The first-generation BTK inhibitor ibrutinib was first approved by the US Food and Drug Administration (FDA) for mantle cell lymphoma in 2013 and then for CLL in 2014, so we have about a decade of experience with the drug if you include the preapproval experience with clinical trials. Ibrutinib has transformed the management of CLL, particularly for those with high-risk disease such as 17p deletion or TP53 mutation and for those with unmutated IGHV, but also for low-risk patients. Nonetheless, patients with CLL tend to be older; in addition, age-associated comorbidities are common, and treatment-limiting toxicities with ibrutinib are a concern in certain patients. Some of these toxicities may be related to the broad inhibitory nature of ibrutinib on a number of different kinases. These concerns include risks for bleeding, atrial fibrillation, hypertension, and even some ventricular dysrhythmias, as well as other less serious but still bothersome side effects such as arthralgias, muscle cramps, and rash.

The experience with ibrutinib motivated the development of a second generation of more specific BTK inhibitors, including acalabrutinib and zanubrutinib, with a goal of reducing toxicities. Acalabrutinib is FDA approved for CLL, while zanubrutinib has shown promise in CLL but is currently only FDA approved for relapsed or refractory mantle cell lymphoma. These agents do appear to have a lower risk of toxicities such as atrial fibrillation and hypertension, and possibly also less rash, arthralgia, and muscle cramps. Further, the second-generation agents appear to have efficacy that is similar to that of ibrutinib, although we do not yet have prospective comparative data. In the relapsed/refractory CLL setting, we recently saw in a press release that the phase 3 ELEVATE-RR trial met a key secondary end point for safety, with researchers reporting that patients treated with acalabrutinib had a statistically significantly lower incidence of atrial fibrillation compared with those on ibrutinib. Similarly, in the phase 3 ASPEN trial, zanubrutinib was found to be at least as effective as ibrutinib in patients with Waldenström macroglobulinemia and was associated with less toxicity.

As we await the full results of the ELEVATE-RR study, several retrospective analyses have been helpful in filling in the data gaps. A network meta-analysis of B-cell lymphoproliferative disorders presented at the 62nd American Society of Hematology Annual Meeting and Exposition found that acalabrutinib appeared to have lower rates of several adverse events compared with ibrutinib, including atrial fibrillation and hypertension. Similarly, a matching-adjusted indirect comparison found that acalabrutinib with or without obinutuzumab was associated with a reduction in clinically important adverse events compared with ibrutinib with or without obinutuzumab without compromising efficacy. Still, it should be noted that lower risk is not zero risk, and, compared with ibrutinib, the more specific BTK inhibitors do appear to have higher rates of certain toxicities, such as headache (acalabrutinib) and neutropenia (zanubrutinib). This underscores the important point that it is helpful for patients to have options, and each of these BTK inhibitors is likely to continue to play an important role in CLL treatment in the future.