Georg Hess:

So, hello everybody. I’m happy to be here with a good colleague and friend from Munich, Professor Martin Dreyling. My name is Georg Hess, and we have the opportunity to discuss around the field of mantle cell lymphoma. And as you realize, this has been really a topic of great advances over the last couple of years. And so, I think it’s a great time to just sit down and review a little bit what happened. And this directly goes to Martin who can introduce himself. So, maybe you comment from your side on the most important changes in the treatment of younger patients in the last couple of years and you have been involved heavily, let’s say, that way. So, Martin.

Martin Dreyling:

Well, thank you very much Georg. I’m privileged to have a little, let’s say, a chat with you really talking what has happened in mantle cell lymphoma during the last… Well, in fact we just had a historical review you might say, and we looked about the outcome of especially younger patients during the last 30 years. And what we’ve seen, we started from essentially having an overall survival median around three to four years. And then the first step was adding rituximab. And then it’s about 20 years ago when we have established the standard of care as chemotherapy intensification. And the result of that was in fact taking the standard R-CHOP and adding up high dose chemotherapy with autologous stem cell transplantation. And anyway, that somewhat doubled the overall survival. But meanwhile, we also did a couple things. We added the less toxic things, rituximab maintenance, applied induction in a more intelligent way. And then again, this brought us to an overall progression-free survival in the range almost 10 years. At least in the young patients, you have to be aware these are the low-risk patients. But anyway, during our last study, we even supplemented and cut down chemotherapy and substituted by targeted therapy. And essentially in some patients, we skipped autologous transplant and instead added the targeted BTKi. And well, what was expected, the add-on design autologous transplant plus BTKi was superior, but what was, at least for me, totally unexpected and this is why the statistical design did not target on that, even the ibrutinib only arm was superior to autologous transplant, the old standard of care. And that was a major step now with the adding of overall survival of the three, four years in the range of 10%. So, to make a long story short, we started with the disease where we did not have standard of care and only achieved a median overall survival of three years. But now we are, let’s say, at five, six, seven years in the range of 90%, which is really a land shift.

Georg Hess:

And you just were talking about where younger patients and I think there is several important topics on that. I mean the former days younger was defined by age, so 60 was something which was a solid cut for autologous transplantation. But maybe you can comment on the impact of skipping autologous. So, in your general practice, what is a young patient now who qualifies for that intensive treatment, but without autologous transplantation?

Martin Dreyling:

There is this old-fashioned joke that old age means the age of the speaker plus 10 years, which is what we all approach. But anyway, you’re right, there is historical shift which essentially nowadays whatever 70-year-old chap, I talk male because mantle cell lymphoma is mostly male patients is corresponding to a 60-year-old chap about 20, 30 years ago. This is one point. The other point though is as we skip autologous transplant, this was the age-limiting part of the treatment. Based on these excellent results, we can expand what I would now call young plus median age. So, we more or less go on a clinical routine up to 70 years.

Above 70 years, yes, we have these super-fit marathon runners, but to be honest, these are rare at age 80 or so. So, for the majority of patients below 70 years, this is more or less the standard of care and that significantly extends what you were referring to what we previously called young patients.

Georg Hess:

I think this is important, right? So, this means that basically, I would say 50% to 60% to 70% of the patients now newly diagnosed could be at least evaluated for that approach. And I have a second question and there is a lot of discussions going around the field, can we really skip autologous transplantation from time to time? You and me, we go to presentations and we’re always in the position to skip autologous. And then you do this voting and you still get a lot of people who are in favor of using autologous. And basically, the trial doesn’t reflect that in the entire group, it has a benefit. But we both had discussions around the field. Is there a risk group or is there a kind of a clinical decision-making where you personally still consider autologous a reasonable choice for patients? How would you approach that, or how would you describe this scenario?

Martin Dreyling:

Well, first of all, one has to be honest, the study population is always a highly selected patient population. So, in the study, it was, let’s say, the real fit younger patients and real life is different. We all know that. So, therefore, yes, toxicity plays even a greater role than within the study. Secondly, it’s fair to say, especially in mantle cell lymphoma we do know it’s such a diverse kind of disease. It might be rather indolent where you anyway tend to skip autologous transplant, or you may consider really the aggressive mantle cell lymphoma. And the question is what are our criteria in clinical routine?

