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Brian T. Hill, MD, PhD, Co-Director of the Lymphoid Malignancies Program at Cleveland Clinic, joins the Cancer Advances Podcast to discuss advances in mantle cell lymphoma. Listen as Dr. Hill highlights current treatments and how promising strategies like BTK inhibitors and CAR T-cell therapy are being used. He also addresses challenges such as TP-53 mutations, discusses potential advancements, and emphasizes the importance of individualized treatment approaches.

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Advances in Mantle Cell Lymphoma Treatment

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic Directing the Taussig Early Cancer Therapeutics Program and Co-Directing the Cleveland Clinic Sarcoma Program. Today, I'm very happy to be joined by Dr. Brian Hill, Director of the Lymphoid Malignancies Program here at Cleveland Clinic. Brian was previously a guest on this podcast to discuss biomarkers that predict outcomes for CAR T-cell therapy in patients with diffuse large B-cell lymphoma and that episode is still available for you to listen to. He's here today to talk to us about advances in treatment of mantle cell lymphoma. So, welcome back, Brian.

Brian T. Hill, MD, PhD: Thank you for having me.

Dale Shepard, MD, PhD: Remind us a little bit. What do you do here at Cleveland Clinic?

Brian T.  Hill, MD, PhD: Yeah, so I see patients with lymphoma and related conditions, chronic lymphocytic leukemia, lymphomas, Hodgkin and non-Hodgkin lymphoma. And I'm the Director of the Lymphoid Malignancies Program. So, we oversee the clinical care of these patients and get all of our physicians aligned in terms of how we approach and manage these patients. But also, I am pretty actively involved in clinical research so we have a large portfolio of clinical trials for novel therapeutics in the frontline and relapse settings, as well as cellular therapies for lymphoid malignancies.

Dale Shepard, MD, PhD: Excellent. Today, we're going to talk about mantle cell lymphoma. A lot of different people might be listening in. Lots of different kinds of lymphoma can get confusing. Remind us. Mantle cell lymphoma, what is it?

Brian T. Hill, MD, PhD: Yeah, so mantle cell is not the most common lymphoma, but you see it. It's somewhere around 8% of non-Hodgkin lymphomas. It is a B-cell malignancy and it tends to have a pretty variable clinical course, but we think of it generally as being aggressive, meaning that for most patients at the time of initial presentation, it does need to be treated.

The characteristic biologic features are Cyclin D1 expression. That's the hallmark of it. Although that's not really pathognomonic for mantle cell, that's seen in over 90% of the cases. And although there are about 10% of patients who can have mantle cell that looks very similar to CLL, we call it leukemic non-nodal with just a high white count and no other symptoms. Most patients will have large lymph nodes, probably high LDH, frequent B symptoms, and frequently present with signs or symptoms that warrant immediate treatment.

Dale Shepard, MD, PhD: And give us an idea. What are the current treatments? What's first line. What do we do?

Brian T. Hill, MD, PhD: Over the years, not being terribly innovative, we gave R-CHOP, as we did and do for many.

Dale Shepard, MD, PhD: Very clever.

Brian T. Hill, MD, PhD: Yeah, very clever. But it turns out if you just give R-CHOP for mantle cell lymphoma and do nothing else, that the survival is actually very short, two to three years. So, R-CHOP really isn't the standard or best treatment.

There are a few different options. We know from randomized studies coming out of Europe, the so-called Nordic regimen in which you alternate or combine regimens or cycles of R-CHOP with chemotherapy containing high-dose cytarabine that you improve outcomes. We also know that if you consolidate patients in first remission with an autologous stem cell transplant that they tend to have longer remissions than if you don't. But that probably also depends on what they got as their induction regimen.

Beyond that, there's very good data supporting the use of maintenance therapy in mantle cell lymphoma. So, a dose of rituximab every two months for up to two to three years actually improves survival, in contrast to indolent lymphomas or follicular where maintenance therapy improves PFS but not survival.

And more recently, I would say for patients that are older, let's say 70 and older, and you don't think autologous stem cell transplant is really a great option, or maybe they're too far away or don't want to go through that effort, actually head-to-head studies of R-CHOP with bendemostine rituxen, or BR, show that BR is actually better than R-CHOP and safer. So, for older patients with mantle cell lymphoma, just doing six cycles of BR and then maintenance therapy is a very reasonable approach.

Dale Shepard, MD, PhD: What is some of the challenges with sort of first line? We'll talk first line, then we'll talk about later.

