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Dr. Brad Kahl:
Welcome to The ASCO Post Roundtable Series on Clinical Advances in Mantle Cell Lymphoma. I'm Dr. Brad Kahl from Washington University in St. Louis. Joining me today are two of my colleagues.
Dr. Jonathan Cohen:
Hello, Brad. I'm Dr. Jonathan Cohen from the Lymphoma Program at Emory University's Winship Cancer Institute in Atlanta.
Dr. Peter Martin:
Hi. I'm Peter Martin from the Lymphoma Program at Weill Cornell Medicine in New York.
Dr. Brad Kahl:
Welcome, both. Today, we will be discussing recent updates in mantle cell lymphoma and integrating these new developments into three patient case studies. Our last installment will focus on relapsed/refractory mantle cell lymphoma, so let's look at the case.
Mr. HS is a 76-year-old man with a history of mantle cell lymphoma. He was treated with bendamustine/rituximab followed by rituximab maintenance at age 71 when he was diagnosed with advanced stage disease. His recurrence was detected recently by physical examination with the development of new cervical and axillary lymphadenopathy. You note that he has now normal blood counts and the bone marrow was not involved. His first remission lasted approximately 5 years. Here, we see PET scan imaging in multiple stations as well as splenic involvement. He currently feels well with a performance status of zero and he is relatively healthy without major comorbidities. I think I'll pause here and ask a question. I'll start with Peter. Peter, when you have a patient with recurrent mantle cell lymphoma, do you typically get repeat biopsies? And if you do, do you test for P53 mutations?
Yes to both of those. I think there are pretty convincing data that suggests that mantle cell lymphoma tends to sort of pick up speed with each subsequent recurrence and it's a good idea to see whether that's the case. In fact, TP53 mutations do impact prognosis, although I think we're moving clearly away from chemotherapy in the relapse/refractory setting. But still, I think it's helpful to know. And then I will tell you that I have in the past year, for whatever reason, had several cases of people who we have re-biopsied and they had different cancers entirely. Just because it's a lymph node, it doesn't mean that it's lymphoma necessarily.
Very good point. Jonathan, do you tend to get repeat biopsies in your mantle cell lymphoma patients?
Absolutely. Sometimes if you have a patient with a lymph node that may be difficult to assess who has marrow or peripheral blood involvement, you can sometimes confirm that there's recurrence that way. But in this particular case where he doesn't have any apparent marrow involvement, I would certainly want to get a biopsy before moving forward. And like Peter mentioned, I typically will as much as possible repeat the prognostic evaluation because we do sometimes see the disease behave in a different way.
So Peter, what are your major treatment considerations when you move into the second line? Walk us through the different options. BTK inhibitors, which one? Lenalidomide/rituximab, repeating immunochemotherapy. We have CAR T-cell therapy. How do you sort through those options in a case like this?
If we look at the FDA-approved therapies, we have bortezomib, which I don't think anybody is really using in this setting as a single agent right now, so we'll leave that one alone. Lenalidomide/rituximab is approved in this setting. It may have a role, but I think that most of us are probably not using that combination in this setting right now. So really, the question becomes one of BTK inhibitors or CAR T-cells. Both classes are approved in this setting. I think for the most part, CAR T-cells probably belong after BTK inhibitors, although often, we can predict that transition from BTK inhibitors to CAR T-cells may be fairly rapid. My bias, I think, in this setting is to go with BTK inhibitors and then you're right, it becomes a question of which one? There are currently four that have accelerated approval.
First-in-class was ibrutinib followed by acalabrutinib, zanubrutinib and most recently, pirtobrutinib. I think pirtobrutinib is approved for after a prior BTK inhibitor, so may or may not really apply. Ibrutinib was just withdrawn from the US market, but not the European market. So in the US right now, we're effectively choosing between acalabrutinib and zanubrutinib. I feel that both agents have significant activity in this setting and using them in the second-line setting is likely to be more effective than using them in the third or subsequent lines of therapy. I don't know that either one has a strong rationale for choice between the two of them. I think there used to be a clear indication when acalabrutinib had some contraindications related to proton pump inhibitors. That's no longer an issue. There may be subtle distinctions between them, but absent head-to-head combinations, I think for the most part both are very reasonable options.
Jonathan, anything to add to that? Do you think through a case like this any differently or similarly to Peter?
Very similarly. I think the overwhelming majority of the time my choice in this particular case is going to be one of those two BTK inhibitors, either acalabrutinib or zanubrutinib. And I completely agree with Peter that in general, it's not clear that one is better than the other. I think that there are some subtle differences in toxicity profile that may or may not inform those decisions, but I think in general, both are quite good options and are typically where I go in this setting.
So let's say in this instance, the patient was found to have a P53 mutation on the repeat biopsy. Let's say you chose acalabrutinib or maybe you chose zanubrutinib, but you put them on a covalent BTK inhibitor and the patient is doing well, tolerating the treatment nicely as they usually do. And after 6 months on therapy, your repeat evaluation shows the patient has achieved a nice partial remission but is not in a complete remission. How would you think about managing the patient at that point in time? Jonathan, I'll start with you.