And we started with simple clinical parameters almost identical to IPI, the MIPI, but this is highly biased by age, so it does not help us in this setting. And therefore, meanwhile we totally switched over to biologically driven prognostic scores, namely high cell proliferation, blastoid immature cells, blast-like and thirdly p53 mutations. And these three parameters really identify the different risk groups and about 70% to 80% are rather indolent. So, they’re anyway well off without autologous transplants. So, there is no more discussion about this patient population, but we are still discussing about the 20% high-risk patients. And there, it’s interesting that we did a subgroup analysis and thanks to the large study size of TRIANGLE, we were able to give some reasonable advice. And in these patients, yes, dose intensification did improve results. The question is, is it worthwhile? Because you also buy in higher toxicity, not only during autologous transplant, this is what we’re used to handle, but during the two year of combined rituximab plus ibrutinib maintenance. And there, it’s always an individual decision. My personal bias and I wonder how you manage it in minds, but really my driving force currently is Ki-67.

So, if that is skyrocket high, not only 20% to 30% or 35%, but let’s say, 50% and above, I tend to discuss in the fit patients autologous transplants, but not in the other ones. But how do you manage your mind?

Georg Hess:

Yeah, first of all, I really agree that Ki-67 probably is a good marker if you have a pathologist who really does it properly. That is important so that it’s not eyeballing, it’s really something you can trust on. Then it’s more or less the describing the biology of the disease. In part, that is something we are taking into account, but we really have switched a little bit from a pre-treatment recommendation to a non-treatment recommendation. We really monitor what’s happening to the patient. And I mean if a patient has a CR, whatever his initial risk score has been after the six cycles of induction, I feel and I totally agree it’s a point about feeling, but my point is then it’s hard to justify additional toxicity without any clear data and we don’t have data to support autologous at this time anymore. But we just last week had a patient who he had a bulky disease, he responded well, but he had residual masses. And then we argued, “He’s chemo sensitive, why don’t use the principle of chemotherapy up to the end? Because in the second and third line, there won’t be any chemotherapy.” So, there is nothing to spare for later on. And in this case, we discussed with the patient whether or not we should use an autologous transplantation. All in all, I think to sum that up, I think that is a very important development, right? So, instead of always getting more and more intensive for the first time, we really have a biology driven targeted agent modified treatment which gives excellent results and we can really look for tolerability. And this brings me to the other fraction of patients, the elderly ones. So, whenever elderly starts, and we both would argue that’s at least 20 years from our age, but I’m not totally sure, whatever. There, other concepts play a major role. And recently, there have been at least three trials who explored around the field of BTKis, the ENRICH and SHINE, ECHO. And maybe you may comment on these approaches and the impact on the current strategy.

Martin Dreyling:

I think you bring up important points. So, first of all, we started with our success story. So, definitely in younger patients, mantle cell lymphoma is a success story. And in older patients, we did improve outcome, but it was not such a land shift advantage. And the reason is both. First of all, we could not optimize treatment with, for example, cytarabine because it’s too toxic and at least for the bulk of patients. And secondly, it’s also that we were not able to go into other kind of autologous transplant or even that. And toxicity even of targeted approaches does play a role. That’s the major second point.

