The approach to BTK inhibitor intolerance is individualized, as each patient is different and each BTK inhibitor has its own unique profile. However, when initiating BTK inhibitor therapy in a patient with CLL, I typically recommend a second-generation agent such as acalabrutinib, as the data show that many of the side effects of ibrutinib may be less of an issue with acalabrutinib. Another second-generation agent, zanubrutinib, might receive US Food and Drug Administration approval for CLL as well.

Randomized, phase 3, clinical trials show equivalent or better results with both second-generation BTK inhibitors compared with the first-generation agent ibrutinib, with lower rates of atrial fibrillation, and we now have very good follow-up data for these studies. We must rely on the data when prescribing drugs that patients with CLL will be taking for years. These treatments can affect other variables that may impact quality of life. For example, cardiac arrhythmias and hypertension can lead to stroke and other issues over time.

For those patients who are already on ibrutinib and are experiencing the effects of ibrutinib intolerance, and for the rare patient who is on ibrutinib and has a marked cardiac risk profile, I will discuss switching to acalabrutinib. If they are doing well on ibrutinib, I will not necessarily recommend switching therapies, but I am interested to hear what others in the field are doing. Even in younger individuals who might be exposed to treatment for years, if they are doing well on ibrutinib, one must consider that switching to acalabrutinib, for example, might lead to new issues such as headaches.

I do talk to patients who are taking ibrutinib about the ELEVATE-RR study findings because I think that the data suggest that, over the long-term, events outside of CLL progression are likely driving outcomes. ELEVATE-RR is the first phase 3 comparison of acalabrutinib vs ibrutinib in previously treated patients with CLL, and headache and cough were the only adverse events that were more common with acalabrutinib than with ibrutinib. Some of the problems that were unique to ibrutinib were muscle cramps, including cramps that were severe enough to wake the patients up at night. Skin changes occur with both treatments, but with ibrutinib, particularly in patients who take it for long periods, bronze lymphedema may be observed, whereby patients will develop thickened, brownish-hued skin.