iwNHL 2024 | Evolving frontline treatment in MCL: disease biology, the changing role of SCT & novel agents

Dr. John Kuruvilla:

Hi, I’m John Kuruvilla. I am a hematologist working at Princess Margaret Cancer Centre in Toronto, and very pleased to be with you today speaking from iwNHL in Nice, 2024. And I’m very happy to have a couple of colleagues who are also in this session on mantle cell lymphoma today with me here for this discussion.

Dr. Caron Jacobson:

Hi, everyone. I’m Caron Jacobson from the Dana-Farber Cancer Institute in Boston. I’m happy to be here today.

Dr. Michael Wang:

I’m Michael Wang from the MD Anderson Cancer Center in Houston, Texas. I’m very glad to be here today.

Dr. John Kuruvilla:

All right. So let’s get right into it. So we had a session that encompassed a number of important issues looking at biology and pathology in mantle cell lymphoma, the integration of novel therapies into frontline, and asking relevant questions about the current roles of chemotherapy and stem cell transplant, and thinking about how frontline decision-making is influencing how we’re treating relapsed/refractory mantle cell lymphoma.

And so maybe I’ll start with you, Michael. When you’re looking at your typical frontline patient in mantle cell lymphoma, what sorts of biologic information are you looking for from the pathologist to help you manage and treat that patient?

Dr. Michael Wang:

So I believe in the clinical care to take care of mantle cell lymphoma patients, it is very important to risk stratify. So John, I think your question is really a critical one. And when you see the patient, you have all kinds of assessment. You see the patient’s performance status when they come in, whether the patient has any symptoms, and how big the lymph node, and what’s the IPI after some basic lab work?

Then under the microscope, what are the Ki-67? Whether the patient have a blastoid or pleomorphic. And molecular studies, sequencing, if you have any p53 mutations. p53 mutation is very important. But we at MD Anderson, we have a profile of 170 genes. We test C-MYC. We test NOTCH1, NOTCH2. We test many, many others. Then we actually put that into our treatment decisions. And also, we in the frontline, we also set up an MRD. So risk stratification, the age of patients, all kinds of information you have to take into consideration finally to see whether this patient is a high risk, or low risk, or moderate risk, and then you treat accordingly.

Dr. John Kuruvilla:

Okay. And Caron, maybe just to build a little bit on that, Becky Kelly had talked a little bit about some of the diagnostics around leukemic non-nodal subtype. And are you doing routine testing in that patient population to look for it? Or how are you using that to guide your decision-making from a frontline treatment standpoint?

Dr. Caron Jacobson:

I mean, I think this is a population of patients that you can really identify clinically, and the SOX-11 can be very helpful to confirm that. But I don’t know that you necessarily need all of the next steps in order to feel that you have correctly identified this patient population. They typically present with circulating disease without other hematologic abnormalities, with a borderline or moderately enlarged spleen, and without significant lymphadenopathy. So unless they behaved differently than I anticipated while I follow them, I probably am not going down a pathologic rabbit hole, so to speak.

Dr. John Kuruvilla:

And so, we’ve talked a little bit about how we’re using some of these factors to influence patient management, observation, and treatment. Let’s kind of get at where we started talking around some of the controversies in our session.

And so firstly, how are we looking at the evolving role of autologous stem cell transplant, given what we’ve seen with early follow-up from the TRIANGLE study that incorporated ibrutinib frontline, and what we’re seeing with other BTK inhibitor regimens in the non-transplant population. And again, I’ll maybe start with you then, Caron, and then I’d ask Michael to comment as well.

Dr. Caron Jacobson:

Yeah. I mean, I think actually Michael Williams actually made some very, very good points, which is that the follow-up for TRIANGLE is short, and a lot of the benefit of our chemo-heavy and transplant regimens that show seven to 10-year median PFS, that benefit comes out after five and six and seven years. So I do think we need longer follow-up from TRIANGLE to truly understand whether transplant is dead.

We do have the ongoing Alliance study in the United States, which is taking patients with investigator choice chemotherapy regimen who are in an MRD-negative CR, and randomizing patients to transplant or no transplant. I think that will give us other important information.

I do think that the real-world data though, that Michael Williams also shared, showing that very few patients eligible for transplant are getting a transplant, and it doesn’t seem to be impacting PFS, although that’s certainly, there are some built-in referral biases there is also very provocative. So I think it’s possible transplant is dead, but I am not totally sure we have all the answers right now. And so, I just feel fortunate, given how confusing it is, that we have the Alliance study open at my center, so that at least I know that I can put my patients on it, and I’m answering an important question.

