CLL: Next Steps in Research

Nicole Lamanna, MD:So the future of CLL [chronic lymphocytic leukemia]: First of all, it’s an extremely exciting and wonderful time for patients and patient care right now. But obviously, there’s a lot that we have to figure out because a lot of the field is moving towards time-limited duration of therapy of these novel agents. The question is, what are the correct combinations? So there were many presentations that looked at ibrutinib and venetoclax together in frontline and in relapse. Those got presented at this [American Society of Hematology] meeting. Triplet combinations. So ibrutinib/obinutuzumab, and venetoclax got presented at this meeting, both in relapsed and frontline.

So what is the optimal combination? And then, what happens again if you use a doublet or a triplet in the frontline setting? Can they get restarted back on venetoclax and be sensitive to that agent? Would the disease change and be resistant, depending upon if we’re using a triplet? Is it necessary? So I think these are some of the unanswered questions on the future direction of CLL and looking at MRD [minimal residual disease] to help guide us with that time-limited duration part. I think all of us are very keen about looking at this because it will, again, hopefully spare extra toxicity and cost for patients. But we have to look at which ones of these combinations might be better. I think there are going to be a lot of future studies that are going to have to compare some of these therapies.

We had very little data. As I said, we went from chemoimmunotherapy to novel agents, and we know what that’s like. Now that ibrutinib is being adopted frontline more commonly, we can salvage with venetoclax or venetoclax/rituximab. But what happens if you’ve used all of these agents up front? What do you salvage patients with then? And I think this obviously remains the huge unknown. Hopefully we’ll have more therapies by that time, that we can utilize. We likely will go back to maybe tweaking depending upon the time period, similar to what we did in the chemoimmunotherapy era; we might switch drugs here or there. Our patients presumably will be much older, so that doesn’t really allow a lot of room to go back to chemoimmunotherapy because they might be more frail and have more comorbidities. And you’re certainly not going to do that. But we have very little data about can you go back to chemoimmunotherapy after a novel agent? I suspect you can in a subset of patients. They will respond. The question is how will they respond. What kind of quality of response will they have? And it also depends on the cytogenetics at that time. Did any of these patients then develop more adverse or high-risk features, which often happened in the chemoimmunotherapy era? And then you wouldn’t really want to go back to chemoimmunotherapy if they have now acquired a 17p or a p53.

So there are some unknowns that we have to work out, but the field is very exciting right now because we’re getting to a point where we can really start fine-tuning how we treat patients, their comorbidities, and use novel agents if they have aggressive features. What to go to has changed dramatically. So, definitely all of this has translated into better patient care and better, I think, quality of life for our patients than they were ever before. But we still have a lot more to do. There’s a lot more to work out in the field.

Transcript edited for clarity.