Brian T. Hill, MD, PhD: Yeah.

Dale Shepard, MD, PhD: What are some of the challenges of therapy? How has that sort of changed what we're thinking about doing?

Brian T. Hill, MD, PhD: I think a lot of it depends on aging comorbidities. Even bendemostine rituxen can be difficult for the older, frailer patients, 75-, 80-year olds and beyond with comorbidities. So, that's one obstacle. And looking at the use of novel targeted pathway inhibitors for those patients in front-line therapy is something that's of active interest.

The other thing that's really important and has been increasingly recognized over the past five to 10 years is that a subset of patients with mantle cell will have TP-53 mutations. Similar to CLL, if you have a 17-P deletion or TP-53 mutation, the outcomes of chemotherapy are really dismal. And so, it's become more and more common to test at the time of diagnosis using next-generation sequencing from tissue biopsies to make sure you're not missing a TP-53 mutation because if you have that, traditional chemotherapy is really not going to get you where you want to go.

Dale Shepard, MD, PhD: And those are patients you might think about targeted therapies earlier?

Brian T. Hill, MD, PhD: That's right. And there's new studies looking into those.

Dale Shepard, MD, PhD: From a practical standpoint, as a solid tumor guy who is jealous of most of your response rates, how effective are most of these first-line therapies?

Brian T. Hill, MD, PhD: Yeah, so highly effective. I think response rates in all comers with a regimen like BR should be in the 80 to 90% range remissions.

Dale Shepard, MD, PhD: Did I mention being jealous?

Brian T. Hill, MD, PhD: Well, sarcoma is a difficult set of diseases and we're envious of your commitment. Let's put it that way. But yeah, the response rates are extremely high. It's really more the durability that we look at. Again, it's great to respond, but if six, nine months later the lymphoma is rapidly progressing, it hasn't, again, got us where we and the patients want them to go.

Dale Shepard, MD, PhD: And I guess, when you get those relapses, what does treatment look like at that point?

Brian T. Hill, MD, PhD: Yeah. Historically, if patients didn't have an auto-transplant in first remission and there was a recurrence sometime after achieving remission after frontline therapy, auto transplant was done. But I would say now it's fallen out of favor because usually patients have had an auto transplant up front or weren't great candidates or didn't make it there in the first place.

So, really we have two really good approaches for relapse mantle cell at this point. We have several FDA-approved covalent BTK inhibitors and I'll list them in order of FDA approval: ibrutinib followed by acalabrutinib followed by xanabrutinib. These are all oral, once or twice a day medications that are, again, highly effective, response rates up in the 70% range, for mantle cell lymphoma in relapse. They work better the sooner you use them, so fourth line or third line isn't as good as second line. Really, it is the standard of care to really introduce a BTK inhibitor in relapse mantle cell lymphoma. And any of those three are highly effective. Probably acalabrutinib and xanabrutinib are more commonly used because of the better tolerability in terms of cardiovascular risk. So, those are the kind of mainstay of oral therapy, targeted therapy in the relapse setting.

But the challenge again is the durability. So, unlike CLL where you can control for years and years and years with the BTK inhibitor, with mantle cell, the median progression-free survival is on the order of 24 to 36 months. So, it's not really a home run. It's good, but it's not exactly where we want to go.

That kind of brings us to the other approach. The other approach is cellular therapy, which we've talked a lot on this show and I'm sure your audience is familiar with. But CAR T-cell with brexucabtagene autoleucel is FDA-approved for mantle cell lymphoma. And again, it's highly effective. Happy to go into more of that.

Dale Shepard, MD, PhD: Yeah, if you want to just briefly give us a little bit of an idea on that role of CAR T therapies, that is something people are frequently interested in. And then, are there other cellular approaches that are being explored?

Brian T. Hill, MD, PhD: Yeah, so CAR T therapy has some barriers to it.

Number one, it's only available at authorized treatment centers. So, if you live some distance from an authorized treatment center, which is usually an academic tertiary care type setting that has a bone marrow transplant program, if your patient can get to one of those sites, then there is leukapheresis, so a cell collection that has to be arranged after some period of staging and insurance approval. And then, there's about a three-week manufacturing period. And then there's lympho-depletion chemotherapy for three days, followed by usually a hospitalization to administer the cells and about a two-week period of time of monitoring for toxicities. The toxicities with CAR T include cytokine release syndrome, which is characterized by fever, cardiopulmonary instability, but also sometimes neurologic events, neurologic toxicities, including confusion and sometimes even more significant neurologic changes.

