Novel Combinations for Frontline CLL

John M. Pagel, MD, PhD:One of the interesting things we are considering is if we need to add an anti-CD20 antibody to therapy. We do recognize that anti-CD20 antibodies can work in CLL [chronic lymphocytic leukemia]. Perhaps they don’t work as well as they might in other lymphomas. We’ve actually now learned that rituximab [Rituxan] probably doesn’t add a significant benefit, at least to ibrutinib in the frontline setting. We’ve had at least 2 randomized trials of ibrutinib, either with or without Rituxan, and we’ve seen no difference in patient outcomes. This suggests that rituximab probably doesn’t add much, if anything, to a BTK [Bruton tyrosine kinase] inhibitor.

However, we now have a second-generation, or newer-generation, anti-CD20 antibody: obinutuzumab. I mentioned that the ELEVATE-TN trial of acalabrutinib, the next-generation BTK inhibitor, looked at the therapy with and without obinutuzumab. The acalabrutinib-obinutuzumab arm did have a progression-free survival advantage over the single-agent acalabrutinib-alone arm, but it doesn’t appear that there’s a survival difference between the 2 different arms. It’s approved where you can give acalabrutinib as a single agent or acalabrutinib with obinutuzumab. This is a choice between the patient and the physician—if you want to add the anti-CD20 antibody or not. Maybe you would want to add it because you want to extend progression-free survival. However, it’s important to remember that it comes at a cost with some infusion-related reactions, probably a little more neutropenia and maybe even febrile neutropenia—when you add the antibody to the BTK inhibitor, at least obinutuzumab.

The other unanswered question is, should we be using BTK inhibitors or should we be using venetoclax, a BCL2 inhibitor? There are now data that led to the approval of venetoclax in combination with obinutuzumab in the frontline setting. The beauty of that study, which compared it with chlorambucil and obinutuzumab—and it was shown to be very advantageous, not surprisingly—is that it’s 1 year of time-limited therapy. It’s very appealing, perhaps, for a younger patient—someone who wants to get some treatment, have the treatment stopped, be off therapy for hopefully a considerable amount of time, and then if and when the disease comes back, they can be rechallenged as well.

One of the caveats we have to remember is that the people who do the best and the people who come off therapy at a year are typically people who become undetectable for minimal residual disease [MRD]. Fortunately, the majority of patients are able to do that with that regimen and can come off therapy. But the high-risk patients are proving to not become undetectable for MRD. Or if they’re showing that their MRD level is rising at the year end point, they probably don’t want to come off the drug because they’re going to relapse quickly.

How you choose between the venetoclax-obinutuzumab regimen or a BTK inhibitor, either with or without obinutuzumab, comes down to a judgment call and a decision between the physician and the patient about what might be right. There may be comorbidities that would drive you away from a BTK inhibitor and toward venetoclax. They could be things like bleeding risk in people who are on anticoagulation, or they may be things like renal insufficiency. That might drive you more to a BTK inhibitor and away from venetoclax. These are discussions that we commonly will have with patients every day in the clinic. Remember, if you are on the BTK inhibitor, you are on a single-agent BTK inhibitor indefinitely until you either progress or until you become intolerant to treatment.

That leads us to where we’re going next, and that’s combinations of agents. In particular, combinations of a BTK inhibitor with venetoclax. Actually, even 3-drug combinations are emerging—ibrutinib-venetoclax-obinutuzumab or acalabrutinib-venetoclax-obinutuzumab. These agents are proving to be, in combination, very, very powerful at achieving undetectable MRD, and that’s allowing for the opportunity to give time-limited treatment. We do understand that the ibrutinib-venetoclax regimen and, likely down the road, the acalabrutinib-venetoclax regimen, will be approved, and combinations might also be the way to go, with or without an anti-CD20 antibody.

Transcript edited for clarity.