Second-Generation BTK Inhibitors in CLL

William Wierda, MD, PhD: Following on those thoughts about BTK [Bruton tyrosine kinase] inhibitor–based therapy, there are second-generation BTK inhibitors that have been developed. The acalabrutinib was relatively recently approved for patients with CLL [chronic lymphocytic leukemia], and the data that supported the approval was recently published with the ELEVATE-TN trial. John Burke, maybe you can comment on—particularly if you’ve had any experience using acalabrutinib—what your experience has been in terms of efficacy, activity, and tolerability of the second generation, particularly acalabrutinib.

There’s another 1, zanubrutinib, which is not approved for CLL but is approved by the FDA for mantle cell lymphoma. We also may have zanubrutinib available for CLL eventually. What are your thoughts on the second-generation molecules?

John Burke, MD: If you want, I cansummarize ELEVATE-TN data. These were presented by Jeff Sharman at the ASH [American Society of Hematology] Annual Meeting and then published in April of this year in Lancet. This is a phase 3 trial that had 3 arms. The control arm was chlorambucil-obinutuzumab, and the 2 investigational arms were acalabrutinib alone and acalabrutinib plus obinutuzumab. The patients were those similar to iLLUMINATE and CLL14. These were patients who were either older or had higher CIRS [cumulative illness rating scale] scores and thought not to be candidates for more aggressive therapy.

The primary end point was PFS [progression-free survival]. The median follow-up is just over 2 years. The data show that PFS with either acalabrutinib arm was superior to PFS with chlorambucil-obinutuzumab. There was a numerical improvement in PFS in the combo acalabrutinib-obinutuzumab arm compared with single-agent acalabrutinib. The authors were careful to state that they could not comment on the statistical significance because that was a post hoc analysis and not part of the primary end point.

In terms of toxicity, they reported the rate of atrial fibrillation [AF] at 3% to 4%, which as I just mentioned, is similar to what we saw in the earlier follow-up with ibrutinib trials. There’s a lot of talk about how AF rate may be lower with some of the second-generation agents and we’ve seen documentation of that in the phase 3 ASPEN trial of zanubrutinib in Waldenström macroglobulinemia as compared with ibrutinib. Those are the only randomized data I’m aware of, and we’re waiting on acalabrutinib-versus-ibrutinib randomized data to see if that difference in AF rate holds up.

I hear experts talk about how acalabrutinib is likely to cause less AF and less cardiac toxicity. I’m a little cautious in drawing that conclusion myself and a bit agnostic on that. The bleeding rate in the ELEVATE-TN trial was in the 35%-to-45% range. The grade 3 bleeding rate was 2%, similar to what we heard early on with ibrutinib. The 1 comment on the acalabrutinib toxicity that is a little unique, but practitioners should know, is headaches. If you haven’t heard this before, headaches are relatively commonly reported with acalabrutinib.

The data that I saw early on was that it was about a third of patients. There is probably more attention paid to that now. In the studies coming out now, we’re seeing about two-thirds of patients reporting headaches. How many of those are actually because of acalabrutinib versus the fact that people get headaches and they get reported, I’m not sure. It certainly seems that there’s a headache signal. The headaches are usually manageable. I tell my patients to try caffeine and Tylenol and those types of things.

Usually it will help manage the headaches, and most patients are not having to stop the drug because of intolerable headaches. In my hands, acalabrutinib has been well tolerated. I haven’t used as much of it as I have ibrutinib. So far, I haven’t had any major problems. However, I did have 1 bleed in a patient who I was forced to use acalabrutinib concurrently with an anticoagulant, so there you go. I’d be cautious about that.

Transcript Edited for Clarity