So, it's a difficult treatment for younger, fitter patients. You'll have to have a caregiver to help you when you leave the hospital. You're not supposed to drive a car for eight weeks. So, there's all of these challenges that are difficult.

But that being said, the complete remission rate is on the order of 70% so it's extremely effective. And we have patients who had exhausted all therapies who've had CAR T treatment five years ago and they're still in remission. So, it has the advantage that it's a one-and-done, potentially curative approach for a subset of patients with mantle cell lymphoma.

Dale Shepard, MD, PhD: I guess if you think about patients who are relapsed, you have oral medications. You have these more complex cellular therapies, more complex, more expensive. How do you make the decision which path to go down for most patients?

Brian T. Hill, MD, PhD: Yeah, great question. I think it does have to be individualized.

For patients who are young and had a short remission after their frontline therapy, we'd really try to get them to get to CAR T if they can and will because I do think it has the best opportunity for complete remissions and long-term remissions. There are some potential long-term effects, including immunosuppression, which is part of this. But again, for younger fitter patients, I think it's a really good option.

For older patients who have had a nice long remission after treatment eight years ago and now they're relapsing, the durability of the response to a BTK inhibitor is much better than it is if it's early relapse. So, I think that if they're never going to get to CAR T anyway, then going straight to a BTK inhibitor makes sense.

I think where we get into difficulty is the sort of middle ground, when you have a patient who you think is a candidate for CAR T, but maybe don't think it's the right time and you get them on a BTK inhibitor to control their disease. When do you sort of pull the trigger, so to speak, on CAR T therapy? If they're in remission, it's a little bit of a difficult sell. On the other hand, if you wait until they relapse, it might be difficult to get them collected, approved, and treated because, beyond covalent BTK inhibitor treatment, historically the outcomes of patients has been pretty poor.

Dale Shepard, MD, PhD: I guess one of your roles is to oversee a program that is not here on main campus alone, but in our regional sites here in Cleveland, sites that are in other states, and even other countries. How do you think through that same sort of question, what to offer what patients, how you define what therapies are best globally for patients?

Brian T. Hill, MD, PhD: Yeah, certainly. So, we do have a care path for lymphoma. And we do have a care path for frontline treatment that outlines what we think is best depending on the age and whether they're a candidate for autotransplant or not. Beyond that, it's a little bit difficult to be prescriptive, but we do want to and try to engage with our colleagues in the general oncology practices, both within the Cleveland Clinic system as well as outside of our system because we have a large referral network, so trying to be available to talk through these cases. It's also true that therapeutics evolve rapidly when we get new approvals. And that might bring us to where we are in 2024.

Dale Shepard, MD, PhD: You mentioned about referrals and people being treated at other places. It would seem that there are a lot of patients that could be in places where, if there's a pill available, they may have a local doc that will just go straight to the pill.

Brian T. Hill, MD, PhD: Yeah.

Dale Shepard, MD, PhD: I mean, I guess what would you think is who should really be seen at a center that sees this disease?

Brian T. Hill, MD, PhD: Yeah, I actually think that, if possible, every patient with mantle cell should at least get an initial consultation with a lymphoma specialist if possible. And if not at the initial diagnosis, at least maybe the treating oncologist can and should reach out to their neighborhood specialist wherever in the country they are, just to make sure that the frontline regimen they're using is best for that patient. But certainly at the time of relapse, I think that either patients should be consulted with, either directly or indirectly, with someone who's treating a fair amount of lymphoma. Because again, it's relatively uncommon. And the number of patients seen in a general practice with relapsed mantle cell is probably pretty limited, whereas at a referral center, we're seeing a fair amount of patients with these cases on a monthly basis.

Dale Shepard, MD, PhD: You mentioned looking at some of the targeted therapies earlier on, first line. Clearly, there's a couple of different therapies for relapse. What's the area of greatest need at this point? Better therapies up front, better therapies for relapse, or maybe a little of both?

Brian T. Hill, MD, PhD: Yeah, I would say a little bit of both. The obvious question across oncology is always, "Well, you've got these great agents in relapse. Let's move them forward."

