An Expert Assessment of Available BTK Inhibitors Within the CLL Treatment Spectrum

Brad S. Kahl, MD

BTK inhibitors have revolutionized the treatment paradigm in chronic lymphocytic leukemia (CLL). In an interview with OncLive, Brad S. Kahl, MD, director of the Lymphoma Program at the Siteman Cancer Center, discusses this game-changing therapeutic class.

OncLive: Ibrutinib and acalabrutinib are approved within the chronic lymphocytic leukemia (CLL) treatment space. Could you briefly highlight the pivotal studies of these 2 agents?

Kahl: Ibrutinib has been around for CLL treatment longer than acalabrutinib, so we have some long-term follow-up data on ibrutinib usage. The RESONATE-2 study was the frontline study that led to approval for ibrutinib in frontline CLL, and we now have 5 years of follow-up showing [that] 70% of patients are still in their first remission at 5 years, so that’s excellent results in long-term follow-up data. The data for acalabrutinib as frontline therapy for CLL are less mature, but [the drug] looks equally strong to ibrutinib at the same point in time. Now that acalabrutinib has an indication in frontline CLL, it will be very interesting to see how practitioners choose one [medication] over the other.

They seem to be quite comparable in terms of efficacy. There may be a slight advantage for acalabrutinib in terms of tolerability over ibrutinib, and I think as people get more experience with [acalabrutinib] that they might be attracted to that tolerability. Acalabrutinib is a twice-a-day medication, whereas ibrutinib is a once-a-day medication. There may be trade-offs in terms of the tolerability versus the convenience and the ease [between the 2 agents]. I guess the bottom line [is that] this is a good problem to have with 2 incredibly active Bruton tyrosine kinase (BTK) inhibitors that are both options for the management of CLL.

Do any specific situations come to mind as to when you would consider using a novel BTK inhibitor over ibrutinib?

[A] specific situation where you might pick one BTK inhibitor over ibrutinib [is] if your patient has a history of arrhythmias. This part I’m a little reluctant to sound too definitive on because I think the jury is still out on the risk for arrhythmias with the newer drugs.

We know the risk of developing atrial fibrillation in other arrythmias is there with ibrutinib, and it probably is in the 10% range. About 10% of patients will develop some kind of arrythmia, and the problem, frankly, is not so much the arrythmia because atrial fibrillation can be managed, but it’s the requirement for anticoagulation and then the bleeding risk that comes along with having to be on ibrutinib plus an anticoagulant for atrial fibrillation. That’s where the danger comes in. If the risk of arrythmia turns out to be less with acalabrutinib or newer generation BTK inhibitors, that would be nice because it’s just one less hassle factor. When patients do go into atrial fibrillation with a BTK inhibitor, it is a problem—you have to hold it, you have to get them to the emergency [department] to deal with their atrial fibrillation, you have to get them on blood thinners—anything we could do to minimize that complication therapy would be welcomed. If the new BTK inhibitors truly have less risk for arrythmia, that would be a welcome development.

On that note, what data have we seen with zanubrutinib?

I have not seen as much data on zanubrutinib. You know, they [have] a few modest mantle cell lymphoma trials. They haven’t really reported a lot of their CLL data. So far, the atrial fibrillation risk looks pretty low for zanubrutinib. I will tell you that [the risk of atrial fibrillation] also looked very low in the early days of acalabrutinib, but as the acalabrutinib data accumulated, the atrial fibrillation risk increased. I’m not yet ready to say that the zanubrutinib atrial fibrillation risk is really low. I think we need a bigger patient experience before we can say that for sure.

Are there any anticipated trials regarding other BTK inhibitors within the CLL landscape?

I think the trials that are of the most interest in CLL with BTK inhibitors are the combination trials looking at time-limited options. There are several trials combining ibrutinib with venetoclax with and without an anti-CD20 monoclonal antibody comparing indefinite therapy [with] time-limited therapy. Most clinicians are very anxious to develop time-limited therapy options for a patient with CLL so that they are not stuck on therapy for years and years, because of the [adverse] effects and because the drugs are expensive. That’s what I’m really interested in seeing—how these time-limited combination therapies pan out in the long run, and I’m hopeful that [it] will turn out to be the best option for our patients.