Dr. John Kuruvilla:

Yeah. It can be challenging to walk away from that data when you’ve seen that platform develop and really see the long-term PFS benefit, as you pointed out. Michael, you’ve done a lot of work in that area as well. So comment how you’re using transplant in mantle cell lymphoma in the frontline setting these days.

Dr. Michael Wang:

So I almost never use a transplant autologous upfront, even before the TRIANGLE study came from. I remember that when I studied the four drugs, the BEAM for the transplant. BEAM therapy is so intensive, is such a… Chemotherapy is so intense, and we have to bank the stem cells way before we give the patient the chemotherapy, the high dose chemotherapy. Otherwise, the high dose chemotherapy just kill the patient, right? So you give the highest dose chemotherapy you can deliver to a human, and you rescue them with stem cell transplant, and then the consequences is, and the chemotherapy, each one of them are now specifically attack DNA, not only the tumor cell but the whole body of the cells, the normal cells, right? Of course, this cell’s chemical attack will lead to secondary malignancies, in addition to the acute toxicity.

So I really think transplant is something we need to get rid of, but transplant was associated with a prolonged survival. So you have to have good drugs to do that. I believe we have adequate drugs those days. Philosophically, I really think transplant should go away. It’s not precision, it’s too much chemotherapy, and several consequences. So I really think that we are in the age, that we have trials, Alliance with other, we need to get rid of the transplant.

Dr. John Kuruvilla:

And we also see, I mean you’ve highlighted the toxicity, but thinking about the patient population in mantle cell in general, it is an older population. The median age is in the late 60s. So we’re often thinking about patients that aren’t going to go down that route at all, due to toxicity concerns from the get-go. So it’s been nice to see.

We’ve had other generations of studies like trials incorporating ibrutinib frontline, acalabrutinib frontline, in comparison with chemoimmunotherapy where we’ve seen PFS benefit, we have seen toxicity issues there. So now the bigger picture here, I’m wondering if again, are we seeing more commonality in these patients, and the opportunity that potentially a chemotherapy/immunotherapy backbone with a BTK inhibitor? So mixing targeted and chemoimmunotherapy approaches is really where the future, in the short term at least, is likely to be. And again, Caron, why don’t you comment?

Dr. Caron Jacobson:

I think there are a number of studies that have shown PFS benefits to adding BTK inhibitors in the frontline. Think the bigger question is, is that initial PFS benefit going to be larger than the additive PFS if you sequence these therapies? And I don’t think we’re positioned to understand that answer, other than looking at historical controls.

I think one question that comes up, if the outcomes for TRIANGLE persist over longer periods of time is, when you take transplant out of the equation, is the chemo plus BTK inhibitor backbone of TRIANGLE actually appropriate for some of our older patients as well? Is that the best frontline therapy? I think TRIANGLE may be able to answer that, because the BR plus a BTK inhibitor studies show, I think potentially, a more modest PFS benefit. But maybe if you combine it with cytarabine-based chemotherapy regimens, that maybe our older patients could get through that.

Dr. John Kuruvilla:

That’s a great point. And Michael, maybe you could comment as well. We still have trials that are accrued or accruing that are going to look at that frontline population exploring chemo-free regimens compared against R chemo as an example. So we touched on those. Maybe you can highlight that for the audience today. Some of the other studies that you’re excited about in that frontline setting that are coming.

Dr. Michael Wang:

So the treatment of mantle cell lymphoma in the past, it was totally chemotherapy as the mainstay. Young people, we use stem cell transplant, high dose chemotherapy. And in older people we have bendamustine/rituximab, our top therapy. And now we try to repeat this with chemo-free therapies. So the chemo-free therapy, there’s a trial called the MANGROVE study, and it has a finished enrollment. One arm is BR, bendamustine/rituximab, another arm is a Rituxan with a zanubrutinib, the BTK oral inhibitor. And so we really wanted to see which one is better, which arm is better. Probably the overall survival is difficult to see, but the PFS will give us some idea, right? It is hard to predict which we, but I really think that even the MANGROVE study is positive or negative, it is only a doublet. It only what we talked about, rituximab-zanubrutinib. But we already know the best therapy, the chemo-free frontline at this point. Maybe in the future it will change. But at this point, the three drugs with the addition of venetoclax.

So I really think we should use chemotherapy to compare with the best triplet therapy in the frontline. Unfortunately, we don’t have such a study. Mantle cell lymphoma is a rare disease, so we don’t have the luxury of doing that. And so, we are using in practice three agents anyways. But I do believe that in the high-risk patients we should have some kind of a consolidation.