At the American Society Hematology meeting, not 2023, but the year before, so December 2022 was presented something called the Triangle study. It was the plenary session. In the Triangle study, it was a three-arm study that came, again, from largely northern European countries that compared standard what's called Nordic-style induction chemotherapy with anthracycline-based and citerabine-based alternating induction regimen followed by autologous stem cell transplant. That was sort of the control arm. And then there was a second arm where they added ibrutinib, the BTK inhibitor, with transplant. And then the third arm again had ibrutinib with the standard chemotherapy backbone, but it subtracted the autologous stem cell transplant.

And the results have yet to be published in a peer-reviewed journal, which many of us are waiting for. But the results as presented at the meeting showed that, if you use a BTK inhibitor during induction and afterwards instead of an autotransplant, showed that actually your outcomes were as good as if you did the autotransplant without the BTK inhibitor. So, it's I think leading many people in the field to question whether we really need that autotransplant because there's lots of toxicity and late effects of high doses of chemotherapy. Plus it suggests that using a BTK inhibitor as part of your induction may allow you to avoid that.

So, that's the big frontline question right now. And we're kind of, I think, moving that way and there's some more important studies that are going to be reported in the near future that will help inform that.

The other question about relapse is, what do you do, again, older patients or people who've had a covalent BTK inhibitor and it stops working?

It turns out that mantle cell lymphoma is very addicted to that B-cell receptor signaling pathway. And the covalent BTK inhibitors I've mentioned, ibrutinib, acalabrutinib, brutinib, and xanabrutinib all bind to the same cysteine residue. It's a sulfide bond right in the active pocket of the enzyme. And in CLL, we know that you can develop mutations there that prevent all three of those drugs from binding and they lose their activity.

Similarly, in mantle cell lymphoma, patients can develop resistance to these covalent BTK inhibitors. And there's a newly-approved agent, pirtobrutinib, which sounds very similar, but has a very important distinction from the covalent BTK inhibitors, which is actually is what's called non-covalent BTK inhibitors. It binds in the hydrophobic pocket right next to or adjacent to that active cysteine residue. So, it can actually work when the covalent BTK inhibitors stop working. And this is pretty remarkable. There was recent publication showing that the response rate, again, with pirtobrutinib, both in CLL and mantle cell, is in that 70% range and extremely well-tolerated agent, so very few toxicities. It's oral, once a day.

So, we've used this agent in patients who've been previously treated with a covalent BTK inhibitor and seen good activity. At the end of the day, it's still going to be about the durability. So, how long can you stay in remission? The PFS here on these studies is maybe a year or two at best. So, it's still much better than what we've seen before, but it still, I think, needs some help.

Dale Shepard, MD, PhD: But importantly, if the covalent BTK inhibitors move earlier in therapy, you'll still have a couple of options for relapse.

Brian T. Hill, MD, PhD: For sure, yeah.

And the final thing that's I think on the horizon that I'll mention again, at the 2023 ASH meeting, we saw in a late-breaking session a randomized study called Simpatico. The Simpatico trial compared ibrutinib to ibrutinib plus venetoclax, randomized trial in relapse patients. And there was a major advantage to combining the BCL-II inhibitor venetoclax with ibrutinib. The challenge right now is that ibrutinib actually has lost its FDA approval for mantle cell because of failure of confirmatory Phase III trials. So actually, even though I mentioned at the beginning that it was the first to be approved, it's actually the first to get pulled and probably hopefully the only to get pulled probably mainly because of some of the cardiovascular toxicities. So, it's still available for CLL, but it's not FDA approved for mantle cell lymphoma anymore.

There's a lot of excitement, I think, about the combination of venetoclax with a covalent BTK inhibitor. But right now we can't really prescribe that doublet. They're both oral and they're not approved or on NCCN guidelines yet. But I think it opens the door to combining venetoclax with the other BTKs, both covalent and brutabrutinib in the non-covalent category.

Dale Shepard, MD, PhD: Well, it's great to hear that, for a fairly small subset of lymphoma, there's so many good therapies that are available. There's good active research.

Brian T. Hill, MD, PhD: For sure. Yeah, it's nice to see. I think it really is a global effort. There's big efforts in the United States through the cooperator groups to answer some of these questions. There's big efforts in Europe to answer some of these questions in randomized trials, and there's continued interest from the private sector to develop drugs for this relatively uncommon lymphoma. And it's good to see we've seen our patients do better over the years as a result.

Dale Shepard, MD, PhD: That's fantastic. Thanks for your insights today.

Brian T. Hill, MD, PhD: Yeah, great. Thanks for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive a confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts. Don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer.

Thank you for listening. Please join us again soon.

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