John P. Leonard, MD: Tycel, the other area that we see more and more, some of which was at ASH [American Society of Hematology Annual Meeting], some of which are ongoing trials, is various combinations. I know you’re involved in some of these. We have zanubrutinib-rituximab, venetoclax with zanubrutinib-obinutuzumab-ibrutinib-rituximab, acalabrutinib-bendamustine-rituximab. It’s the mix and match. It’s like pick 1 from column A and 2 from column B. What’s the takeaway? I mean, it seems to me you add drugs to get more toxicity and you might have more efficacy, and we just have to see. Is there a lot of rationale behind these, and what are some of the early data that we’ve seen?

Tycel Jovelle Phillips, MD: To your first point, the obvious goal is if you have an effective agent in a relapsed/refractory setting, you want to move it up. We’ve seen quite a few trials that have tried to move the BTK [Bruton tyrosine kinase] inhibitors earlier on in therapy. As I mentioned earlier, in the SHINE study, which looked at ibrutinib-bendamustine vs bendamustine, you know the acalabrutinib study that resembled that. Very good points. You get more toxicity in some of these situations, and sometimes just because an agent works doesn’t mean it adds to something else. As we know, the SHINE study still hasn’t resulted out, which raises more red flags. Maybe BTK doesn’t add anything to bendamustine and then BR [bendamustine-rituximab] is just as well if we left it alone.

Some of the other combinations, obviously we know zanubrutinib has a study that looked at rituximab-zanubrutinib plus BR [bendamustine-rituximab], because they’re trying to emulate CLL [chronic lymphocytic leukemia] and replace a lot of the chemotherapy regimens with some of these noncytotoxic regimens in the up-front setting. The Rituxan/BTK studies and the addition of venetoclax, which was shown in a relapsed/refractory setting, isn’t safe. When you add it up front, the goal is obviously to try to deepen the response. Probably something we’ll touch on later is obviously this mythical attainment of being MRD [minimal residual disease] undetectable. Can we get there with some of these noncytotoxic agents? With the combinations, we would assume that you have a greater pass to get to that point with some of these agents.

I think there was a French publication with obinutuzumab-venetoclax-ibrutinib, and they also looked at MRD. I think MRD in a lot of these other industry-sponsored studies will be collected and reported out later. All these combinations are really just trying to move some of these agents up earlier and expose more patients than what you would typically see in a relapsed/refractory setting. Not to mention adding BTK to CAR T, which is, I’m assuming, on its way for mantle cell as well.

John P. Leonard, MD: Andy, what’s your take on some of these combinations? It seems like it’s pretty clear it’s something to try in the TP53 mutated. Besides that what are your early impressions?

Andrew D. Zelenetz, MD, PhD: One of the trials that we’re talking about is this combination of zanubrutinib and obinutuzumab with venetoclax, what we call the BOVen trial, initially piloted as an adapted duration of response in CLL and found that, at a median of 10 months, people could stop treatment because they were MRD undetectable. We’ve adapted that same study to TP53-mutant mantle cell lymphoma. Patients are being monitored. However, it’s not response adapted. Everyone will get 24 months of treatment, and the reason for that is because the TP53 mutation is there, as I mentioned before. We know that these are harder to treat, but the goal is to have time-limited therapy. If we start with ibrutinib, or acalabrutinib, or zanubrutinib as a single agent up front, you’re going to be on that drug forever. By combining the drugs, we actually have complementary mechanism of action. There is a rationale. There’s preclinical rationale for synergy and laboratory in xenografts. The idea is to get to undetectable MRD. Those are the goals of the study. We have these very sensitive measures, so we can really test that hypothesis, and that’s true with all the combinations.

Transcript Edited for Clarity