Before we wrap up, I’m going to ask Krish, and then Tycel, and then Andy: Where do you think things are going in the future for mantle cell lymphoma. How will we be treating patients in 5 years? Will we still be giving chemotherapy? Will we still be doing transplants? Will everybody get a CAR [chimeric antigen receptor] T cell? Will they get bispecifics with a BTK [Bruton tyrosine kinase] inhibitor? Krish, pull out your crystal ball, and tell us what you think.

To borrow from what’s been said before, mantle cell is becoming CLL [chronic lymphocytic leukemia]–like. In some ways, we can imagine that perhaps with these novel agents and combinations of novel agents in all the patient types we described, perhaps we will have a chemotherapy-free initial therapy—combinations of perhaps BTK inhibitors, BCL22 inhibitors, what have you.

Just like in CLL, the role of transplants in particular, allotransplants, becomes exceedingly smaller with novel and more refined immunotherapies. Then certainly there is the question about autologous transplant in the frontline setting for fit patients. We’re all hoping to learn something from the MRD [minimal residual disease] story there to more carefully select patients for that therapy. I think mantle cell lymphoma is very much following the path of CLL. In 5 years perhaps we will have less chemotherapy.

I completely agree. Think that’s where the field is heading at this point. As far as transplant, we’re trying to move away from that. Specifically for a certain patient population, especially if the CAR T data continue to play out, CAR T will probably move up front for these highly aggressive 

-mutated patients unless we find some other treatments that give us similar outcomes with less toxicity.

I agree that we’re going to move away from conventional cytotoxic chemotherapy. Remember these targeted therapies are not adverse-effect-free. When you say 

, people think adverse-effect-free; that’s not the case. But the important thing is that we have to build combinations that allow for time-limited therapy because quality of life is really impacted by having to give therapy forever. If we can get high-quality remissions, particularly MRD undetectable, with combinations and a time-limited fashion, that’s going to be helpful.

I agree that we’re probably going to see CAR T cells move up because if we’re using the novel agents combined in the first line, they may not work a second time. If we give them in a time-limited way, it’s possible that we can actually re-treat patients. That’s another thing we need to ask. The goal is, I would love to say, “Oh, we’re going to cure mantle cell lymphoma.” But I would be perfectly happy to turn it into follicular lymphoma and have people live their age-matched, sex-matched expected life span. If we can do that and they’re dying of things other than their lymphoma, that’s OK. I’ll leave it to the next generation to cure the disease. I just want them to live their normal life span.

My analogy for follicular and for many patients with mantle cell is that it’s a hitchhiker, and we want them to make their destination. Sometimes it will be in the trunk of a car, sometimes the back seat. We want to keep it out of the front seat grabbing the steering wheel and playing with the radio. We don’t want to crash the car either, so the more things we have in our armamentarium to hold that trunk of the car down is a good thing. It sounds as if, from what we’ve talked about, there are lots of new opportunities and agents on the horizon, as well as some pretty good things in our bag of tricks right now and lots of work going on. There is reason for optimism.

I really want to thank my coconspirators today, my copanelists for this great discussion: Dr Krish Patel, Dr Tycel Phillips, and Dr Andy Zelenetz. It’s been a lot of fun to hear your perspectives and talk about some of the new things out there. I want to thank you again, our audience. We hope you’ve found this 

 discussion to be useful and informative, and we hope to have the chance in the future to speak with you about other interesting topics.

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Next Steps in Mantle Cell Lymphoma

I want to ask Andy about the issue of MRD [minimal residual disease]. That seems to be a very big deal with mantle cell lymphoma. We’ve had a number of studies correlating MRD to outcome. There was a bit of an update at ASH [American Society of Hematology Annual Meeting] about this issue. How do you see MRD being used in the future, depending on how things play out?

The fundamental observation, which has pretty much held true no matter what assay you use, you have a somewhat worse outcome if you’re MRD detectable vs MRD undetectable. But it all depends on what test you use and when you look. We saw the MRD results from the LyMa101 trial, and they used a relatively insensitive assay. It has a sensitivity of 1 of 104, which is actually what we use in CLL [chronic lymphocytic leukemia], and we know that it’s a validated threshold. In the LyMa101 trial—remember, it was chemotherapy, then high-dose therapy, and then maintenance—they looked at before the high-dose therapy and after the high-dose therapy. Before the high-dose therapy, if you were detectable, you had an inferior outcome. It was statistically significant barely, 

 value of .04. The curves did not dramatically separate, but it’s partly because both curves went down. Clearly, there were a bunch of people who had MRD in the MRD undetectable group because they were using insensitive tests.

Interestingly, we looked at our own trial, which I mentioned before, the R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–lenalidomide followed by rituximab–HiDAC cytarabine, followed by rituximab-lenalidomide maintenance. We actually used next-generation sequencing with immuno-sequencing and looked at different threshold levels. When we looked at a threshold of 10-5, it really did not predict for outcome. We used a threshold level of 10-6, and all of a sudden the curves are like you could drive a truck between them. The people who had truly undetectable MRD had a very flat curve, and the people who had anything detectable—10-6 or above—failed.

We need to learn more. There’s a big interaction between the treatment, the testing, and the depth of sensitivity, so we have to figure out how to best apply MRD tools to a particular treatment setting. And if it works in 1 treatment setting, it may not absolutely work in the next. What’s important is you prove that MRD is valuable with treatment X, so then when treatment X becomes standard, you can use MRD to help predict what’s going to happen. But because it works with treatment X doesn’t mean it’s going to work with treatment Y. That’s 1 of the lessons we learned from the data that were presented back to back at ASH.

Tycel, you may have referenced this earlier: There’s an ECOG study looking at MRD negativity with 1 in up-front therapy looking at MRD negativity as a primary end point, and the other using MRD negativity as a point of randomization to decide whether to do a transplant. That that is accruing very well. I don’t know if you’ve enrolled patients on that trial, but what’s your impression of that approach.

We are participating in the transplant portion of that study, and we have enrolled some patients. Oddly enough, obviously they come back for the maintenance whether they get to transplant or not. We are trying to open the other trial as well, the up-front study. The trial in and of itself has worked out fairly well. It has been almost seamlessly at our institution, so we haven’t run into any issues. Thus far, all the patients we’ve sent that have actually had a clone that has been able to be followed. That portion of the study has worked out before because historically there have been some issues, depending on how old the tissue is, of not being able to find the clone to follow. At least in that sense we haven’t had any troubles.

I’ll be looking forward to seeing what the results are. And if you are MRD undetectable with the Adaptive Biotechnologies assay, whether transplant is really needed in this patient population. If not, obviously that also moves us potentially further from giving cytotoxic agents, especially if you can get to MRD undetectability with some of these other drugs and maybe have more of a finite treatment plan. You would have pretty much a benchmark to transition to maintenance, which I think we all agree is very important in mantle cell lymphoma, irrespective of whatever you give up front.

MRD Assessment in Mantle Cell Lymphoma

We referenced MRD [minimal residual disease] earlier, and we’re going to come back to that because it’s an important issue. But first I want to talk about all these new agents that are being studied, and these are not necessarily mantle cell specific. We have combinations with CAR [chimeric antigen receptor] T-cell therapy. We have bispecific antibodies—for lymphoma the theme at ASH [American Society of Hematology Annual Meeting] was how much is going on in bispecific antibodies; there’s a lot there. We have a new antibody targeting 

. Krish, give us your sense of the key things people should keep an eye out for in the future and what seems promising to you among the different agents in development.

