John P. Leonard, MD: Now let’s move on and talk about the relapsed patient setting. I think we’ve alluded to the idea that relapsed disease can be more challenging. Andre, what’s the typical way that a patient presents? Then, I’m going to ask Steve to talk a little bit about deciding on a therapeutic approach. Andre, are these patients that you are monitoring closely, that come in with a scan finding or a new node, coming in with rip-roaring disease? What’s the typical pattern?

Andre Goy, MD: That’s a very good question. Again, I see a big spectrum, not surprisingly. It makes it very difficult because of, as we just talked about, the heterogeneity in the management of these patients in the real world, or even on trials. You have patients who have different types of treatment for various heterogeneous diseases. So, it’s a very different evolution. You’re going to have patients that present to us because they have a few nodes on a routine study. And you’re going to have the opposite, someone who has seen 5 rounds of therapy in the community clinic, and then comes to see us with accelerated disease. Here we think more about transplant.

Now, we have the study with the CAR (chimeric antigen receptor) T-cell data. This patient could be a candidate if they fail ibrutinib. But the mechanisms of resistance, clearly, over time, and particularly in the cytotoxic setting, have very short response and survival once they fail R-chemotherapy. Definitely, high-dose therapy and autologous transplant doesn’t help those patients.

Then, the other situation is the patient that presents with minimal disease that you monitor. We talked about colonoscopy before, because they had a history of mantle cell lymphoma. On a repeat colonoscopy, there’s minimal disease. You can probably watch these patients for quite a while. So, I agree that there’s a whole spectrum of presentation.

John P. Leonard, MD: Steve, how do you approach a relapsed mantle cell patient? My guess is, if they’re asymptomatic with minimal disease, you may watch them. But there’s a rationale to starting something easier, sooner perhaps, and obviously the symptomatic patient.

Stephen J. Schuster, MD: There is a spectrum, but if you look at every study out there on mantle cell lymphoma, patients that have had 1 or more relapses have a shortened survival. That’s regardless of what therapy is being studied. For example, if you look at the data for patients who get ibrutinib in first relapse versus patients that have had more than 1 line of therapy, it’s hugely different. I think there was an abstract at this meeting, in fact, that showed that. I think that once these patients have seen chemotherapy agents, and I don’t know if this is true if you were to start with ibrutinib, this is genetically unstable disease. Once these patients have seen chemotherapy and they relapse, it tends to be fairly aggressive. And if you study them, you’ll find acquisition in mutations like p53. I’ve seen double hits. People get a MYC translocation when they recur.

All of the treatments, I say, are palliative. But there is a benefit to the autologous transplant or intensive therapy upfront because you have a long progression-free survival. And in fact, when you look at the literature, all studies that have long-term follow-up are basically retrospective studies. The future is changing so quickly in terms of new agents. There’s a benefit to being progression-free, regardless that they don’t show an overall survival benefit. So, I think we should try to be aggressive, upfront. When they recur, though, you’re likely to be stuck with a patient that’s going to have a bad prognosis. Sometimes you’ll get the same disease back, if you’re lucky. But if it’s aggressive, I tend to want to put those patients on trials like the CAR T trial that Andre was mentioning. If it’s somebody that has a p53 mutation, if I can get them into remission with a kinase inhibitor, and they’re young and they have a donor and are a candidate for transplant, that would be the one situation where I might consider doing an allogeneic transplant. I wouldn’t do it in first remission in most patients in mantle cell lymphoma. But in that particular situation, I would consider it.

John P. Leonard, MD: Have you been giving everyone ibrutinib as their second-line therapy, pretty much? We also have bortezomib, lenalidomide, chemotherapy regimens. How do you treat outside of trial?

Stephen J. Schuster, MD: Outside of trial, yes. A trial is ideal, actually, for these patients. We need guidance. But I would say that I was a great fan of lenalidomide and lenalidomide/rituximab in these patients with less aggressive relapse presentations, and I still am. I also use ibrutinib, as well. I kind of do it by toxicity. If somebody is on one, and they’re having side effects, I may use the other. If the presentation at relapse is not of an aggressive nature, with a lot of mutations and additional findings, then I’ll go to a non-chemotherapeutic approach like ibrutinib or lenalidomide/rituximab.

John P. Leonard, MD: John, what is your approach in the relapsed patient?

John M. Pagel, MD, PhD, DSc: I’m right on board with Steve. In those patients, I will typically go to a kinase inhibitor. And typically, I’ll go to ibrutinib. There are patients, of course, for whom you might want to stay away from ibrutinib in as a first choice. Those might be patients with underlying structural heart disease, somebody who is at risk for atrial fibrillation (AFib), has AFib, or is on an anticoagulant. In those patients, I might choose Revlimid (lenalidomide).

Stephen J. Schuster, MD: Of course, we now have acalabrutinib.

John P. Leonard, MD: We’ll come back to that in a second.

John M. Pagel, MD, PhD, DSc: But I think these are tremendous options for patients that we just didn’t have very long ago.

Stephen J. Schuster, MD: That’s why you want that first remission with these patients to be as long as possible. The future is going to be better and better.

Transcript Edited for Clarity