inhibitor, at least for a period of time. We see Tp53 mutations acquired in a number of patients at relapse and then looking specifically at BCL2 mutations in the cohort of patients who progressed on venetoclax, 30% of those patients were identified to have mutations in BCL2. Five of those patients, there was only one BCL2 mutation, but actually in eight of them multiple BCL2 mutations were identified. In those patients who were in continuing remission, we still saw 11% of them have a BCL2 mutation.
When we look at time to acquisition of a mutation, we see that the acquisition of BCL2 mutations tends to be a late event, both in the progressers and in the non-progressers. Most of these BCL2 mutations are sub-clonal as has been previously reported. We especially see very low allelic frequencies of the mutations in those continuing responders as you might expect. So I think that this is a really interesting study that continues to show that BCL2 mutations are associated with venetoclax relapse, again, suggesting that these mutations potentially are going to be able to be identified prior to clinical relapse. And we don’t know exactly how long that interval is going to be between when a BCL2 mutation can be identified and the time of relapse.
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