We talked about the current iteration of CAR T cells that’s available in brexucabtagene, and then we saw from other trials of other CAR T cells that there may be differences in terms of the patient population we can treat, based on toxicities and setting of treatment. That would be very important to follow and exciting to have different tools there.

In terms of novel mechanisms, as you mentioned, Dr Leonard, the bispecific antibodies are very exciting. We talked about some of the challenges of delivering an autologous CAR T cell. You’ve got to leukapherese the patient. You’ve got to make sure their disease is under control while you’re waiting for the CAR T cells. One of the big appeals of bispecific antibodies is that we can use that T-cell–mediated antitumor effect but in an off-the-shelf manner. These are drugs that can really be pulled off the shelf and delivered to the patient right away. In some ways I would say it’s like CAR T cell in a bottle. Exactly the same—they have similar toxicities, albeit perhaps less severe.

Novel targets are of course an important area too—we start going through the sequence of patients having had BTK [Bruton tyrosine kinase] inhibitors, having had CAR T-cell therapy. We know that there are going to be patients who need more therapies. ROR1 is a cell-surface protein that’s present on a number of malignancies, including B-cell malignancies. Dr Michael Wang presented the antibody-drug conjugate VLS-101. That’s a drug that the monoclonal antibody targets ROR1 and delivers an MMAE [monomethyl auristatin E] payload, so it’s similar to brentuximab vedotin with a toxicity profile that looks quite similar. In the data he presented, albeit in a small number of patients, there was a response rate of about 50% in patients who were post BTK inhibitor, so patients with relatively heavily pretreated mantle cell lymphoma and also activity in large cell lymphoma.

Andy, which of these agents are you most excited about?

The bispecifics really have a lot of promise. The problem is developing drugs in mantle cell lymphoma. It’s a huge challenge. It’s a relatively rare disease. We have about 4000 cases a year in the United States. People are getting pretty good responses after first-line therapy. We don’t have a lot of bispecifics. I mean, we have 4 trials of bispecifics for large cell lymphoma, but we have 0 for mantle cell lymphoma. You can throw mantle cell lymphoma in a couple of the phase 1 portions of some of the dose escalations, but there are no planned expansion cohorts in mantle cell lymphoma. We’re a little bit of a victim of our own success. We’ve had improvements. We’ve improved outcomes. The number of patients to treat are few, and they’re terrible patients. Those terrible patients need treatments, and they need active treatments. We just need to be able to persuade the sponsors to let us do these trials. But with the bispecifics, because we can then manipulate it with other factors and suppress T-cell exhaustion, there are some tricks we can play that would basically recapitulate CAR T cells without all the fuss.

Tycel, your thoughts on some of the newer agents that we just referenced? Bispecifics, VLS-101, new CAR T—where do you think they’re going?

I haven’t had much experience with the VLS-101, but the data look very compelling. I do agree with Dr Zelenetz about the CAR Ts. The newer ones do appear to have a better toxicity profile, to some degree. As time moves on, those will also play a big part in what we do. With the bispecifics, there are a lot. Obviously, there’s mosunetuzumab, the Genmab molecule, the Regeneron molecule, the Xencor molecule. So there are a lot of bispecifics. I think most of them will start expanding in mantle cell lymphoma because some of the preliminary data looked very interesting.

Similar to Krish, I’ve treated some patients on the Xencor study. Some of had mantle cell lymphoma. I’ve had some good responses. I’ve treated patients with mantle cell lymphoma, even those with 

 mutations with mosunetuzumab with some good responses. I know the Genmab study is potentially looking to expand to allow patients with mantle cell lymphoma to enroll. Afatinib will allow patients with mantle cell lymphoma to enroll. Regeneron did present some data as well, so I think bispecifics will play a big part. Because of the ease of use and obviously not having to have patients admitted to the hospitals for the long CAR T studies, and if some of them become more subQ [subcutaneous], then it eliminates some of the observation period. They may be more useful, especially for community physicians to use vs what we’re dealing with now with CAR T.

Yeah, I agree. Particularly in mantle cell, where it’s an older patient population, we alluded to earlier, we all cited a few patients that could be eligible but few that actually have received CAR T before. If we have alternatives that are close, even if they’re no cigar, if they’re close enough and less toxic, it does seem as if this is 1 setting in which it’s not necessarily quite as compelling to go to the CAR T if you have 1 of these alternatives.

Novel Therapies in the Pipeline in Mantle Cell Lymphoma

Tycel, the other area that we see more and more, some of which was at ASH [American Society of Hematology Annual Meeting], some of which are ongoing trials, is various combinations. I know you’re involved in some of these. We have zanubrutinib-rituximab, venetoclax with zanubrutinib-obinutuzumab-ibrutinib-rituximab, acalabrutinib-bendamustine-rituximab. It’s the mix and match. It’s like pick 1 from column A and 2 from column B. What’s the takeaway? I mean, it seems to me you add drugs to get more toxicity and you might have more efficacy, and we just have to see. Is there a lot of rationale behind these, and what are some of the early data that we’ve seen?

To your first point, the obvious goal is if you have an effective agent in a relapsed/refractory setting, you want to move it up. We’ve seen quite a few trials that have tried to move the BTK [Bruton tyrosine kinase] inhibitors earlier on in therapy. As I mentioned earlier, in the SHINE study, which looked at ibrutinib-bendamustine vs bendamustine, you know the acalabrutinib study that resembled that. Very good points. You get more toxicity in some of these situations, and sometimes just because an agent works doesn’t mean it adds to something else. As we know, the SHINE study still hasn’t resulted out, which raises more red flags. Maybe BTK doesn’t add anything to bendamustine and then BR [bendamustine-rituximab] is just as well if we left it alone.

Some of the other combinations, obviously we know zanubrutinib has a study that looked at rituximab-zanubrutinib plus BR [bendamustine-rituximab], because they’re trying to emulate CLL [chronic lymphocytic leukemia] and replace a lot of the chemotherapy regimens with some of these noncytotoxic regimens in the up-front setting. The Rituxan/BTK studies and the addition of venetoclax, which was shown in a relapsed/refractory setting, isn’t safe. When you add it up front, the goal is obviously to try to deepen the response. Probably something we’ll touch on later is obviously this mythical attainment of being MRD [minimal residual disease] undetectable. Can we get there with some of these noncytotoxic agents? With the combinations, we would assume that you have a greater pass to get to that point with some of these agents.

I think there was a French publication with obinutuzumab-venetoclax-ibrutinib, and they also looked at MRD. I think MRD in a lot of these other industry-sponsored studies will be collected and reported out later. All these combinations are really just trying to move some of these agents up earlier and expose more patients than what you would typically see in a relapsed/refractory setting. Not to mention adding BTK to CAR T, which is, I’m assuming, on its way for mantle cell as well.

Andy, what’s your take on some of these combinations? It seems like it’s pretty clear it’s something to try in the 

 mutated. Besides that what are your early impressions?

One of the trials that we’re talking about is this combination of zanubrutinib and obinutuzumab with venetoclax, what we call the BOVen trial, initially piloted as an adapted duration of response in CLL and found that, at a median of 10 months, people could stop treatment because they were MRD undetectable. We’ve adapted that same study to 

-mutant mantle cell lymphoma. Patients are being monitored. However, it’s not response adapted. Everyone will get 24 months of treatment, and the reason for that is because the 

 mutation is there, as I mentioned before. We know that these are harder to treat, but the goal is to have time-limited therapy. If we start with ibrutinib, or acalabrutinib, or zanubrutinib as a single agent up front, you’re going to be on that drug forever. By combining the drugs, we actually have complementary mechanism of action. There is a rationale. There’s preclinical rationale for synergy and laboratory in xenografts. The idea is to get to undetectable MRD. Those are the goals of the study. We have these very sensitive measures, so we can really test that hypothesis, and that’s true with all the combinations.

