Examining the Role of Frontline BTKi Monotherapy in CLL - Episode 2

Tolerability of Ibrutinib, Zanubrutinib, and Acalabrutinib

March 29, 2021
Jennifer R. Brown, MD, PhD

Citing results from recent trials, Jennifer R. Brown, MD, PhD, compares patient tolerability levels of ibrutinib, zanubrutinib, and acalabrutinib.

Jennifer R. Brown, MD, PhD: Ibrutinib has been associated with significant adverse effects, including in the frontline setting, where some real-world data demonstrated a 40% discontinuation rate after a median of just 6 months on therapy. Even in RESONATE-2, the randomized trial, we have a 40% discontinuation rate after 4 years. This is because of a variety of adverse effects. Joint pains and arthralgias can be quite bothersome for frontline patients and lead to many discontinuations. There are also cardiac events, particularly atrial fibrillation and hypertension. Bleeding events also can be a major issue. We still don’t have head-to-head data comparing acalabrutinib with ibrutinib in terms of these adverse events, but a number of studies that have suggested that it may be better tolerated in this regard.

At ASH [American Society of Hematology Annual Meeting], a summary of 4 trials that included acalabrutinib monotherapy arms was presented with a particular focus on cardiovascular adverse effects. The overall incidence of any cardiac adverse events was 17%, with the most common being atrial fibrillation or flutter, which was seen in only 5%. The next 2 were tachycardia and palpitations, not particularly real events. The great majority of patients were able to remain on acalabrutinib despite a cardiac event, with a less-than-1% discontinuation rate due to the cardiac event. The rate of cardiac events over time also appeared relatively constant. We know with ibrutinib that there is an initial peak of atrial fibrillation in the first 6 months in which the relative risk is highest. With ongoing use, there is a continuing low rate of recurrent atrial fibrillation. There was also a meta-analysis of 27 studies presented at ASH that demonstrated significantly lower rates of any grade and grade 3 hypertension as well as any grade and grade 3 atrial fibrillation, with acalabrutinib compared with ibrutinib.

At the same time, we heard data from [The University of Texas] MD Anderson [Cancer Center] suggesting that the majority of patients on ibrutinib do develop worsened or new hypertension over time and that this is associated with other cardiac events, such as heart attacks and strokes. The summary of these data strongly suggests that for patients with underlying cardiac disease, there is a definite reason to prefer acalabrutinib. That’s certainly been my own personal practice for some time.

We also have data from the Alliance [North American Intergroup Study A041202] trial. In particular, they show that with increasing age, the toxicity of ibrutinib becomes more apparent. The treatment-related mortality over 3 years with ibrutinib, in both the ibrutinib and the ibrutinib-rituximab arms in the Alliance trial, was 7%, which is much higher than what was seen in the younger patient population in the ECOG trial. Increasing age is a reason to favor acalabrutinib over ibrutinib. The bleeding risks are not so clear. Most studies continue to show a significant rate of low-grade bleeding and bruising with acalabrutinib on the order of 40%, similar to ibrutinib. The major hemorrhage rate is usually around 3% or 4% in these studies, which is similar to ibrutinib. I remain hesitant about either BTK [Bruton tyrosine kinase] inhibitor in a patient who has had significant bleeding problems.

What if zanubrutinib gets approved? That’s a little complicated. We don’t have a lot of long-term follow-up data on zanubrutinib. In general, the adverse-event profile seems improved compared with ibrutinib and may be similar to acalabrutinib. We do…have head-to-head data with zanubrutinib compared with ibrutinib. That’s the first head-to-head trial that has been published, and there is a significant decrease in the rate of atrial fibrillation, from 15% with ibrutinib to 2% with zanubrutinib, as well as trends toward less hypertension and less edema. You do see more neutropenia with zanubrutinib, but in my experience, that’s been pretty manageable.

A switch between acalabrutinib and zanubrutinib is still challenging. We have longer follow-up data with acalabrutinib, but we actually have head-to-head data comparing zanubrutinib to ibrutinib. By the time zanubrutinib gets approved, we’ll likely have the head-to-head acalabrutinib data as well, which provides a further point of comparison. My personal anecdotal experience has been that zanubrutinib has even fewer symptomatic adverse effects than acalabrutinib. For example, you still have some patients who will get significant arthralgias with acalabrutinib, which I haven’t ever seen with zanubrutinib. For that reason, for example, zanubrutinib has now been listed in the NCCN [National Comprehensive Cancer Network] Guidelines who have been intolerant to ibrutinib and acalabrutinib in a relapse setting.

Transcript edited for clarity.