Dr. John Kuruvilla:

So Michael has published already on the regimen looking at AVR, so acalabrutinib/venetoclax/rituximab as a triplet. A larger study, again, just accrued globally. And now we’re seeing the ENRICH study, where it’s looking at ibrutinib in a randomized comparison against R chemo. I think we may be seeing data from that later this year. So hopefully increasing evidence, accumulating, looking at these novel regimens. And if we learn about doublets now, maybe triplets will be the next studies that are being done.

Maybe touching base on relapsed/refractory disease. Caron, you presented data looking at a wide variety of things, including CAR T-cell therapy and allogeneic transplant. And so again, now we have a couple of CAR options available, with brexu-cel and axi-cel. So can you tell me a little bit about how you’re picking therapy there. And we didn’t talk much about bridging, but how you might use response, and if that influences what product you may use in that patient population that has progressed and now needs something new?

Dr. Caron Jacobson:

So I think the top-line summary of brexu-cel versus liso-cel for mantle cell lymphoma is, you have a more toxic treatment in brexu-cel, but with a potentially longer progression-free survival compared to liso-cel. Some points were made about whether the patient population on each study were similar, although I will point out, that we have now real-world evidence with brexu-cel. Where we didn’t have liso-cel available, we were putting these rapidly progressive patients on, bridging them with available therapies, and we were actually seeing very, very similar responses.

So Michael alluded to it during the panel, but I think I follow very similar sort of patient selection pattern. Which is for a younger patient who can tolerate the toxicity of brexu-cel, I choose brexu-cel. And for an older patient who’s more frail, and who I think the toxicity would be more significant, I would choose liso-cel in that setting.

I do struggle sometimes, and this came up with the question of allogeneic stem cell transplant, is what we have learned from some of the real-world data, is that even though patients with p53 mutation, patients with blastoid or pleomorphic morphology, patients with high Ki-67s, can do quite well with CAR T-cells in mantle cell lymphoma, their PFS does seem to be diminished. The question that I posed is, with all of our available therapies, when is the time to bridge someone to an allo transplant? I think we just don’t really know that at this point.

Dr. John Kuruvilla:

Yeah. There’s a lot of history again with that, with allos and the potential to cure refractory disease in late line setting. But again, when you think about the patient population in mantle cell, we’re normally dealing with, again, typically older, typically not going to be in the patient population from an age and fitness standpoint, that we normally think about allografting, even with non-myeloablative techniques.

Maybe Michael, I’ll just ask you one more question. Caron also showed some other data about some of the other novel agents that are being used in mantle cell lymphoma, next-generation BTK inhibitors, like pirtobrutinib, zilovertamab, etc. So where do you see those agents fitting in when we have CAR-T perhaps a little more established? We see bispecifics also coming in. So it’s an exciting time for us with a number of different molecules available.

Dr. Michael Wang:

Yeah, it is very exciting. First of all, I wanted to echo the need for allogeneic transplant, because CAR T-cells probably can only put a 10 to 15% of the patient into long-term remission. The vast majority relapse and progress. So allogeneic transplant is very important. We need to know early whether the patient have a full match. If the patient have a full match, then sibling match, then probably we should have a low threshold to go that way.

Now coming back to the novel agents, zilovertamab vedotin is a good drug to reduce the induction, to use in the induction, because the vedotin toxic component, the payload, it causes severe neuropathy, and it cause a neutropenia, is really limiting. So you want to use upfront for a few cycles, and then you use other agents too.

And so the BTK degraders is also a very important class. So far, BTK degraders in mantle cell lymphoma has not caused very high response rate different from other diseases, but it will be a future player. It will probably be approved for mantle cell lymphoma. In the near future, so other therapies like BCL-2 inhibitors, there’s a drug called the sonrotoclax I’m going to talk about tomorrow. And you also have activities competing with the venetoclax, the BCL-2 inhibitor, and many other like BAFFR and CAR T-cells are coming from City of Hope. And so like you said, John, it is extremely exciting.

And then there’s bispecific antibodies. There’s the epcoritamab, glofitamab, mosunetuzumab, and odronextamab, and this is more to come. And dual CARs and all that. So really, we –

Dr. John Kuruvilla:

The list goes on, for sure.

Dr. John Kuruvilla:

And so, as you can see, there’s a ton going on in the space in mantle cell lymphoma. We’re very happy to be able to have this type of a discussion. Lots of answered questions over the past 20 years, but many more to come. And so, thank you.