MCL: Emerging BTKi-Combination Approaches

For the next section of our discussion, I want to get into some of the exciting new things. We just came out of ASH [American Society of Hematology Annual Meeting], and a lot of data were presented, some of which touched on mantle cell lymphoma. I want to ask Andy, what is your take on some of the next group? And there seem to be several. As I said, every meeting I go to it seems like there are a few more names I haven’t heard of or recognize. But we’ve got a few more BTK [Bruton tyrosine kinase] inhibitors on the horizon. What’s your take on those? Are they more of the same, or do they have some new and potentially useful properties for some settings?

We have some of both: more of the same and some new stuff. The tirabrutinib is actually the Ono Pharmaceutical, Inc, Ltd drug, which a number of years ago we were all excited about because it had a much more restrictive kinome, and then the development got held up. It is a highly active BTK inhibitor, but it’s a covalent inhibitor, like the approved drugs. Orelabrutinib is another covalent BTK inhibitor out of China. We saw data presented—a much more narrow kinome— more like actually acalabrutinib in terms of its kinome, so the adverse-effect profile looks like acalabrutinib. It’s quite safe and highly effective, and it has once-a-day dosing, so that’s 1 small advantage of that agent potentially. Obviously the big disadvantage is it’s got a long way to go.

The drug I’m most excited about is LOXO-305. It’s really the new kid on the block because it has a shiny new toy. It acts by noncovalent inhibition. It does not depend on the cysteine 481. In fact, if there’s a cysteine 481 serine, the drug is active. We have seen that mostly in the CLL [chronic lymphocytic leukemia] population because that’s a rare mutation in mantle cell lymphoma. Michael Wang presented the data for LOXO-305 in mantle cell lymphoma. They were pretty impressive: 93% of the patients who went on that study had had a prior BTK inhibitor, and there was still a 52% response rate. Data are early. We need more follow-up to know about durability, and we really need to know more about resistance of mantle cell lymphoma to BTK inhibitors. Because the typical mutations that we see in CLL, the 

 mutation, the PLC-gamma mutation, we don’t see very frequently in mantle cell lymphoma.

There are different mechanisms, and we need to understand those mechanisms and to know what it is about: LOXO, can they really overcome those mechanisms? But the preliminary data look quite exciting for patients, many of whom progressing on BTK inhibitors are responding to this drug. Why is that important? Because it adds another drug to our armamentarium. It prolongs the time we can stay on a BTK inhibitor before we need to think about a CAR [chimeric antigen receptor] T cell or something else.

I want to follow up on what Andy said and ask Krish your sense of, in particular, the LOXO-305 compound. What’s the difference between covalent and noncovalent? Explain to the audience. It’s potentially an important distinction. We’ll see how it matters clinically, but as Andy said, it may be useful in the resistant setting.

The LOXO-305 drug is, as you mentioned, a noncovalent inhibitor, so it doesn’t permanently bind to BTK. Whereas our approved BTK inhibitors all bind irreversibly or covalently. When patients develop resistance to our current generation, 1 of the common resistance mechanisms is the mutation of cysteine at the 481 site, and that basically renders our irreversible inhibitors as reversible inhibitors. But they’re not very good reversible inhibitors, so they fall off the target and they don’t really inhibit BTK. LOXO is designed to overcome that. It doesn’t bind permanently, but it binds in a different way that allows it to be active in patients who have that mutation.

Emerging BTK Inhibitors in Mantle Cell Lymphoma

Another big category of agents that’s applicable, at least in trials, to many types of B-cell lymphomas, and is recently approved in mantle cell, is CAR [chimeric antigen receptor] T-cell therapy. Krish, tell us a little about the data leading to that modality’s approval in mantle cell.

CAR T-cell therapy was approved for relapsed/refractory mantle cell lymphoma just this year based on the ZUMA-2 trial, and that was a single-arm study of patients who had been previously treated with chemoimmunotherapy-containing CD20 and a BTK [Bruton tyrosine kinase] inhibitor. All the patients in the study had had prior BTK inhibitor exposure. The primary end point of that study was response rate. The response rates were very high, 80% or so and 60% complete responses.

A post-BTK setting, which several others have mentioned, can be very challenging, with really high response rates of at least 12 months and what looks to be encouraging progression-free survival. If we say that BTK inhibitors are commonly second-line therapy for those of us who have access to CAR T cells or patients who are eligible, this fits a post-BTK hole, so this has become our preferred therapy for patients after a BTK inhibitor.

Andy, your take on CAR T in this setting?

Brexucabtagene autoleucel is a good drug. It’s approved. It’s pretty toxic. It is the same exact transgene as axicabtagene ciloleucel. There’s a lot of CRS [cytokine release syndrome], there’s a lot of neurotoxicity, and it’s tougher to give to older patients. Mantle cell lymphoma patients are older. It has not been as broadly applicable to our relapsed/refractory population.

We’ve been very lucky to have a couple of CAR T trials open, 1 of which is with lisocabtagene maraleucel that Lia Palomba just presented at ASH [American Society of Hematology Annual Meeting] with excellent efficacy, similar to brexucabtagene but far less toxic. In fact, many of the patients were dosed as outpatients. Not everyone stays in the outpatient setting. A good half of them get admitted and need additional therapy, but there’s no question that we’re seeing durable high-quality responses in the third-line mantle cell lymphoma patients with CAR T-cell therapy. We’re going to see improvements. We’re going to see products that hopefully will enhance the activity and improve it even further. My concern with the approved drug is a little about toxicity. It’s fine for younger patients, but some of the newer drugs that are emerging are a little kinder and gentler.

Tycel, have you been using commercial CAR T for your patients so far in mantle cell?

Since the approval, we probably had 10 patients who would have qualified. Only 1 has even worked toward being collected for various reasons. Some of the same issues have come up before with CAR [chimeric antigen receptor] T in general, but it hasn’t been as accessible as we would have liked, whether it’s because of insurance, space, COVID-19 [coronavirus disease 2019] cases, or patient preference. I do think, as John as pointed out, some patients do have concern about the toxicities at this point. Obviously, insurance still plays a big part as far as waiting for approval, which obviously leads you to do other things because sometimes you can’t wait.

Krish, where is this going to put transplant? We heard that there are patients eligible who aren’t getting it for various reasons. One of the attractions of CAR T is that it’s in the ballpark of or easier than—and I don’t want to oversimplify or overgeneralize that, but 1 might argue that since we know transplant, at least autotransplant is limited in mantle cell lymphoma and allotransplant obviously has significant toxicities of its own. Will CAR T replace some of the patients getting either of those with mantle cell?

 To echo Tycel’s concern, even though CAR T cell is definitely a different tool and offers something different from allotransplant and the toxicities, it maybe is challenged by some of the same access issues. Patients have to travel to the center to be able to receive that therapy. There’s the timing of it, and even when you have that therapy available in your own center, just like when you’re trying to get a patient to an allotransplant, you still have to control their disease while you’re waiting for your CAR T cells to come back. That can be challenging if the patient is progressing post-BTK inhibitor. As Andy mentioned, we still have a lot to do to improve on that therapy, but I foresee that there are fewer allotransplants that are likely to happen because there are some unique challenges with CAR T-cell therapy. But the long-term toxicities of allotransplant are quite a big trade-off compared with the short-term toxicities of CAR T cells.

