BTK Inhibition: Real World vs Clinical Experience

Ian Flinn, MD: We’ve talked about a number of different clinical trials and the outcomes here with BTK inhibitors. Patients in the clinic aren’t necessarily what we see in clinical trials, and so there’s definitely differences that have been seen in the real-world experience with BTK inhibitors versus what’s seen in the clinical trials. And probably some of it has to do with the elderly population that we’re treating. The average age of someone with CLL [chronic lymphocytic leukemia] is definitely over 65 in most series. Sometimes it’s as high as 70, depending on which publication you’re looking at.

And I think that this age group, they come with comorbidities. They come with heart problems already, they come with risk of atrial fibrillation, they come with other health issues. And so trying to define regimens that are very well tolerated in the elderly is I think a very paramount importance. So just like giving someone FCR to a 75-year-old is not tolerable, we have to think about regimens that even with these targeted therapies that are tolerable in older patients.

Now, I think that there’s a variety of series that we know that patients in the real- world experience that some of these things that we’ve been able to keep people on in clinical trials, whether it’s the arthralgias, whether it’s the bleeding, or whether it is atrial fibrillation, we’re able to manage through that. In the real-world experience, it seems like that’s not as true or at least there’s a tendency to move on to other agents. Jan, do you think that’s because we have other options to use? For instance, you don’t have to keep someone on ibrutinib. You could switch them to acalabrutinib or you could switch them to venetoclax or is there something else going on driving this intolerance issue?

Jan A. Burger, MD, PhD: Yeah, I think the data from Anthony Mato, MD, who put out these data from real-world experience, collecting data from across I think several centers, not just in the US. I think that’s instructive and the way I read it is to say if you’re not in a clinical trial, the rate of BTK inhibitor and ibrutinib discontinuation is quite high. In the first 2 or 3 years, up to 30% or 40% of patients eventually come off treatment due to adverse events. They’re not becoming resistant but they’re coming off for various adverse effects.

And then if you look closer into what kind of adverse effects are driving this, I think it is certainly the atrial fibrillation issue. That’s always an important issue. But, otherwise, it’s oftentimes also nonspecific adverse effects, musculoskeletal complaints. And for physicians who are relatively new to BTK inhibitors, maybe also the threshold to consider new treatments versus maybe adjusting treatment, maybe optimizing supportive measures for managing these adverse effects. Maybe the threshold to go to something else is somewhat lower because you have alternatives, because you’re interested in trying a second-generation BTK inhibitor. So that’s a complex issue and situation which in the end leads to many patients eventually moving on to something else.

Whether this second choice is much better, I think we have to wait to see that. Also patients who are now going on to frontline BTK inhibitor therapy, they haven’t been exposed to chemoimmunotherapy. Maybe their tolerance for adverse effects is different than earlier patient populations who went on the BTK inhibitor in second-, third-, fourth-line after receiving chemoimmunotherapy. So that’s also something we need to take into consideration. So I think what helps with this situation is a more awareness of the adverse effects, maybe some better guidance how to manage side effects with the BTK inhibitors. But, on the other hand, it’s a learning process and it’s good that we have alternative agents to move to.

Ian Flinn, MD: Well, Anthony Mato’s data really resonates with me in terms of experience I’ve seen in the clinic. There’s definitely a number of patients that can’t come off. I really think the number 1 reason people come off in my population is the arthralgias, these musculoskeletal issues that you’re bringing up. I’ve tried various different ways. I’ve stopped it, restarted it, started dose escalation. I’ve started steroids. I’ve tried all those things. And I think sometimes it works in some people, it doesn’t in others. It’s not 100% any one thing.

I guess I am comforted by some of these studies that have looked at using alternative BTK inhibitors or alternative therapies. Personally I think it’s not wrong. I mean, if someone doesn’t tolerate ibrutinib, then why not try them on acalabrutinib. There seems to like little to be lost there in terms of perhaps you can keep them on a BTK inhibitor instead of giving up on the class altogether and switching them to venetoclax-based therapy. You hate to throw away a class of drugs without being sure that you’ve really maximized them to a great extent.

And I guess you could come back later, right? If someone had an adverse event, maybe with more therapy they might actually tolerate these things well. Certainly in the original studies when people had 3 or 4 therapies and they were started on ibrutinib, we had less problems with some of these adverse effects. They were able to tolerate everything, maybe just because they felt so poorly to begin with, that by starting this it was a real improvement in things.

Transcript edited for clarity.