iwNHL 2023 | Evolving treatment landscape of MCL

Stephen Ansell: Hi, my name is Steve Ansell from Mayo Clinic, and we’re grateful to be together talking about mantle cell lymphoma here at iwNHL. I’m going to let my colleagues, all of whom are really experts in the field, share who they are. So, John, you want to get us started?

John Kuruvilla: Thanks, Steve. I’m John Kuruvilla. I work at the Princess Margaret Cancer Centre in Toronto, Canada- great to be here.

Stephen Ansell: Great, Marek?

Marek Trněný: Thank you. I’m Marek Trněný. I’m from Prague, Czech Republic.

Stephen Ansell: You, Yucai?

Yucai Wang: Yeah. My name is Yucai Wang, I’m a lymphoma doctor at Mayo Clinic, with Steve.

Stephen Ansell: So anyway, really a fun session on mantle cell lymphoma, and we’d like to just talk a little bit about your takeaways from that time. So the main focus was about biology and talking about high risk patients, but then really talking about the impact of new therapies and how it’s changing things. So, John, I’m going to start you off, because you have got the unenviable task of talking about what’s the future of autologous stem cell transplant. So your thoughts based on kind of involving data as to how that field is moving.

John Kuruvilla: Yeah, it’s an interesting time for us because we’ve seen major impact with the development of stem cell transplants, the incorporation of rituximab maintenance, intensive chemotherapy and excellent ten-year results now. So we have a really good platform, but at the same time, we have a ton of novel therapies coming to the forefront. And now, we finally have randomized trial data showing that the incorporation of BTK inhibitors, particularly ibrutinib, in terms of data that’s read out to date, now showing impressive results in front-line, both in transplant-eligible populations as well as transplant-ineligible populations.

Stephen Ansell: Right. So, Marek, you really kind of highlighted that data talking about the TRIANGLE trial. So your take on: has that changed the standard of practice or not?

Marek Trněný: Yeah, I think that there are two things. One, I think that the role of the stem cell transplant is going to disappear. So we are not yet saying to everybody, okay, do not go to transplant, but I think that we are on the way. The other issue is that the BTK inhibitor ibrutinib is not reimbursed or approved for this indication. So we are really in a tricky situation. We could rely on the data which are not mature yet- so we have to wait. But on the other hand, we do not have- really- approved medication for the first line for this setting, so this is something we have to discuss. But I think that for the low-risk, for instance, we are already discussing with patients the option to skip the stem cell transplant, the toxicity, et cetera. For high-risk patients, it’s a more difficult issue because the high-risk TP53-mutated patients, they have a poor outcome. So there is no plateau for the stem cell transplant as well. And if you see the brexu-cel data, they are the highest high-risk population, which is failing from a long term perspective as well.

Stephen Ansell: Right. And you, Yucai- we had this conversation about do we treat younger patients and older patients differently. And in the old days, we did, based on our transplant plans. But do you think that’s changing? And in your practice what are you doing?

Yucai Wang: Yeah. With the TRIANGLE data showing that transplant may be omitted when you incorporate novel agents at frontline, that perspective may be changing. Because historically, first question is whether this patient going to go through transplant or not. So with the TRIANGLE data, you know the algorithm may be changing. So now, if you think a novel agent is going to move to the frontline to be combined with chemotherapy, it’s a different question: which chemo do you give for young versus old patients? So in a sense still relevant- not in a transplant sense- but in the future if the novel agent combination comes to the frontline, then eventually, probably just like in CLL, age will no longer be relevant.

Stephen Ansell: Right. Go ahead. Marek.

Marek Trněný: We’ve published a couple of years ago, data where we treated elderly patients, median age 73 years old, with alternating co-regimen R-CHOP/R-ara-C. (4.32) And currently we are treating with R-CHOP/Ara/[inaudible]. So I think that the data are quite promising. I think that if the patient is able to go through this therapy, I think that those components ara-C plus cisplatin or oxaliplatin, rituximab, rituximab maintenance. So you really can get some very interesting data.

Stephen Ansell: So I agree with you, I think things are changing a lot in frontline. John, you made a point in the meeting which I thought was very valuable, about maintenance therapy. So often, rituximab maintenance has been our standard, now potentially adding a BTK inhibitor. So, is it important to add the BTK inhibitor in the maintenance or in the frontline or both? What do you think?

John Kuruvilla: It’s hard to know at this point given how the data have developed. What we can say from a study like the TRIANGLE trial is that when you look at the magnitude of all of the effect, it clearly speaks to the benefit of the drug in both settings. When you look at the data from SHINE now, it was pointed out in the meeting as well, that the separation of those curves appears to happen with the use of maintenance, as opposed to during the induction phase when it’s being given in combination with chemotherapy. Part of that may also be that we don’t have good enough tools to really appreciate the depth of remission- a PET scan may not be adequate, and MRD may not be assessed routinely in clinical practice. So I’ll say the jury is out there. But we certainly know even looking at rituximab, the magnitude of the benefit certainly was mostly with maintenance. And so, if you’re limited in terms of how you may access the drug, building it in wherever you can. If it’s only in the maintenance setting, that’s better than not at all.

Stephen Ansell: Yeah. So, Marek, I just want to ask you a question. You mentioned a number of different regimens that you’ve been using, and we’ve mentioned about the BTK inhibitors and how they are really bringing promise. Do you think it matters whether you add the BTK inhibitor to R-CHOP or the BTK inhibitor BR? So in other words, does the backbone that you’re adding the novel treatments to make a difference?