So, to make it very clear internationally, BR is standard of care for the majority of older patients with mantle cell lymphoma. And that’s fine if it’s a low risk mantle cell lymphoma, then you’re really well off. However, when it is again bringing in the biological risk factors, if you have a high cell proliferation, I think patients are better off with a CHOP like regimen like VR-CAP or whatever. That might be true or not, it’s not really proven to be honest. And here, we come in. So, to try to adapt this to elderly patients, BR plus targeted therapy and that has been explored in the SHINE trial. And what we have observed, PFS was a little bit improved, well not only a little bit, but clinically relevant, 10% to 15%, but overall survival not. And that may indicate that you buy in toxicity and to be honest, cardiac disease is a problem in older patients and therefore, the exact study had been repeated but now with a second generation BTKi. And concerning PFS, the curves are almost super imposable. Again, hazard ratio is identical, but now also the overall survivor curves split apart at least a little bit. And then if you do a statistical trick, essentially censoring or COVID events, this becomes almost borderline significant. So, therefore the second trial led to registration of BR plus acalabrutinib, whereas the first one SHINE was considered negative, at least concerning OS. And based on this one, the third question is, well do we still need chemotherapy at all? Because BR people say, “Well, we tell all of our patients is well-tolerated,” our patients don’t think so. Our patients, it’s still chemo, it’s let’s say, a more smarter chemo you may call, it’s still chemo and that is very interesting. In the SHINE trial, BR was tested against IR. And what came up, the typical side effects concerning chemotherapy, myelosuppression infection were lower in IR and the outcome on the other hand, PFS for the whole group was even better. But again, we have to look into the subgroups and interestingly in the standard risk patients, in fact, the IR was better, but in the higher-risk patients, and that’s the interesting thing, chemotherapy still did add. So, a similar story as in younger patients, interestingly perfectly fitting to the results of the TRIANGLE, but definitely not what we were achieving for or hoping for. And therefore in lower-risk patients, IR may be an alternative if your insurance system does allow that. However, in high-risk patients and these are the ones you really have to treat, we probably still stuck with chemo.

Georg Hess:

Yeah, I think that’s a pretty good summary and I mean it’s a rational strategy anyhow. I mean censoring and modifying that is always something, I don’t know maybe we will see in the future, but the important point is we have left chemotherapy as the standalone solution. I mean it has been visionary what you have been doing over the last 20 years. So, what is your expectation on the next, let’s say, era of novel treatments, what would you put money on, maybe in the younger and then briefly in the elderly patients?

Martin Dreyling:

Well, it’s funny, it’s probably the same theme for younger and elderly in that way that, because we are probably moving more away from chemotherapy. In younger patients, we have already skipped or are skipping a high dose chemotherapy in the majority of patients. And so, again, toxicity plays a smaller role. So, why not move to a uniform treatment to be honest? And that may be possible if we move to targeted treatment overall. Having said that, there is a belief and the belief is probably, and that has to be proven in randomized trials. In low-risk patients, probably we’re pretty well off based on the ENRICH trial with a non-cytostatic approach, BTKi plus something. And we try to improve by taking the wonder combination, everyone’s darling, which is BTKi plus BCL-2 antagonist, namely venetoclax. So, that has to be tested in a randomized fashion. This is a hypothesis, but these studies are going on the MCL Elderly III study and we’ll see what the results will be, whether this combination is really able to match chemotherapy. And for the younger patients, well it’s fair to say we think they can tolerate treatment even better. So, for them, it may be possible to add another player, which is immunotherapy. We do know that CAR T-cells play a major role in relapsed treatment, so why not move on right away to first line? But then it should be really tailored to young high-risk patients, only the high-risk patients. And again, the jury is still out, will that really be able to improve outcomes in high-risk patients? But I’m a strong believer in randomized studies, may be even Phase II studies, but these two studies may open the door to a chemo-free first-line treatment. We’re not yet there. In CLL, it’s already a standard of care, but I hope we’ll get there. But that brings me to the second part to and asking you, now it’s my turn to nail you down here, be prepared. So, I mean if you have a nowadays patient having been treated in the past with a standard of care with chemotherapy only, what is your current first salvage treatment?

Georg Hess:

I think that is a very important question because looking back, I mean most of the treated patients out there having one line have still been not treated with a BTKi. That’s the majority of patients. And so, the key question always was can we repeat chemotherapy or should we switch to a targeted agent? And I think it’s the work of Carlo Visco who did two important retrospective analyses, but still I think very important. And first, he asked what about the patient with an early progression of disease and intuitively, BTKi were better than chemotherapy, but still the argument would always that we keep the good drug to the end, blah, blah, blah. And so, he did the late POD trial and then he proved that even for patients having a late progression, ibrutinib in this case was clearly better than chemotherapy. And that to me places clearly a BTK inhibitor into the first place for anybody having a relapse after not being treated with a BTK inhibitor. There is the SYMPATICO trial and you name this magic combination of BTK, BCL-2 and the trial showed superiority of the combination over the single drug treatment. So, if this would be approved, this would be a rational alternative, especially in patients where maybe you don’t have a chance to go for a CAR or you take the maximum out of this remission, that could be a rational choice.

