Ibrutinib is a first-in-class BTK inhibitor. Second-generation BTK inhibitors such as acalabrutinib and zanubrutinib have been developed for B-cell malignancies, with acalabrutinib receiving US Food and Drug Administration approval for CLL in addition to mantle cell lymphoma. Zanubrutinib is approved for mantle cell lymphoma and is also listed in contemporary guidelines as an option for consideration in patients with CLL who are intolerant of alternative BTK inhibitors. One can look at a kinome map to determine what is inhibited by BTK inhibitors. Some of the newer BTK inhibitors have less off-target activity than first-generation BTK inhibitors. This may have implications as we look to incorporate BTK inhibitors in investigational combination regimens.

Head-to-head studies have compared acalabrutinib with ibrutinib and zanubrutinib with ibrutinib, showing advantages with the second-generation BTK inhibitors in both analyses. For instance, lower rates of atrial fibrillation and arthralgias were reported with acalabrutinib and zanubrutinib, although we did see slightly higher rates of neutropenia with zanubrutinib and increased frequency of headache with acalabrutinib.

Ibrutinib, acalabrutinib, and zanubrutinib are all covalent BTK inhibitors, so they inactivate BTK until such time as it is resynthesized. Since BTK resynthesis begins around the 20- to 24-hour mark, some have argued that twice-daily treatment is, functionally, a better way to suppress BTK. Alternatively, a drug with a longer half-life might yield more prolonged suppression of BTK and enzyme activity. From a potency perspective (BTK inhibition), there is little differentiation among the currently available BTK inhibitors.

Antibody-dependent cellular cytotoxicity (ADCC) is another mechanism that might be affected by off-target activity. ADCC requires intracellular signaling, and such signaling through interleukin-2–inducible T-cell kinase is inhibited by ibrutinib but not by acalabrutinib or zanubrutinib. And so, in theory, ibrutinib’s off-target activity might interfere with ADCC, which may impact the concurrent use of anti-CD20 antibodies.

There are several studies in which ibrutinib was administered with or without rituximab. These studies have not demonstrated an advantage of adding rituximab to ibrutinib therapy. Further, the ELEVATE-TN study compared acalabrutinib with or without obinutuzumab vs obinutuzumab plus chlorambucil in patients with treatment-naive CLL. Improved progression-free survival was reported at 4 years when obinutuzumab was added to acalabrutinib as compared with acalabrutinib monotherapy (87% vs approximately 78%). Still, the addition of obinutuzumab to any regimen comes with additional toxicities, including infusion reactions, neutropenia, and infections, and it adversely impacts COVID-19 vaccination.

Finally, we are seeing high degrees of selectivity and very low rates of adverse events with the reversible BTK inhibitors that are under development (eg, pirtobrutinib). Some of the data with these agents are less mature, so whether these toxicity profiles will hold up will be subject to future evaluation.