Marek Trněný: Yeah, I think that for us, we do not use BR very often, only for patients who are compromised. So, for the patients up to 70, 75 and maybe some more, we use combination with R-CHOP. And I do not have the answer to the question if it does matter- but I think it’s very interesting that from the TRIANGLE study, the patients didn’t receive ibrutinib in each cycle. They got the six cycles of the chemotherapy, but they got the ibrutinib only with R-CHOP, which means three cycles out of six. And the response rate, the complete remission rate was really improved. So, from 36 to 45%, in relative ways it’s almost a 30% increase in the complete remission rate. So I think that I would be very cautious to say that it’s only the maintenance part. I think that it really plays a role as a part of induction.

Stephen Ansell: I think you make some good points. So maybe moving on a little bit, and Yucai, I will try to bring you in too- where do you think in this changing environment, are we going with the cellular therapies? And specifically you and others highlighted a little bit of data about the different CAR-T cell products. So your thoughts on: where do they fit? Are they going to make it all the way to frontline? And is there a preference on how you manage and which one you use?

Yucai Wang: Yeah a great question, Steve. So, so far, brexu-cel was approved by the FDA, but they did not specify how many lines of therapy you should have received in the relapsed setting. So, you can use it as early as the second line. But in practice, most of us I think, still use brexu-cel in the third-line setting, most frequently after a BTK failure in the second-line. So, definitely, there are data emerging when you use brexu-cel in the second line, outcome might be a little bit better, but limited by small numbers- it certainly needs to be confirmed. So, in high-risk patients, you can certainly try to get insurance approval to use brexu-cel in the second-line because in the NCCN guidelines, interestingly, they say that you should use brexu-cel in the third-line. So that made it a little difficult, although the FDA label was that you can use as a second-line. But yeah, for high-risk patients, you should certainly try. Will they eventually land in the frontline? There are studies going on. So, there are single arm studies in Houston and MD Anderson.(9.20), they’re doing a so-called WINDOW-3 study. They are leading with acalabrutinib, and then adding a CAR-T cell very early for high-risk patients only so far. So it will be very interesting to see what that data shows. Our European colleagues are doing randomized studies comparing BTK/chemo versus BTK followed by CAR-T cell therapy- again for high-risk patients. Very exciting trials! We await the data. The other CAR-T cell product that’s coming is liso-cel. We saw exciting data at Lugano this year. This product uses a 4-1BB setting (9.54). It seems to have a better toxicity profile- a higher response rate as well. We just need to see, when used in standard of care practice, whether the duration of response is similar to brexu-cel, because in the pivotal trial, it seemed to be a little different compared to ZUMA-2 data, although different trial population.

Stephen Ansell: So, John, it seems to me CAR-T cells are in the ascendancy and autologous transplant may be descending a little bit. Do you think the one’s going to replace the other?

John Kuruvilla: I would think so, Steve- eventually. My sense with auto, one of the questions that comes up, much like we think about this in the similarities to the myeloma world, as novel therapy has come there and was heavily dependent on transplant. Will it become a relapse setting treatment, autologous transplant? And I would argue there, if we already have something else that’s quite effective, I think it will be less likely to be used. And given all the other novel agents that are available in combination and new ones coming down the pipe- I personally think I’m okay with saying that a therapy from 25 years ago has probably had its day, and we’ll move on.

Stephen Ansell: So, Marek, what I want to ask you: do you think we’re going to start curing mantle cell lymphoma? We’ve always said these are to give us durable responses. You presented some very nice data that there’s an autologous transplanted subset of people who may have a very long-term outcome. Now that we’re bringing cellular therapies and novel treatments Marek, are we going to fix everybody?

Marek Trněný: Yeah, I think it’s a very good question because the patients usually ask us if I could be cured. I think that definitely for low-risk patients, low and some intermediate-risk, we really see very long-term survival, and we almost see the plateau for those patients. But I think that we still have a challenge with the high-risk patients because they are going to relapse. And at least in our hand, there is no plateau. And I think that for mantle cell lymphoma, although we have some subsequent treatments available already, treating patients who are failing the BTK inhibitors by CAR-T cell, it’s not very easy because sometimes they are progressing very quickly and you do not have so much time to do something. So I think that we should afford to balance the toxicity and efficacy, but to give the best we can in the first-line, because then we can proceed to the cure. I really do not believe very much in being cured in the second or the third-line.

Stephen Ansell: Right. So Yucai, you get the last word here. So thinking about the novel things that are in the pipeline, as Marek mentioned, what are you excited about and what do you think is really going to contribute to the curative potential in this disease?

Yucai Wang: Yeah, so there are different classes of drugs that are in development showing promising data. I think a few classes to highlight: one is the bispecific antibodies, like glofitamab, a CD20xCD3 bispecific antibody showed very high response rates, and seems to be durable in trials. They are now going to randomized trials. I’m sure this agent, just like CAR-T, will probably move to the frontline in the future. So if it has a better toxicity profile than CAR-T, it can be used in the community setting. Maybe this holds the promise for the future frontline with bispecific antibodies, whether with or without other novel agent or even chemotherapy.

Stephen Ansell: Right. Well, just to say thank you very much to my colleagues for their comments on the session. It was a great session, and thank you very much to you, the audience, for listening to this discussion.