So, that would be the setting of the BTKi naive patients and the BTKi pretreated patients. The scenario gets a little bit more complex because first of all, you have two groups, those being progressive while being on a BTK inhibitor, so they’re refractory and the other ones after a cessation. So, having TRIANGLE, two years of maintenance, then three years of remission and having a relapse. And so, there is no data out to be very honest, what is the best choice in the later one. But still I think in our hands, we would re-expose those patients who had a solid break and we would use again ibrutinib or acalabrutinib, which is now approved in this scenario or the SYMPATICO combination.

I think we would do so and depending on the response we would reserve to directly go or not to go to CAR-T in this scenario. It’s more complicated on the refractory cases because in the refractory cases, in my understanding, there is a clear hint that probably placing a CAR T-cell treatment as early as possible is a rational thing to do and I wouldn’t then continue with ibrutinib. There is one chance to add venetoclax. I would say that is something a low progressive disease patient starts to have some lymph nodes, you see ibrutinib fails and then you add some venetoclax and you have a remission. Again, you do the CARs, it works nicely. And those with more massive progression, I would not stay on ibrutinib.

I probably would put my money on the new player pirtobrutinib, the non-covalent BTK inhibitor, which has proven to be efficient even in the pretreatment scenario. And that would be a very good bridging strategy to CAR-T, or if you’re not CAR-T eligible as a standalone solution or if you have a CR. I mean nobody knows what to do in this situation. So, that would basically today set the scene to me what to do and what not to do. Clearly in third line, and I know, you were going to ask me that question. One of the available or available CAR T cell treatment if you can do so, is the primary choice of treatment.

Martin Dreyling:

Fair taken. So, you mentioned patients, let’s say, the other way around. Now, we have three BTKi essentially in Europe registered, which is ibrutinib, which is also acalabrutinib in relapsed mantle cell lymphoma and you already mentioned pirtobrutinib. So, which BTKi to be applied in which patient?

Georg Hess:

Yeah, I mean the scenario is complex because acalabrutinib is approved in BTKi naive patients. That’s the tricky thing. It’s not approved in BTKi pretreatment. So, for the reuse scenario, formally it’s ibrutinib which you can use. But in a patient with a cardiac risk, I would apply for acalabrutinib or a patient who has not tolerated ibrutinib very well in the first line. For somebody has done excellent with ibrutinib in first line and he’s in label and had four or five years of remission, I would not hesitate to re-expose that patient. So, that would be the distribution between acalabrutinib and ibrutinib. And if somebody is naive, I would use acalabrutinib for the side effect profile. I would preserve pirtobrutinib for a BTKi failure, because you cannot turn it the other way around. But it’s important and it’s good that you readdress this point, there is a trial pending, right? So, in BTKi naive patients that it tested pirtobrutinib against investigator’s choice. So, you could then choose from ibrutinib, acalabrutinib and zanubrutinib as far as I recall. And let’s see. And if this trial shows better results for pirtobrutinib than for the others, then I think my choice would even throw the argument of having a reserve strategy is nice. I always prefer the argument, use the best treatment available for a patient and there is no such thing as keeping the good stuff for later lines. You never know what happens. So, that is open to me and in the refractory cases. If somebody is refractory to ibrutinib, I would not use acalabrutinib. The data are scarce. And to be very honest, the few patients, there was not a major response rate. So, in this case, I would use pirtobrutinib indeed.

Martin Dreyling:

Fair taken. You also mentioned CAR T-cells, especially for BTKi failures and I fully agree, but you also mentioned that not all patients are qualifying for CAR T-cells. Which in your personal practice, daily practice, daily routine, which patients do you not consider fit enough for CAR T-cells? Just give us some advice.

