Therapies in the Pipeline for Frontline CLL

Nicole Lamanna, MD: When we talk about the future of CLL [chronic lymphocytic leukemia] and we talk about these combinations, there are many studies that are looking at multiple combinations as I alluded to earlier, looking at a Bruton tyrosine kinase [BTK] plus a BCL2 inhibitor, even triplet combinations, looking at a BTK, and venetoclax, and a monoclonal antibody. There are chemotherapy novel agent combinations with reduced-intensity chemotherapy plus a novel agent like a BTK or venetoclax. There are multiple strategies looking at whether these other options might be better for disease. As I alluded to earlier, I think it would be naïve for any of us to think that these combinations wouldn’t have great efficacy in our patients; they do. Those combinations are often time-limited, which I think is an advantage and appeal for many of us and our patients, that they’re not on chronic, continuous daily therapy.

However, I think we have to figure out whether that’s appropriate for all. We see these high response rates; one thing we need to learn about is how long that will last, how do we salvage those patients who have gotten a doublet or a triplet, what they will be sensitive to, and have we changed the resistance pattern or the milieu of their CLL, or complications that they may incur by those doublets or triplets. I think there’s a lot to learn. I don’t think we have the right answer just yet. That’s why that discussion of do you do frontline monotherapy versus a venetoclax/anti-CD20 antibody combination with your patient is relevant because it’s a preference, and there are many factors to consider. Unless there’s something that really stands out, I don’t think we have the answer that one is better than another just yet. And again, there are many trials looking to address this issue of if they start this combination, whether they continue one of the agents versus stopping.

There will be many randomized studies that hopefully…it will take us time to figure out. Given how well patients are doing, these data got presented recently at ASCO [the American Society of Clinical Oncology annual meeting], the updated data of long-term ibrutinib or acalabrutinib as monotherapy in front line. There were really great PFS [progression-free survival] curves in the frontline untreated population, albeit those patients are continuing on oral therapy. You can see that patients are doing really well with these novel agents. Figuring out whether there is one strategy better than another is going to take us some time to do. Obviously there’s a great appeal to get people off of therapy for many reasons, financial considerations, long-term toxicity issues because they’re on chronic, continuous therapy; there are many advantages to looking at time-limited durations of therapy. Of course, we have to look at the adverse effect issues, change of resistance patterns, how do we salvage those patients after, things like that because then our patient population only gets older, and are you going to go back to chemoimmunotherapy? There are a lot of factors to consider.

Having those patients appropriately enrolled on these clinical trials I think is paramount. It’s very important as we study these exciting combinations to figure out, long term, what might be the best strategy. Again, it may not be one-size-fits-all unless there’s a home run entirely. I think there are many patients who are completely appropriate, happy, and content to be on monotherapy. Just stay tuned, we’ll have to see, but many exciting combinations are being evaluated.

Transcript Edited for Clarity