It seems as if there are very few patients who would get CAR T before they would get a BTK inhibitor, at least now. We’ll see. I’m curious if any of you have had any experience, before we move on, with CAR T in mantle cell in 

-mutated patients. Have you seen responses there? Obviously, the data may be relatively limited, but has anybody formed any impressions about that in your algorithm?

 I had a patient who was treated on the ZUMA-2 trial who had a 

 mutations. This was a patient who received CAR T-cell therapy as a fourth-line therapy, and that patient has been in remission for almost 3 years and has done very well. So that’s encouraging.

Dr Maria Lia Palomba presented those data at ASH for lisocabtagene, and there was no difference in outcome by 

That’s 1 of the nice things so far about CAR T. As we’ve seen in large cell, it seems to me like CAR T can work in, for instance, the double hit, which is almost the bad-actor equivalent in large cell lymphoma as 

 mutation is in mantle cell. It seems that CAR T can work there too, so it’s good to have something that seems to have some efficacy in that group of patients.

CAR T-Cell Therapy for R/R Mantle Cell Lymphoma

There was a comment earlier that mantle cell lymphoma and CLL [chronic lymphocytic leukemia] have these parallels. Andy talked about mutated and unmutated disease. Now we have venetoclax. I don’t want to call it a CLL drug, but it certainly is active and used in CLL. What about its role in mantle cell lymphoma?

 Regarding venetoclax, the oral BCL2 inhibitor, we have data in the relapsed/refractory setting, albeit in a BTK [Bruton tyrosine kinase] inhibitor–naїve population that showed a very good overall response rate. Its role in mantle cell lymphoma will likely be just in combination with some of these other agents that are already established, such as the BTK inhibitor lenalidomide and some of these other things you can combine with. The data as a single agent, especially in the relapsed/refractory setting and the post-BTK setting, haven’t been very impressive. We have 2 published articles that show very short durations of response with venetoclax. Then we have a recent abstract from ASH [American Society of Hematology Annual Meeting] that also shows a very short duration. I look at it in the relapsed/refractory setting as kicking the can down the road. It’s not really going to get you to where you need to be, but it can sometimes be a bridge to get to something else as a transition.

Our current guidelines have listed it as a single agent and also in combination with ibrutinib, based on some of the early data that came from the early study with ibrutinib and venetoclax. Obviously we have SYMPATICO, which compares ibrutinib-venetoclax with ibrutinib. Its role in the relapsed/refractory setting and up front is really going to be in combination vs as a single agent.

Andy, what’s your sense of venetoclax? Is it a similar scenario, in which you may use it in combination? Do you ever add it on to a BTK inhibitor in a patient who’s progressing? What are your thoughts about that?

Earlier on, we had some good results with venetoclax plus rituximab in patients even who had multiple recurrent disease. But with broad exposure to BTK inhibitors, I agree that the responses aren’t as robust. What you just pointed out is something that I often try to do. We’re starting to lose a response to the BTK inhibitor. We want to improve that response. If I can get the insurance company to pay for it, I’ll add venetoclax to it, hoping that we’re going to get that synergy that seemed to be present from Constantine Tam’s publication.

Venetoclax in Mantle Cell Lymphoma

Tycel referenced 1 thing earlier and that was CNS [central nervous system] penetration and potential use. We’ll probably be seeing more occasional CNS involvement with mantle cell lymphoma in people who are living longer. Do you want to comment on a BTK [Bruton tyrosine kinase] inhibitor? I know that’s not the central use of a BTK inhibitor, perhaps. But at least for CNS penetration, how do you think about it for those cases where it might be a factor in a patient, Tycel?

We know from various data, especially from CNS lymphoma, that ibrutinib penetrates into the CNS. There was a recent abstract from the French that actually compared ibrutinib with high-dose methotrexate and some of the other agents that we use for CNS prophylaxis in mantle cell lymphoma. And the ibrutinib actually looked better. Given that, I just don’t know necessarily the penetration of the acalabrutinib and zanubrutinib. That’s not to say that they don’t get into the CNS; I just don’t know.

I tend to have situations where there is concern for CNS involvement. I will tend to resort to ibrutinib just out of the assurance that I know that the drug is also going to get into the CNS, and if the patient responds systemically, I’ll also get some CNS control. It’s 1 of the things that until further data come out with the other agents that I’ll use to help discriminate picking from the 3.

I don’t want to call it a pearl, but 1 tidbit that is worth mentioning because it does occasionally come up: Krish, you mentioned that second line is the most common place where you’re using a BTK inhibitor. What are the other factors that come into this. Is it molecular information, clinical data, the patient status? What figures into when you use it and which 1 you might use?

Often I will use it as a second line, so I think that applies equally to all 3 that are available. In terms of selecting from the 3—zanubrutinib is the newest—comorbidities in particular and medications that the patients are taking, as Andy and Tycel mentioned, are particularly important. For my patients who have cardiac comorbidities, or a history of atrial fibrillation [AFib], or are on medications that increase their bleeding risk, I feel much more comfortable with a second-generation BTK inhibitor. For patients who have been on ibrutinib already, those aren’t patients that I would switch their therapy if they’re tolerating it well for mantle cell lymphoma. But it’s nice to have alternatives available. It’s much more about comorbidities and medications in terms of the selection from the 3 because we don’t have any comparative data.

The other thing I’ll mention is that when we see patients who have high risk or ultra-high-risk mantle cell lymphoma in the relapsed setting, 1 thing that Andy mentioned earlier that is very important to reflect on is that while the BTK inhibitors are active in patients with 

 aberrations, the duration of response tends to be a lot shorter. For that patient I’m picking a BTK inhibitor, but I’m also picking an exit strategy. What’s going to be the next step for that patient? In our practice that is often going to be a CAR [chimeric antigen receptor] T cell, whether that’s a Tecartus trial or some other cellular immunotherapy.

Andy, any other factors for you as far as selecting a BTK inhibitor?

No, we covered the different aspects pretty well. I agree that the drug we know gets into the CSF [cerebrospinal fluid] is ibrutinib. We just don’t know about acalabrutinib and zanubrutinib. We’d like to see data, but in those rare cases where we need CNS penetration, I agree with Tycel: I would stick with the ibrutinib. I also don’t change anyone who’s responding and doing well on ibrutinib. It’s not, “There’s a new drug, so let’s switch to it.” They have to be intolerant of it to be switched because the last thing I want is to switch them and then have them be intolerant of the thing I just switched them to. If it ain’t broke, don’t fix it.

To follow up on that, we haven’t talked about the switch. Obviously, we want to give the drug that’s not going to have the problem from the start, rather than having to switch things around. But what about the scenarios where you made a switch based on toxicity? I’ll ask you first, Krish. Have you had good experience? Do patients have adverse effects? Which ones tend to go away and which ones don’t?

We had the opportunity to participate in some of the intolerance studies. In that setting, I’ve had patients who were intolerant of ibrutinib for a variety of toxicities. Often those are things that maybe we don’t think about as much of a problem, things like arthralgias or skin rash or even more troublesome diarrhea. In general, when I’ve switched agents, those patients have done fairly well on a more selective inhibitor. So, having those different options is very valuable if a patient is coming off ibrutinib. I haven’t had the same experience with a patient who’s on acalabrutinib and is intolerant and what you might expect if you switch them to, say, zanubrutinib. That’s a much less common occurrence.

