The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 7

BTK Combination Therapy

April 16, 2020

Jan A. Burger, MD, PhD: Another approach we’ve done and that we could maybe discuss as well is the combination BTK [Bruton tyrosine kinase] inhibitor with venetoclax. Our experience in the frontline setting has been encouraging. You’ve seen the data where the vast majority of patients, after 2 years of treatment, achieve a deep remission and are able to come off treatment. The follow-up is short, so therefore we can’t really say is this maybe the way to go for a certain subgroup of patients. It’s treatment that has been well tolerated. It was geared toward either high-risk patients or elderly patients.

But what argues for that approach is that the majority of patients achieve MRD [minimal residual disease]–negative remissions can come off treatment. The counter argument you could make as well; it’s a bit more intensive regimen. You get more myelosuppression by combining those 2 agents. It’s very expensive, obviously, because you combine 2 targeted agents for almost 2 years. But then, on the other hand, you can stop the treatment. And I think it could be successful if, in 5 or 10 years, we learn that some of these patients may not relapse and may be functionally cured. So that’s the promise of this approach. On the other hand, I don’t think it’s ready for prime time until we really have maybe 5 years of follow-up. How would you think about those data?

Ian Flinn, MD: Yeah, I think you’ve hit on all the salient points. I think 1, the notion of getting patients off of therapy avoids all the cumulative toxicities you might expect with some of these agents. Being able to get them off is attractive from that standpoint. It is expensive; it’s very expensive. But if you think about it, if you’re giving them a relatively short amount of treatment with 2 or 3 agents instead of keeping them on it indefinitely, maybe in the big picture it’s not more expensive and you might avoid some of the issues with adverse events. All that research is really exciting and something that needs to continue.

You talked a little earlier about combining with different agents. You mentioned CD20-targeted antibodies. Of course, I think this is also very controversial. We know from a series of studies you first presented a number of years ago that combining ibrutinib with rituximab maybe accelerated the curve a little but really didn’t seem to change things. The progression-free survival [PFS] and things like that really seemed like it was unchanged.

More recently we’ve seen the data from iLLUMINATE, which was a combination of ibrutinib with obinutuzumab—so a different CD20 antibody, 1 geared for more ADCC [antibody-dependent cellular cytotoxicity]. That was a trial that was comparing it to obinutuzumab with chlorambucil. So we don’t have direct evidence, but there’s a suggestion that maybe it’s better but hard to convince a lot of people that that’s better. There’s also the more recent ELEVATE-TN trial, where acalabrutinib was combined with obinutuzumab. In that there are clear randomized data. There’s a difference in progression-free survival that by adding the antibody to acalabrutinib, you improve progression-free survival compared with the BTK inhibitor alone.

So there is a lot to think about there. The pros and cons. I’ll get your take on this in a second. But maybe it matters not only what the antibody is—not all CD20s are the same—[but] what the BTK inhibitor is. Of course there are probably fewer problems with decreasing efficacy of acalabrutinib on ADCC. Whereas, we think with ibrutinib, maybe it does play a little bit of a role there. Maybe that’s the explanation for the differences with that. A lot of data. Some people think, “Well, it doesn’t really make any difference because you’re not improving survival.” So maybe we’re splitting hairs there. It really doesn’t make any difference. In your practice, outside of a trial, what’s your approach?

Jan A. Burger, MD, PhD: We are just so used to using CD20 antibodies. They have been so beneficial to so many patients. When we think about 10 years ago when we used chemoimmunotherapy, adding CD20 antibodies had such a profound effect on getting so many more patients into CRs [complete responses] and prolonging PFS and overall survival when we think about the CR data. We are so used to using CD20 antibodies, and now the notion that CD20 antibodies are not adding so much benefit when you think about BTK inhibitors, at first glance that might be a bit disappointing. At this stage, when we use BTK inhibitors outside clinical trials, there’s not very solid evidence to say we need to add a CD20 antibody.

But where CD20 antibodies could come back into the play, when we talk about BTK inhibitors, is when we talk about limited-duration treatment. Maybe they can just be a way to get patients into deeper remissions faster. I think that’s pretty clear from all the data: if you add rituximab, if you add obinutuzumab to BTK inhibitor, patients will be in the remission faster. And then if you like the idea of treating patients not for years but maybe for a shorter period of time, then a CD20 antibody could be a good addition. That way, we might still see like a renaissance of CD20 antibodies when it comes to BTK inhibitors.

For venetoclax, I think the evidence is pretty clear that the addition of CD20 antibodies with venetoclax deepens remissions, and that has an effect on PFS because here we’re talking about limited-duration treatment anyway. I’m thinking that’s my reading of the data, that maybe with BTK inhibitors, if we had thought about limited-duration treatment earlier, we would maybe have data that looked similar to what we’re seeing with venetoclax where you see a benefit, where you see that more clearly if you talk about limited-duration treatment.

From a practical standpoint, as long as most patients still get long-term treatment with BTK inhibitors, the CD20 antibodies. Their addition to BTK inhibitors outside a clinical trial is probably not necessary for most patients unless you want to get a patient into a remission faster, you want to debulk them with a CD20 antibody. But they may come back. I think they will come back if we talk about limited-duration treatment. And with venetoclax, I think the data are solid that they should be added as usual.

Ian Flinn, MD: So the renaissances really would be with a 3-drug regimen, combining all 3 where you’re getting the added benefit, if I understand you correctly.

Transcript edited for clarity.