BTK Inhibition in CLL: Real-World Data

Alan Skarbnik, MD: Again, in terms of discontinuation, since you mentioned that, there are a lot of studies going on with real-world evidence. There are a number of groups that have been evaluating the real-world data in trying to compare that to what we’re seeing in clinical trials, particularly with ibrutinib which has been available longer. As we know, clinical trial patients are more selected. They tend to have less comorbidities. They have more oversight when taking the drug and have more monitoring. They tend to stick to their dosages for a longer period of time. Whereas with the real-world data, sometimes it’s not as good. What’s your opinion on that?

Jennifer R. Brown, MD, PhD: I think it’s particularly come to the fore with ibrutinib. It was also true with chemoimmunotherapy. Trials often had selected young patients—median age of 60 or so—whereas we know the median age of diagnosis for CLL [chronic lymphocytic leukemia] is age 72. And then, it takes several years more to be treated. So we’re looking at patients mostly in their mid-to-late 70s, when they start to get treatment. But in the early ibrutinib trials, I think because of the hype about the drug and the early data that it was looking so phenomenal, there were many patients on wait lists who flew from around the country to get on these trials. Even though they were age 70 or age 71, their comorbidity scores were extremely low. I think that once we got ibrutinib out into non trial populations, that’s when we started to see the hypertension. We started to see the other cardiac adverse events like congestive heart failure, heart block. Atrial fibrillation showed up in [patients in] the randomized trial, but not in the nonrandomized phase 1b/2 study.

The early real-world data with ibrutinib suggested there was a 40% discontinuation rate at a median of only 6 months or so, which is obviously really high. Hopefully, that has improved somewhat as doctors have become more comfortable with the drug. For example, if people have early cytopenias, early infection, those aren’t really reasons to stop the drug. Even for atrial fibrillation, you don’t necessarily need to stop or change if you can control it and manage it. So, hopefully that’s improved somewhat.

But, it’s still the case. As I mentioned earlier, in the ALLIANCE trial, there’s a 7% death rate from ibrutinib toxicity in both the ibrutinib arms, versus 1% with BR [bendamustine/rituximab]. Especially in older patients, the toxicity is significant. The ALLIANCE trial probably enrolled a broader range of patients than some of the early trials, so it’s moving a bit more toward the real-world data. But these are the types of observations that have driven us more toward acalabrutinib as our preferred drug, especially in older patients.

Alan Skarbnik, MD: Yes. There were trials for patients who were intolerant to ibrutinib, switching to acalabrutinib afterward. An early trial showed no loss in efficacy by changing from one to the other, although sometimes we’ve seen recurrence of the same toxicity. Particularly, rash seems to be class dependent there. But you didn’t see as much atrial fibrillation afterward. I had a couple of patients in my clinical experience who I changed from one [drug] to the other because of intolerance, and they have been quite successful with that. No patients have been on ibrutinib for a prolonged period of time, except for [those with] hypertension because you see that with acalabrutinib as well. We don’t have the long-term data yet to see if that increases over time, but I will expect a similar finding with acalabrutinib. The other adverse events tend to be hampered by the switch from 1 drug to the other. Again, cardiovascular is the biggest concern in older patients with the use of a BTK [Bruton tyrosine kinase] inhibitor, particularly because of hypertension and atrial fibrillation. That’s why I favor acalabrutinib in that patient population. The risks seem to be lower, at least in the absolute numbers, comparing trial to trial here. And in clinical experience, it should be the case as well.

However, we did see a slightly higher rate of atrial fibrillation in the relapse data from the ASCEND trial with acalabrutinib compared to what we saw in the frontline setting with acalabrutinib in the ELEVATE-TN trial. Both of them included older patients. What are your thoughts on that?

Jennifer R. Brown, MD, PhD: Well, it was slightly higher, but the control arm was much higher.

Alan Skarbnik, MD: Yes.

Jennifer R. Brown, MD, PhD: So it looked less different than the control arm to me. And also, as patients are treated with more therapy, they tend to experience more problems. But I was more convinced that there was a slight signal for atrial fibrillation in the ELEVATE-TN data compared to the ASCEND data.

Alan Skarbnik, MD: Because of the control arm…

Jennifer R. Brown, MD, PhD: Because of the control arm, exactly.

Alan Skarbnik, MD: Yeah, that makes sense.

Transcript edited for clarity.