A Rapid Shift in Treatment for Chronic Lymphocytic Leukemia - Episode 5

Comparison of BTK Inhibitors for CLL


Nicole Lamanna, MD: Now that we have second-generation BTK inhibitors—acalabrutinib and the frontline studies with acalabrutinib as well—do you foresee a change? We have other second-generation inhibitors, zanubrutinib as well, coming down the pike. We know that many patients do well on ibrutinib, and then there are those who do have these troublesome adverse effects and do come off therapy after hypertension and atrial fibrillation. What do you think about the acalabrutinib data? I know the zanubrutinib data are more immature and nothing in frontline, but how do you feel? There are head-to-head trials right there that are closed, but we just don’t have that data of acalabrutinib versus ibrutinib, or zanubrutinib versus ibrutinib. What do you think? Do you think the second-generations will replace ibrutinib?

Jan Burger, MD, PhD: Right now we are in this situation where we can tell for sure that second-generation BTK inhibitors are very effective. What we don’t know for sure is that they are definitively better in terms of adverse effects and toxicity. There’s going to be a transition time right now in patients who have, or who are developing problems on ibrutinib, for example, could potentially be switched to the other BTK inhibitors. Right now, there’s acalabrutinib, which recently was approved. Then the hope would be that those adverse effects do not recur. There are some data to suggest that. Is a replacement needed? I don’t think so, because ibrutinib data are very solid in terms of long-term follow-up and in terms of a lot of comparative large trials, which support the use of ibrutinib. It’s going to be, in my opinion, a gradual thing. The defining answer to that question would be these randomized studies. I know acalabrutinib is doing that right now. But zanubrutinib, which is third in line, is also doing a randomized study, I think, versus this kinase inhibitor. Once those data come out, then everybody can probably make a more profound decision on which to use.

Nicole Lamanna, MD: Based on the ELEVATE trial data, have you switched over? Are there advantages that you see for the acalabrutinib and obinutuzumab? Or as Jan was saying, does ibrutinib still remain standard of care right now?

Farrukh Awan, MD: Before I address that question, I’ll tell you my personal preference. We’re talking about ibrutinib-intolerance patients, patients who stopped ibrutinib because of the adverse effect. I think we all realize that patients who stopped because of adverse effect and can continue are a completely group of patients compared with patients who truly progress.

Nicole Lamanna, MD: Yes.

Farrukh Awan, MD: One thing that I see in my practice, and maybe you guys see in your practices too, is that the leukocytosis that happened with BTK inhibitors is an expected effect. It’s not necessarily an adverse event, and there is no reason to use a CD20 antibody to necessarily mitigate that adverse event. Don’t use a CD20, and I think that’s the message that I wanted to be quite clear about. The leukocytosis is not an adverse event. We don’t stop the drug for that expected event. We can even argue that sometimes it might be even better. The reason for using a CD20 ofatumumab-obinutuzumab-rituximab is not a reason to use the CD20 antibody, because we know that that would happen and patients would normalize in a few weeks, and we don’t really feel that is related to anything.

In terms of whether I would use acalabrutinib versus ibrutinib, I think that’s a very nuanced decision, and it’s based on a lot of different things. You asked about whether you would use 1 versus the other, whether you would switch. There are some early data that if you switch from ibrutinib to acalabrutinib, there does appear to be less of a recurrence of the original adverse effects that led to the discontinuation of ibrutinib. Again, the numbers are small, they’re early data, and we can’t make any clear decisions. But there does appear to be a slight trend toward better tolerability with acalabrutinib in the early going. Whether that’ll pan out in larger head-to-head studies, only time will tell.

Until we know that it’s a completely different drug, for me, it’s all 1 generation of drugs. They’re exactly the same drugs, hitting the same target, cysteine 481, and I think right now it’s a coin flip. If somebody has a very clear-cut history of cardiovascular issues, I do have a discussion with them about possibly considering alternative therapies, which may be a little safer, although that same thing happened with ibrutinib. Monitoring is exactly the same for both of my patient groups, even if I decide to do it. Just to be completely honest, my first choice for all my patients is always treatment on a clinical trial to address exactly those questions.

Nicole Lamanna, MD: Do you want to comment about second generation and whether [and] how they fit into the treatment landscape?

Richard R. Furman, MD: From my perspective, and speaking about patients who are not going on clinical trials but who are looking at the standard treatment options, I actually do believe that BTK inhibitor therapy as a single agent is the best current therapy that we have for most of our patients. It’s important to recognize that we certainly can predict patients who might run into trouble, patients with prior atrial fibrillation, patients with poorly controlled hypertension, dilated hearts. Those sort of things that would definitely make me want to steer clear from a BTK inhibitor therapy. We have other options, and that’s important. I believe that the cardiac risk profiles of all 3 are probably going to be the same when we get the data. I don’t use 1 to substitute for the other if I do have concerns about that.

I do believe that acalabrutinib is probably a little better tolerated than ibrutinib and zanubrutinib, but I think the tolerability of all these agents is excellent. The big problem with acalabrutinib of course is the need to avoid proton pump inhibitors, which so many people are on. It’s just nice to have different options that you can tailor to the individual.

The important question I always come across is whether or not to add an anti-CD20 to it. At this point in time I always use single-agent BTK inhibitor therapy without the anti-CD20.

Nicole Lamanna, MD: Great.

Transcript Edited for Clarity