We’re going to leave BTK inhibitors a little. I’m going to ask Tycel in a minute about venetoclax, which has a role. But I want to ask Andy about the practical questions of how you approach a patient who has a history of atrial fibrillation or needs to be on anticoagulation and a BTK inhibitor. Do you still use a BTK inhibitor? Do you avoid them? Do you have a preference? How does that work?

Anyone who needs to be on clopidogrel and aspirin, I don’t start a BTK inhibitor. I will try to find something else because the triple combination with any of the BTK inhibitors is not a great combination. But if someone is on apixaban or some other well-tolerated anticoagulant for atrial fibrillation, I typically will start with either zanubrutinib or acalabrutinib. I have some patients who developed AFib on ibrutinib, and this was before I had any alternatives. And they’ve settled out, they’re on apixaban, they’re doing OK. I don’t switch that patient now that I have an alternative. I still wait for a shoe to drop.

Tycel, what about early in the course of treatment? Everybody has more or less said, and I’d agree, that for the most part second-line treatment is the most common place you’ll use a BTK inhibitor at this point. What about up-front treatment? What’s your thought on that? We referenced the 

-altered patients and the need for data there. What’s your take on the early up-front data with BTK inhibitors?

At this point it’s encouraging. Looking at some of the data, especially from The University of Texas MD Anderson Cancer Center, the WINDOW-2 trial, and some of the other clinical studies we participated in, the BTK inhibitors up front appear to be effective and well tolerated. They seem to be easily combinable with some of the other treatments we’ve given. That means we have ibrutinib plus bendamustine from the SHINE study, which still hasn’t resulted. Acalabrutinib had a very similar study as well. It does appear to be safe and tolerable in combination. Even the single-agent studies appear to be efficacious. More and more it seems as if we’re trending toward more of a sero-paradigm when it comes to mantle cell lymphoma, more of these novel therapies and less chemotherapy. I can see a future where we’re not giving chemotherapy to these patients, and they’re all just getting targeted treatments. I hope at that point we would still have the same duration of response that we see with high-dose chemotherapy in transplant.

BTK Inhibitors for Relapsed MCL: Important Considerations

 Andy, let’s talk about the various treatments. I won’t call them dogs, but we’ll talk about their spots as we look at the different BTK [Bruton tyrosine kinase] inhibitors. Obviously, they are different in some ways, similar in other ways. How do you think about the differences from the laboratory preclinical standpoint and theoretical, technical standpoint? What do you really see practically in a patient?

The 3 approved BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—are all covalent, irreversible inhibitors of BTK, binding to Cys-481. This mechanism is reliable and highly effective. The drugs differ by their half-lives and by their kinome map. Acalabrutinib has the narrowest kinome of the 3. Zanubrutinib is in the middle, and ibrutinib has the most significant overlap, including overlap with things like ITK, which potentially does in vitro and inhibits ADCC [antibody-dependent cell-mediated cytotoxicity]. Maybe that’s why all the ibrutinib plus anti-CD20 antibody trials have essentially been negative, showing no improvement when you combine the 2. Neither acalabrutinib nor zanubrutinib have that effect in vitro, and they are the more logical combination if you want to add an anti-CD20 antibody.

We have other molecules coming down the pipeline. We’re going to talk a little about them later, including noncovalent inhibitors. They can be very useful when there are mutations, but they’re also very active on their own without the cysteine-481 serine mutation.

There are some other important differences. As was pointed out, there’s less drug-drug interaction with zanubrutinib. Like Tycel, it’s now my go-to for mantle cell lymphoma. I don’t have to worry about PPIs [proton pump inhibitors]. I don’t have to worry about if someone is on verapamil for hypertension. I don’t have to review with the clinical pharmacist—is it CYP34A, is it this, is it that? There’s much less drug-drug interaction, which makes it much easier to use.

You referenced earlier safety from the standpoint of the adverse-effect profile. How would you generally think about zanubrutinib and acalabrutinib with respect to adverse-effect profile? We even have some comparative data.

We have head-to-head data enrolled in Waldenström macroglobulinemia with zanubrutinib showing a differential toxicity profile. Cardiac adverse effects are clearly less. AFib [atrial fibrillation] was essentially in the background with zanubrutinib but was significant with ibrutinib. But there’s more neutropenia that we see with zanubrutinib, and that’s a consistent finding in all studies except our CLL [chronic lymphocytic leukemia] study, which I don’t quite understand. But we can come back to that later.

But acalabrutinib causes some headache, but it’s usually self-limited. I tell people to get a Starbucks card and drink a lot of coffee because it’s very caffeine sensitive; they’ll feel better after having a cup of coffee or a can of Coke—not caffeine-free. But all these adverse effects are manageable. Also, based on the pooled toxicity data, acalabrutinib looks like it has fewer cardiovascular adverse effects. We’re waiting for the head-to-head comparison, but that should be coming pretty soon.

Selecting a BTKi for Relapsed MCL Treatment

Krish, acalabrutinib is another BTK [Bruton tyrosine kinase] inhibitor I’m sure people are familiar with. What’s your take? Summarize for us briefly the general data with acalabrutinib in relapsed mantle cell lymphoma.

Acalabrutinib is approved based on a phase 2 trial called the ACE-LY-004. It’s an accelerated approval and no comparator for the single-arm study. In that study they reported very high response rates for the acalabrutinib, around 80% with half the patients achieving complete remissions assessed by PET [positron emission tomography] CT.

With the most recent updates of 24 months of follow-up data or so, the median progression-free survival is about 20 months. So you can have very durable responses to therapy, but you take away from that study as well that the toxicity profile for acalabrutinib appears to be distinct. We can’t really make cross-trial comparisons of different BTK inhibitors from the single-arm study, but there are low rates of atrial fibrillation and high-grade bleeding events. In general, acalabrutinib seemed to be well tolerated.

Again I’ll ask Andy the ibrutinib question: Where do you use a BTK inhibitor? And second line, what’s your most common scenario?

BTK inhibitors very much become my preferred second-line therapy. In that regard, primarily based on toxicity profile I tend to use acalabrutinib most commonly.

We now have access to zanubrutinib, an even newer option, and we’re starting to get some comparative studies—we’ll talk a little about comparison later. Tell us about your take on zanubrutinib and mantle cell.

 Echoing what Krish said about acalabrutinib, zanubrutinib is a second-generation BTK inhibitor, and it’s more specific for our intended target with fewer off-target adverse effects. As such, it also gives us the ability to play around with dosing. With zanubrutinib, we can dose it 160 mg twice daily or 320 mg daily, which is nice and convenient because obviously some patients are not very good at taking the medication twice a day. It was part of the argument some people have for ibrutinib over acalabrutinib as far as the dosing being a bit simpler for patients.

Toxicity-wise, at least the newer dogs have fewer spots, so zanubrutinib and acalabrutinib also all look a little better. And because ibrutinib, as Dr Zelenetz has mentioned, has been around for a long time, we know it works.

Over time, obviously we’ll be able to learn more about zanubrutinib, to see if any little late toxicities arise. But right now the toxicity profile looks pretty good. And if I’m prescribing the patient a BTK inhibitor, for the most part, aside from situations in which I want to make sure I get some CNS [central nervous system] penetration, most of what I’m prescribing is second generation. One is acalabrutinib- zanubrutinib. And mostly zanubrutinib lately because it doesn’t have some drug-drug interactions, so I don’t have to worry about dealing with PPIs [proton pump inhibitors] and switching patients off, which is an issue that sometimes comes with acalabrutinib.