Georg Hess:

Yeah, I mean there is formal reasons. No active other cancer, pulmonary disease, cardiac disease. There is formal criteria. The other point is we learned that the tolerability to the brexucabtagene is quite correlated to age. So, initially to be very frank, we were enthusiastic and we trusted that there is no upper age limit, but we see neurotoxicity. And our feeling is that above the age of 75, 77, it’s getting worse. And we would not be, let’s say, that we have no major urge to do so in these patients. I mean you have this marathon runner, sure we would do so, but our feeling is that these patients are… There is expected that liso-cel is going to be approved sometime next year or so. And in the DLBCL field, liso-cel at least has proven somewhat better tolerability than the other CARs around. And I mean we see that shift in the use and I could imagine that this is an important alternative for the elderly ones. The problem is if you look at the data, two trials comparison, it looks like that the more aggressive CAR is doing a little better than the other and therefore, the elderly do better with the liso-cel. So, that could be a strategy for the future that we allocate the one and the youngest and the other one in the elderly shifting the age limit, that would be our scenario. And somebody has had two strokes or whatever. We would be very reluctant to or dementia or something like that. We would be really reluctant to use any CAR. I don’t know. Do you use CARs in the elderly? Do you have other clear-cut ideas? I mean you’re doing a lot of work in Munich on all these criteria.

Martin Dreyling:

No, I fully agree concerning the neurotoxicity, especially in older patients. But I have one last question which I think is clinically really important, which is when it comes generally to the question how to individualize treatment in relapsed mantle cell lymphoma, you mentioned in first relapse, BTKi is really the anchorman of treatment, but what are the risk factors you make up your treatment decision on? Does POD24 plays any role and what are the different avenues you pick? A typical patient, sorry, let’s make him 70 years old.

Georg Hess:

Yeah, I mean basically everything comes together nowadays to be very honest, because let’s say the typical scenario is somebody has no BTKi inhibitor, gets a first relapse, we use acala or ibrutinib or a SYMPATICO, and then we see relapse again after 18 to 24 months. And then our next point would be a CAR-T and there is not a difference very much. In the younger ones, TRIANGLE failures, I mean formerly you had chemo, you had rituximab and you had ibrutinib in first line. And we apply at the health insurance to have the chance to use it in second line. And we were successful recently in two cases. And I think it’s reasonable not to wait. So, basically, there is not a major difference of strategies depending POD24 or not. I mean if you have somebody who had 10 years of remission after BR and says, “Well, BR was wonderful, can we reuse BR?” And probably I would say, “Yes, let’s do another four cycles and it works well and then we can use ibrutinib anyhow.” But basically, we follow very, very similar approach to all these patients with a difference of those being pretreated and not pretreated. And that is more the optional step two in the algorithm. And then if you have the elderly patients, it’s monotherapy with a BTKi. And failure after ECHO would be interesting honestly. It would be pertinent to my understanding at these days and we are eagerly waiting. I mean we had made so many advances, but some things got lost in the meantime. Bortezomib, I mean it doesn’t play a major role. Temsirolimus, lenalidomide, I mean they’re around, but do not play a major role. But I think the more important options to come, the new kids on the block are the BTK degraders. And for example, and especially, I mean we’re just setting a trial up in Germany, the bispecific antibodies, right? So, Sebastian Böttcher is doing the PLATO trial and this is important to combine a BTK plus a bispecific antibody, and this could be a good choice as Philips has shown with this data.

Martin Dreyling:

Well, thank you very much for this overview. I think we have the glass is half full or half empty, so we have definitely done some step forwards, especially in first line mantle cell lymphoma. In relapsed disease, I fully agree it’s still nowadays always a challenge. And what is even worse, we have significantly improved in the low risk patients. Whereas in the high risk patients, we still urgently look for some breakthroughs. So, thank you very much for having this chat and I think it’s really very interesting to see what has happened, where are we right now, what are our clinical challenges? Hopefully next time, we will come to the real difficult questions, for example, CNS relapses. But that’s for next time. Thank you for listening.

Georg Hess: 

Consultancy: Abbvie, ADC, AstraZeneca, Beigene, BMS, GileadKite, Incyte, Janssen, Lilly, Milenyie, MSD, Novartis, Pierre Fabre, Roche, Sobi
Honoraria:  Abbvie, ADC, AstraZeneca, Beigene, BMS, GileadKite, Incyte, Janssen, Lilly, Milenyie, MSD, Novartis, Roche, Sobi
Research Funding (to institution):  Abbvie, GileadKite, Janssen,Lilly
Patents and Royalties: not applicable
Membership on an entity’s Board of Directors or advisory committees: not applicable
Discussion of off-label drug use: not applicable
Travel grants: Incyte, Janssen, Pierre-Fabre