We have seen that the addition of rituximab to ibrutinib does not seem to improve upon ibrutinib monotherapy, and the reasons for this relate to both the mAb and the BTK inhibitor.

We know that ibrutinib abolishes the antibody-dependent cellular cytotoxicity (ADCC) of first-generation anti-CD20 mAbs. Using a third-generation anti-CD20 mAb such as obinutuzumab, which is thought to be a stronger recruiter of immune effector cells, you might be able to partially rescue ADCC, via natural killer cell activity, but only partially. Acalabrutinib and zanubrutinib do not antagonize ADCC. If anything, they improve it by diminishing the surrounding immune-suppressive environment. This may be the reason why the ELEVATE-TN study of acalabrutinib with or without obinutuzumab for treatment-naive chronic lymphocytic leukemia (CLL) showed benefits with the addition of obinutuzumab. In general, the ELEVATE-TN study demonstrated that the addition of obinutuzumab offered the advantage of progression-free survival, along with showing a nice trend toward overall survival in that group.

As new combinations are developed, you hear talk in the field about potentially abandoning anti-CD20 mAbs, but we must remember that these are the first therapies that prolonged survival in patients with CLL. I would say that mAbs are still important in the treatment of CLL, but we will have to work on combining the right antibody with the right BTK inhibitor. The data with second-generation BTK inhibitors and anti-CD20 mAbs are close to what we would see with the combinations of venetoclax with either an anti-CD20 mAb or a BTK inhibitor. I think that the latter strategies create more immune suppression. I am more interested in seeing if we can come up with better mAbs, whether they are anti-CD20 mAbs or another target, administered in combination with a second- or higher-generation BTK inhibitor rather than venetoclax.