Newer dogs have fewer spots. We talked about regional differences of treatment. I like that expression. I’ll have to trot that out once in a while.

Acalabrutinib and Zanubrutinib for Relapsed MCL

I want to ask Tycel about the role of BTK [Bruton tyrosine kinase] inhibitors in general. We’re going to spend time going through a lot of the individual data in the next few minutes, but why does a BTK inhibitor work so well in mantle cell lymphoma? We know it works in CLL [chronic lymphocytic leukemia]. We know it works in mantle cell and Waldenström macroglobulinemia; not so much in follicular lymphoma, less in large cell. What about mantle cell makes this a good target?

Mantle cell lymphoma is probably as close as we can get to CLL without being CLL. It’s a very close cousin, and both are very highly dependent on the B-cell receptor. We do know from all these preclinical studies and research that BTK is essential to B-cell signaling. That probably makes it quite sensitive to ibrutinib. This has given us responses and established itself in most situations as the go-to agent in first relapse in most of these patients. Especially with some of the data that we’ll touch on later showing the responses tend to be much improved the earlier we use it. I really think it’s revolutionizing change how we treat mantle cell lymphoma patients, especially in the relapsed/refractory setting.

Compare it with some of the data we have from bortezomib and lenalidomide—granted, those trials of those patients were heavily pretreated with chemotherapy prior to going on to those studies. But it’s really changed the way we look at mantle cell lymphoma, with some of the changes we’ve made up front contributing to the improvement of overall survival that we’re seeing in our patient population.

Andy, ibrutinib was and has been around for a while. We have some data, and good long-term data, which is 1 of the good parts about ibrutinib. Obviously we have other newer agents with different profiles have come along. What’s your general sense as we look at the pooled data and the longer-term data with ibrutinib? How do you think of it in mantle cell lymphoma?

If you can call it that, it’s the grandfather of the BTK inhibitors. It has been around for a while. We do have some prolonged follow-up. We have follow-up with medians of 4 and 5 years. And so this is really mature. We have an idea of how ibrutinib works in this disease. One of the things that’s really important, and Tycel touched on it, is that it really matters when you give it. If you give it for the third, fourth, or fifth relapse, you know it works. It’s usually transient, but if you use it in second line of the pulled data, the progression-free survival exceeds 2 years. And we get a pretty good complete response rate, a radiographic complete response rate of nearly 60%.

The median progression-free survival, as I said, is 25 months, but the median overall survival actually hasn’t been reached as of the pulled analysis from Simon Rule that was published. However, the flip side is it is the drug, in my opinion, that has the most adverse effects. We see the bruising, we see diarrhea, we see rash; some are off-target effects. We’re seeing the cardiac adverse effects, which are really significant with an atrial fibrillation rate of 6% to 10%.

We see increasing hypertension at least through the first 12 to 18 months; maybe it plateaus after that. But we know a lot about the drug. We know how to manage the adverse effects. We can keep people on the drug for a long time. It’s a little easier to keep people on some of the newer agents, but certainly there’s a lot of comfort with ibrutinib because people have used it for a long time in mantle cell and in CLL.

We’ll talk about the choices among different options. But generally speaking, when in a patient’s course with mantle cell would you go to a BTK inhibitor?

Outside a clinical trial, where we would consider in select patients to do it up front, I would do it at first relapse. Like CLL, the genetic background still makes a difference. Yes, 

 aberrant mantle cell lymphoma, will unequivocally respond to ibrutinib. But if you look at 

 aberrant versus nonaberrant, that progression-free survival is inferior for the aberrant cases. Maybe that’s 1 of the reasons why using it in second line is better, because we have a smaller proportion of patients who have the adverse genetic factors.

BTK Inhibitors for Relapsed Mantle Cell Lymphoma

We’ll move into the second part of our discussion, and we’ve talked in the past about the standard therapies, but I think the tremendous excitement in mantle cell lymphoma is the targeted treatments we have. Every meeting I go to, there’s a new agent in just about every class that’s really coming along.

I want to start with Krish, and before we get to BTK [Bruton’s tyrosine kinase] inhibitors, which I think are the most commonly used drugs now, at least in the relapsed setting, there have been a number of different targeted drugs in particular. The first nonchemotherapy, nonantibody drug was bortezomib going back several years, and then lenalidomide also came along. Tell us about your use, Krish, in your patients of either lenalidomide or bortezomib, or both. And anything that’s guiding your therapy in that regard.

Sure. I can’t say that I use much bortezomib in the relapsed/refractory setting, probably due to the availability of other therapies that we’ll talk about, but just to recognize that VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone] is perhaps used in Europe and can be a frontline regimen for mantle cell lymphoma.

But lenalidomide is a drug that I use. Occasionally we do have patients for whom there are challenges of giving some kind of chemotherapy, even bendamustine-based chemotherapy, for which we have used R-squared [lenalidomide and rituximab] based on the data that have been developed by your group, Dr Leonard, and others. That’s a regimen that I’ve used. And then R-squared [lenalidomide and rituximab] perhaps in the relapsed setting and certain settings where we’re trying to maybe bridge patients from one type of a therapy, to say a cellular therapy or a transplant perhaps, is where we primarily use lenalidomide.

To remind folks, the data regarding lenalidomide include both as a single agent and R-squared [lenalidomide and rituximab], and commonly I would use it in combination with rituximab if I was going to use it, rather than as a single agent.

I’ll occasionally use VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone] on a patient for a variety of reasons. It tends to be reasonable, not my upfront go-to regimen, but on occasion I’ve used it with good response. It’s one of the few areas where there’s an overall survival benefit in mantle cell lymphoma. Tycel, Andy, do you ever use that regimen or some bortezomib combination?

I occasionally use VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone], not very often. Occasionally there’s a patient who’s not good for this or not good for that. And then VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone].

I have to say, recently I had to start a patient, and I was really reluctant to give them bendamustine in the middle of COVID-19 [coronavirus disease 2019]. I started them on VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone]. There’s less T-cell suppression. You get tremendous long-lasting T-cell suppression with bendamustine-based regimens, but not with VR-CAP [bortezomib, rituximab, cyclophosphamide, epirubicin, prednisone]. It’s a little more like giving CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] in terms of the T cells. That’s one situation where I found that it had a role.

Tycel, how about you and lenalidomide, your use of that agent?

I have used quite a bit of R-squared [lenalidomide and rituximab], mostly up front. Originally, in most of my post-BTK failures earlier on, I did use a lot of R-squared [lenalidomide and rituximab], but I wasn’t having a lot of good responses with that. I will use it if it fits, based on toxicities, in BTK-naїve patients, but I tend to defer using it quite often in most patients who’ve already been exposed to a BTK inhibitor, because the responses I had previously were not so good.

Our group recently updated a small study at ASH [the American Society of Hematology annual meeting] with about 7 years of follow-up, of lenalidomide, rituximab up front. Patients tended to taper their therapy one way or another for the long-term nature of things, but most of them were still in remission with a 7-year median follow-up. That being said, obviously that needs to be compared to other approaches. Lenalidomide, rituximab is being looked at in the ongoing ECOG-led study as a maintenance regimen after a bendamustine-based treatment. We don’t have those results yet, but we’ll see the impact there. Andy, you all had a study presented at ASH also that included lenalidomide as upfront therapy, if I’m not mistaken.

