Expanding Options for Treatment of CLL Using BTK Inhibitors - Episode 2
Jennifer R. Brown, MD, PhD: The first-in-class BTK [Bruton tyrosine kinase] inhibitor, as we’re all aware of, is ibrutinib. Ibrutinib inhibits BTK covalently and quite potently, but not that specifically. It does have a number of other targets that it hits. EGFR, for example, can contribute to rash and diarrhea that we see with ibrutinib. One of the targets we worry most about is TEC, which can affect platelet function. Inhibiting BTK and TEC together can often result in increased bleeding and decreased platelet function. ITK has also been of interest, particularly because it inhibits antibody-dependent cellular cytotoxicity [ADCC] when inhibited by ibrutinib, for example, and that could affect the ability to combine with antibodies such as rituximab. But despite this, ibrutinib has obviously been a very effective drug, and it’s the first-in-class inhibitor particularly for high-risk patients. Ibrutinib was astonishingly effective in terms of actually saving the lives of the patients who had heavily pretreated relapsed/refractory disease when they initially received the drug on the trials.
At this point, of course, ibrutinib is approved for any line of therapy for any CLL [chronic lymphocytic leukemia] patient as a single agent as well as combined with obinutuzumab in the front line. It is generally given at 420 mg daily. The only reason to use a dose reduction is if you’re combining with a drug that affects ibrutinib metabolism. Those are mostly moderate-to-strong CYP3A4 inhibitors. In that case, you have to be very careful. You always want to review medication lists before you start ibrutinib. Ibrutinib is better tolerated in younger patients. I do find that toxicity goes up significantly as patients get older, and it can be more difficult for them to remain on the drug.
Now we have a second-generation inhibitor, acalabrutinib. Alan, do you want to tell us about acalabrutinib?
Alan Skarbnik, MD: Yeah, of course. Certainly, as Jennifer pointed out, ibrutinib changed the paradigm of treatment in CLL and other B-cell malignancies. But the issues of off-target enzymatic inhibition may become problematic. So newer, second-generation BTK inhibitors have been developed. There are third-generation ones in development right now. Acalabrutinib is an approved medication for CLL and SLL [small lymphocytic lymphoma]. It is approved for all indications—frontline or relapsed—independent of risk factors and cytogenetics. The goal of the development of acalabrutinib was to try to create “a cleaner drug.” It’s specific for BTK. It does have some off-target enzymatic inhibition, but this is not as strong as ibrutinib. The goal was to try to make a drug that would have fewer adverse effects than ibrutinib.
We don’t know yet if that’s true, because the ongoing head-to-head comparison trials are not finalized. There’s a trial comparing ibrutinib with acalabrutinib in high-risk disease. This is specifically studying patients with deletion 11q and 17p in relapsed disease. But acalabrutinib has been evaluated in the frontline setting with or without obinutuzumab in combination, and in the relapsed setting as monotherapy compared with either idelalisib or bendamustine-rituximab. It was proven to be an efficacious therapy for CLL.
The clinical experience with acalabrutinib in terms of adverse effects and tolerability is a bit different from ibrutinib. There’s still bruising and bleeding with acalabrutinib, but it seems to be a different aspect from ibrutinib. It’s not as overt, and the petechiae rash seems to be better controlled. We’re seeing less epistaxis in our clinical experience. Again, there’s no head-to-head comparison there. It is an efficacious drug, as I said.
Interestingly, the frontline trial combined acalabrutinib with obinutuzumab and has an arm that had acalabrutinib as monotherapy. Unfortunately, this was not powered to do a comparison between both arms. But in the subgroup analysis, the arm that included obinutuzumab did provide an improvement in patients who had IGHV-mutated disease compared with chlorambucil or obinutuzumab. It’s food for thought. It’s hypothesis driving. To some extent, this may be because there is less ITK inhibition with acalabrutinib, as Jennifer pointed out. It is an issue with ibrutinib. It may be that it allowed the antibody-dependent cellular cytotoxicity driven by obinutuzumab to still be effective; whereas ibrutinib may inhibit ITK and decrease the effective ADCC when combined with a different agent.
It’s a newer drug. We don’t have as much experience with acalabrutinib when compared with ibrutinib. Ibrutinib has over a 5-year follow-up in the RESONATE trial, for instance. So it may be that we see more adverse effects down the road; that may be coming later on. We know that hypertension is an effect of ibrutinib that increases over time. This may be the case with acalabrutinib as well. But it’s an efficacious and safe drug, overall, and it’s out there. We have to evaluate this more in the real-world setting. There are a number of studies with ibrutinib in that setting that have looked to see what the adverse-effect profile and the toxicity profile are in the older population. There are still data coming out, in terms of tolerability. But it’s a valid option for patients.
Transcript edited for clarity.