This is a tough one and is something that we definitely see not infrequently. So this is a patient who is doing well, who has some comorbidities, who presumably has good quality of life, but where you can see that train coming down the track, they haven't had a particularly deep remission. They have some high-risk features. And so I think this is really where you have to have a conversation with the patient about what's going on and what you can expect moving forward. In the past where we didn't necessarily have additional options, we knew that patients who were on a covalent BTK inhibitor who subsequently progressed unfortunately had typically very aggressive-behaving disease and a poor prognosis.
In the current era, however, we do have some good options and so in this setting, I would certainly consider moving somebody to CAR T. It is approved in that setting and I think that in a patient that still has some evidence of active disease and who has high-risk features, I think it would be a very reasonable approach and one that could potentially result in a longer remission.
I think on the other hand, if a patient feels that they're doing well and wants to try to ride this out as long as they can, I think that also is a reasonable approach. But to Peter's point before, we know that it's possible that this disease will start to pick up speed, become more aggressive over time and so you do run the risk of not necessarily being able to offer CAR-T or a subsequent line of therapy if they progress and have a rapid decline, but it really is a personalized discussion with a patient based on their own situation.
Peter, how would you approach this situation?
Yeah, pretty much the same as Jonathan. I think obviously, partial response. There are different degrees of partial response and that warrants some discussion, but I think if you're not at least making the patient aware of the potential for needing CAR T-cells in the future, then you may be doing the patient a disservice. The CAR T-cells don't just manifest themselves out of thin air. It takes some preparation and patients deserve some time to think about it. Probably the worst thing you could do is to leave it until it's too late. So it's at least worth a discussion whether or not they move forward right away or not.
Now that we have pirtobrutinib, which is approved in the post–covalent BTK setting, we at least can feel comfortable that there may be an alternative if and when the patient starts to progress. So it's not quite as dire as it might have once been, but I still think this is the exact time when I think it's important to have that discussion.
Peter, talk to us about brexucabtagene autoleucel for recurrent mantle cell lymphoma. Talk to us about the efficacy, about the toxicity profile and where this therapy fits in in mantle cell lymphoma management.
Brexucabtagene autoleucel is currently the only approved CAR T-cell in mantle cell lymphoma. There may be others coming. It was approved on the basis of the ZUMA-2 trial, which enrolled just a little over 100 patients. It was a single-arm, phase II trial, so it has, I believe, accelerated approval in that trial. I believe it was 80 to 90% of patients who responded with about a 60% complete response rate. I think when we saw the data published really on the heels of several large cell lymphoma trials, we were all optimistic that this may, in fact, represent a cure for people with mantle cell lymphoma.
However, as we get longer and longer follow up, we see that although there are some patients who achieve very durable responses, we do see ongoing recurrences. It's clearly... Especially in, as Jonathan mentioned, this BTK inhibitor relapse or refractory population, clearly is the most effective therapy that we have currently available, but there still remains room for improvement. And as you mentioned, Brad, it doesn't come without toxicity. I think we've all heard of some of the side effects associated with CAR T-cells. Brexucabtagene autoleucel is probably a little bit more in terms of the intensity of those side effects with higher rates of ICANS, the neurotoxicity than some of the other products for large cell lymphoma. So there is something to really consider when we're thinking about it and maybe that argues for preparing patients and trying to get them in when they have the least bulky disease possible and also ensuring that they have the greatest fitness possible before entering into CAR T-cell therapy.
Jonathan, anything you want to add to that?
No. I think that's a perfect summary and I would agree with Peter that like the BTK inhibitors did as well when they came out, although this has really transformed the way we think about relapsed mantle cell, it doesn't appear to be the definitive answer for the majority of patients and so that's where it's important to consider to continue to evaluate other approaches for patients because many patients who go on to receive CAR T will ultimately require some additional therapy in the future.
So I'm going to move us to our key clinical takeaways for this session. Relapse mantle cell lymphoma can be quite challenging to manage. P53 mutations become more common in the relapse/refractory setting, and they do tend to predict poorer responses to therapy. BTK inhibitors are really the mainstay of second-line treatment for mantle cell lymphoma, although ibrutinib was recently withdrawn from the US market for mantle cell. So that leaves us with zanubrutinib and acalabrutinib for second-line, and then we have pirtobrutinib for failures of prior BTK therapy. And then of course, we have CAR T-cell therapy, now approved brexucabtagene autoleucel. It has very high response rates and the responses are reasonably durable, although we do not have 4- and 5-year follow up yet and so we're watching this cohort of patients over time very carefully. And it is important to note that the toxicity for CAR T in this population is not trivial, and so one has to have a really thoughtful conversation with their patients prior to selecting these therapies.
So that brings us to the end of this case. Please see the other segments for further discussion about the latest data in mantle cell lymphoma or visit ascopost.com. I want to thank our two experts, Dr. Jonathan Cohen and Dr. Peter Martin, for joining us today.