Tell us about that and your experience with lenalidomide in general in mantle cell.

Our frontline study was RL-CHOP [rituximab, lenalidomide with cyclophosphamide, doxorubicin, vincristine, prednisone] induction for 4 cycles, followed by rituximab, HIDAC [high-dose cytarabine], and then 6 months of rituximab, lenalidomide. Patients did not receive consolidation with high-dose therapy and stem-cell rescue. Technically, we didn’t meet our 60% 3-year disease-free survival, which was the primary end point. However, if you eliminate patients with 

 aberration, we did. It is a very highly effectively, very good regimen if you don’t have a 

 patients except for 1, who is one of my patients, luckily for him. But otherwise, it seems to be a pretty good regimen. The other place I use it, and I agree with Krish, I do not use it as a single agent, I always combine it. I’m always tempted to try to combine it with obinutuzumab, but I stick with rituximab. I’ll use it in patients without 

 mutations if they fail a BTK inhibitor or venetoclax. The thing about the regimen, as you know, if they’re responding early, it does not take months to know if they’re responding. If they’re not responding by the second month and you’re not seeing evidence of shrinkage, you can move on pretty quickly.

 The point you make about your clinical trial, and we’ve touched on others, when you think about it, interpreting data in mantle cell lymphoma is going to get harder and harder for some trials because we’re going to be either preferentially enrolling 

-mutated patients in certain types of trials, and preferentially not enrolling certain types of patients in other types of trials. So, the outcomes compared to trials that didn’t even know about that and incorporate that a few years ago, just based on who ends up, based on our biases of, “Well, you wouldn’t put a 

-mutated patient on a chemotherapy trial any more would you?” That’s going to be interesting, our interpretation of data.

On the other hand, we’re putting a lot of the more challenging patients with these mutations in BTK, venetoclax upfront trials, as an example. I think it’s going to be very interesting to see how we figure out all of that. Hopefully that will lead to better therapy all around, but it may be a lot more complicated to try to figure out beyond what we’ve already talked about.

Lenalidomide and Bortezomib for Mantle Cell Lymphoma

Before we move to the targeted therapies, I’m going to put you all on the spot. I’m going to give you 4 general scenarios. What’s your typical go-to regimen? We’ve talked about all of the nuances, and we sliced and diced the pie. But I’m going to say, a run-of-the-mill young patient who needs therapies; run-of-the-mill older patient who needs therapy; a blastoid patient who’s fit; and a 

mutated patient. You can do that in any order. But those to me are the 4 biggest buckets, so to speak. We all get that it’s complicated, and you might do a little more of this or a little less, or we have our judgment. But most commonly, what are the things that you use for those 4 buckets of patients, recognizing that a percentage of the time you’ll do something different? I’ll start with Tycel.

Clinical trials for all 4 cases. If not on trial, the Nordic Lymphoma Group regimen for young/fit, BR [bendamustine, rituximab], assuming that COVID-19 [coronavirus disease 2019] goes away. Blastoid patients, still we would generally consider the Nordic regimen, with the emphasis of trying to get high-dose cytarabine. Patients with 

mutation, typically we would give Rituxan [rituximab] and some sort of BTK [Bruton’s tyrosine kinase] inhibitor.

And blastoid? Did I miss that? I’m sorry.

Blastoid—I’m still trying to get to transplant, assuming that there’s no 

 mutation, I typically will do a LyMa trial-like approach, but we use DHAX [dexamethasone, cytarabine, oxaliplatin], not DHAP [dexamethasone, cytarabine, salt platinum], times 4, followed by high-dose therapy and stem-cell rescue, with 3 years of maintenance, just as it was done on the trial. For the older, less fit, typically we’re going to start with BR [bendamustine, rituximab], again, if not 

mutated. For the blastoid, it’s tough. It depends on age, it depends on who they are. But a lot of those patients we’re putting on a trial with ibrutinib and venetoclax, the upfront SYMPATICO trial.

 mutated, and we can talk a little more about this later, we have specifically a trial with zanubrutinib, obinutuzumab, and venetoclax, which they get for 24 months. It’s specifically for patients with 

-mutated mantle cell lymphoma that needs treatment.

Yes, very similar. We use the Nordic regimen as well with transplant and maintenance rituximab in young, fit patients; primarily bendamustine, rituximab in older, less-fit patients. Then for both blastoid and 

-type patients, we’ve usually tried to enroll in a trial, the SYMPATICO trial being one of those. Occasionally we’ll use cytarabine-containing regimens for the blastoid patients who don’t have 

Great. I don’t think I could argue with any of the comments because they’re all reasonable, and that highlights the challenge of mantle cell lymphoma. Some of those regimens have differences of PFS [progression-free survival] versus the other; differences in OS [overall survival] are less clear. But they’re all reasonable things to do, and I think it highlights the challenges of facing patients with mantle cell lymphoma, in general. Before we move on, any changes? If you happen to see a patient with stage I disease, Andy, you reference it’s uncommon. I’ll ask you. What do you do with a patient with stage I mantle cell lymphoma.

Mantle cell lymphoma is very radiosensitive. You burn no bridges by taking a radiation approach. I am not a big fan of chemoimmunotherapy with radiation. The data do not really support that the chemoimmunotherapy adds that much. But the radiation can provide certainly short-term, meaning over years, control. And in some patients it will provide what looks like a curative outcome. We have patients out 10 years. But as I said, it burns no bridges. If a patient progresses, we have all the options on the table. We haven’t used up any treatment.

All right. Tycel, Krish, any other thoughts about the patients with stage I and how you approach them? Again, not that common, but we always think a lot about them when they come in.

No. I whole heartedly agree with everything Andy said. Some of you may not remember, I sent an email out a few years ago. We had a patient with localized blastoid disease, and I got 20 different answers from 20 different people.

I just radiated, the patient has been in remission since. I didn’t add chemotherapy, just radiation. But everybody gave me a different answer. I don’t know if any them were wrong, but again, they all included radiation. I think what Andy said is completely correct, radiation is very helpful in mantle cell, especially stage I.

I’ll echo the comment I think Andy made, with the colonic polyps. We have a number of those patients who can go years and often don’t have any other disease anywhere else for a long time. All mantle cell is not the same obviously.

One little twist on those GI [gastrointestinal] cases. Early on we were worried that these were going to bleed when they got treated and such. We almost never see GI bleed, very interesting.

Go-To Treatment Regimens in Mantle Cell Lymphoma

One of the most challenging consults in my practice, and I’m sure yours as well, is the patient with newly diagnosed mantle cell lymphoma. You’re assessing them, you’re deciding what treatment—do they even need treatment? What’s the prognosis? Tycel, take us through how you look at a new patient, and once you have some of the data we’ve talked about, what’s your thought process as far as approaching their treatment?

 I think you adequately touched on some of the issues we have. Part of the problem is there’s no standard care for mantle cell lymphoma, and you will see some degree of regionality as far as treatment choices. But generally, when I see a newly diagnosed patient, some of the things I’ll take into account obviously are symptoms. I think from the paper that originally came out of your institution, we’ve shifted a bit from treating every patients with mantle cell lymphoma who walks in the door and take into account whether these patients are symptomatic.

At the University of Michigan, what we will do now is, for all patients who don’t have a blastoid variant, we will basically observe those patients unless there’s an indication to treat, with the understanding that most of those patients will need some sort of treatment within a short time from diagnosis. But explaining to the patients that we don’t have any evidence that that will impact overall outcome, it does provide some reassurance for those patients.

