Ibrutinib is the BTK inhibitor that has been around the longest and for which we have the most long-term data. It is an extremely effective drug; however, it is associated with a number of dose- and treatment-limiting adverse events, including rash, muscle aches and pains, fatigue, and joint aches. Ibrutinib can also be linked to an increased risk of bleeding, bruising, and atrial fibrillation. Some of these events may require patients to come off treatment.

More recently, second-generation BTK inhibitors acalabrutinib and zanubrutinib have been introduced. Acalabrutinib is US Food and Drug Administration approved for the treatment of CLL, while zanubrutinib is currently only approved for mantle cell lymphoma. The incidence of side effects and toxicities associated with these newer agents compared with ibrutinib are currently under investigation, but clinical experience suggests that they have a lower incidence of many of the BTK-related adverse events. Headache seems to be more common with acalabrutinib; however, this generally tends to be a relatively short-term phenomenon, lasting just a few days.

Differences in the side-effect profiles of ibrutinib and acalabrutinib were announced in a January 2021 press release reporting the results of the phase 3 ELEVATE-RR trial, which compared acalabrutinib with ibrutinib in patients with previously treated CLL. Results showed that there was no difference in effectiveness between the 2 drugs, but acalabrutinib was associated with a statistically significantly lower risk of atrial fibrillation compared with ibrutinib. There is another ongoing trial (the ALPINE study; NCT03734016) comparing zanubrutinib vs ibrutinib in patients with relapsed or refractory CLL, so we will soon have comparative data with regard to efficacy and safety.

Theoretically, a difference in tolerability has the potential to improve clinical outcomes if it results in more patients staying on therapy at the recommended doses and durations. However, we need more long-term follow-up data for these agents to confirm that benefit. The bottom line is that it is important for patients with CLL and their providers to know that there are alternative BTK inhibitors if they cannot tolerate ibrutinib. For such individuals, it is my preference to switch to either acalabrutinib or zanubrutinib rather than switching to venetoclax, as you want to keep on target for as long as possible to reserve other treatments for the future, when they might be needed owing to changes in the disease biology.