Once they do need treatment, some of the factors that have already been touched on, especially 

 mutation, blastoid variant, Ki-67, do come into play.

 mutations, I don’t think anybody knows the right way to treat those patients. Most of the literature suggests that those patients probably don’t benefit from high-dose chemotherapy and transplant. So standardly, if possible those patients have been directed into clinical trials, hopefully utilizing some sort of novel agents. Outside of novel treatments, I’ve been trying to use some of the approved agents in a relapsed/refractory setting up front, such as ibrutinib, zanubrutinib, acalabrutinib, or even R-squared [lenalidomide and rituximab] in this patient population, given the short PFS [progression-free survival] that has been noted with transplant that’s come out of the Nordic Lymphoma Group trials.

Standardly outside of that, I mean it’s usually the idea of age and fitness. If it’s a young, fit patient, again outside of a clinical trial setting, we will still treat with a Nordic regimen with a plan of trying to get those patients to transplant.

With the current ECOG study now, I’m encouraging most of the patients who do get high-dose chemotherapy to enroll in that study, which will randomize patients to transplant plus maintenance versus maintenance if they are MRD [minimum residual disease]-negative after induction therapy.

For those patients who are not fit or eligible for transplant, we generally use bendamustine. In the era of COVID-19 [coronavirus disease 2019], that has taken a bit of a twist out of concern for the immunodeficiency that we know that comes with bendamustine-based regimens. So in that time, we’ll probably lean into more R-squared [lenalidomide and rituximab] in patients who are unfit for aggressive therapy, knowing that the data at least presented now appear to suggest that regimen is very effective up front in patients with mantle cell lymphoma.

Andy, I want to go to you. Tycel referenced the watch and wait. Are you watching and waiting with most patients? How do you decide that? And then, what are your 2 big buckets of younger, fitter patients? How do you generally approach them? And then the older, more frail patients, how do you generally approach them?

I completely agree with Tycel that there’s a lot of regionalization. We look for certain biomarkers. Non-nodal leukemic phase and GI [gastrointestinal] tract only, we typically are monitoring those with active surveillance.

The other patients, even if they’re nodal—though they are frequently not nodal—are patients with 

 mutation. Like CLL [chronic lymphocytic leukemia], mantle cell lymphoma falls into 

-mutated and unmutated, and like CLL, unmutated has a more aggressive course, mutated has a less aggressive course. The unmutated cases, we tend to commit to treatment, particularly if they’re younger, have proliferation fractions of greater than 30%, clearly if there’s pleomorphic or blastic mantle cell.

But we’re also viewing this through the lens of whether there is a 

 aberration. Right now, as I mentioned before, there’s some controversy about the importance of 

 deletion, but there’s no controversy whatsoever about the role of 

 mutation. That has a big impact because the Nordic Group trials show that you shouldn’t transplant these patients up front, and the reason to transplant someone with mantle cell lymphoma up front is not to cure them, it’s to give them a long durable remission. And they’re not going to have a long durable remission if they’re 

 mutated. We have to take all of this stuff into account. I probably observe fewer patients than Tycel, but we observe plenty of patients—probably one-third of the patients get observed.

No, very similar. I will say that those buckets of fit versus not-fit, sometimes you find that slim bucket in the middle, somebody who’s in their late 60s, and that’s a space where we’ve been kind of combining the approaches of bendamustine-based therapy with lower-dose cytarabine, the R-BAC500 [rituximab, bendamustine, cytarabine] regimen. That’s been a regimen that I think allows us to treat that unique subgroup of patients. And then, of course, their transplant eligibility is going to be maybe a little different, but we’ve had relatively good outcomes using that regimen as well.

Treatment Approaches in Mantle Cell Lymphoma

 titled, “The Evolving Landscape in Mantle Cell Lymphoma.”

I am Dr John Leonard from Weill Cornell Medicine and NewYork-Presbyterian Hospital in New York.

Joining me today in this discussion are my colleagues: Dr Krish Patel from Swedish Medical Center in Seattle, Washington; Dr Tycel Phillips from the University of Michigan in Ann Arbor; and Dr Andrew Zelenetz from Memorial Sloan Kettering Cancer Center in New York.

Today we are going to discuss a number of topics pertaining to the contemporary treatment of mantle cell lymphoma. We’ll discuss the latest research in the field and the impact of recent clinical trials, including some data from ASH [the American Society of Hematology annual meeting] 2020. These data center around making decisions for treatment selection.

Let’s get started on our first topic. I want to thank all 3 of you for joining us today. It’s I think a timely point to sit and talk about what’s happening in mantle cell lymphoma. We just finished the ASH meeting. There are a lot of exciting new data, and it’s great to be here with you all and get your perspective, so thank you.

The first part of our discussion is centered around the diagnosis and treatment of mantle cell lymphoma. I’m going to ask Andy to give us some key aspects of how mantle cell typically presents itself, what’s the typical course, things around heterogeneity, and how you approach these patients when they first come into your clinic.

Mantle cell lymphoma can have a variety of different clinical presentations. It is a very male dominated disease, series run anywhere from 60% to 90% men. But the manifestations can be wide ranging. Early stage disease is quite uncommon. Localized mantle cell lymphoma, though it occurs, is quite uncommon. Most patients have advanced-stage disease presenting as nodal disease, but sometimes can present with non-nodal leukemic phase. Increasingly, we’ve appreciated over the years that all mantle cell lymphoma is not created equal. We have some very indolent behaving disease, where active surveillance is the appropriate initial approach. We have other patients who at diagnosis can have blastic mantle cell lymphoma, which is a very aggressive disease.

There are morphologic features, and so first of all, it’s critically important to get an adequate biopsy; fine needle aspirate is usually not adequate for a biopsy. A core needle biopsy, or preferentially even an incision or excisional lymph node biopsy, will provide the pathologist with sufficient material to make a diagnosis. That’s the foundation of a good treatment plan.

Then once we have that, we do standard staging. Mantle cell lymphoma is typically FDG [fluorodeoxyglucose]-avid. At Memorial Sloan Kettering Cancer Center, we do standard PET [positron emission tomography] scans at baseline. We used to do colonoscopies on everyone because GI [gastrointestinal] tract involvement is extremely common. However, that turns out not to be necessary. It doesn’t fundamentally alter the course. Now, there is such a thing as GI tract-only mantle cell lymphoma. There is presentation as lymphomatous polyposis coli, but that’s usually an incidental finding at a colonoscopy.

The diagnostic work-up is a pretty basic lymphoma work-up. When there’s a leukemic phase, obviously adequate and good quality peripheral blood flow cytometry is necessary. There is supportive and important molecular testing that is necessary. On tissue we would look for the expression of cyclin D1, which is seen in 90% of cases of mantle cell lymphoma. Some variants don’t express cyclin D1, but you have to be very suspicious of a diagnosis of mantle cell lymphoma without cyclin D1 expression. But we can also look for the 11;14 chromosomal translocation.

There are other important biomarkers, the complex karyotype, 

 mutation, and some controversial data about whether 

 deletion is important, and we can come back to that as we discuss things a little bit later. Fundamentally, this is a heterogeneous disease. We want to make sure we get an accurate diagnosis so we can formulate a treatment plan.

Krish, can you give us a sense of when you see a patient, and you’re trying to think about what to do and how to stage them and look at their risk, what are some of the things you’d look at?

Krish Patel, MD, Swedish Medical Center

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