Manali Kamdar:

Welcome, everyone. My name’s Manali Kamdar. I’m an associate professor at the University of Colorado and the clinical director of lymphoma. I am super excited to have joined this exciting discussion that’s lined up today on relapsed/refractory lymphomas. We will be covering mantle cell lymphoma, diffuse large B-cell lymphoma and follicular lymphoma. Joining me are my friends and colleagues, Dr Strati and Dr Iacoboni. I’m going to have them introduce both. Dr Strati, why don’t you start?

Paolo Strati:

Yeah. Hello, everybody. My name, as you heard, is Paolo Strati. I’m an associate professor, deputy section chief for indolent B-cell lymphoma and CARTOX program co-leader at MD Anderson Cancer Center in Houston, Texas. I’m very happy to join my friends and colleagues for this discussion focused on lymphoma today.

Manali Kamdar:

Thank you, Dr. Strati. Dr. Iacoboni?

Gloria Iacoboni:

Thank you for the invitation. I’m Dr. Gloria Iacoboni. I’m a hematologist working at Vall d’Hebron Hospital in Barcelona, Spain. I focus on lymphoma and CAR T-cell therapy and lymphoma in particular. I’m really happy to join you here for this fun conversation we’re about to have.

Manali Kamdar:

That’s lovely. So let’s dive right in. Let’s start with diffuse large B-cell lymphoma. Clearly, the management of diffuse large B-cell lymphoma amongst all other subtypes has had a remarkable change over the last four to five years. Let’s start with probably the most impending discussion with regards to CAR T-cell therapy, as well as CD20 bispecific T-cell engagers. Both of you are leaders in the field. You have written tons of publications and manuscripts into both of these topics, but I think they have become quite integral to our treatment. My first question is obviously the obvious one, how do you think about sequencing? You go CARs first or bispecs first? They’re both approved in the third line setting right now, as well as CARs approved in the second-line relapsed diffuse large B-cell lymphoma space. So just sticking to the labels for now, how do you think through it? Maybe I will start with Gloria.

Gloria Iacoboni:

Yeah. I think that’s a great question. Up to last year, we only had CAR T-cell therapy in the third-line setting, so we got reimbursement for second-line CAR-T in February of 2024. We were facing that conundrum. Third line, we have bispecifics, we have CAR-T. Our approach, the approach of our center was to go focus on CAR-T first if they were both available in the same line setting, given many, many issues, many points that I think are important.

The CAR T-cell trials have a longer follow-up. We know CAR T-cell therapy has curative potential. We know the fraction of cure in large B-cell lymphoma relapsed/refractory large B-cell lymphoma and we have abundant real-world data supporting the same efficacy we’ve seen inside the pivotal clinical trials. I think all of those factors maybe just because of time, but they’re lacking for bispecifics. We need real-world data. We need longer follow-up the trials. We need to understand how many patients are potentially cured with bispecifics. Just given that let’s say different evidence right now that’s available, we would definitely choose CAR T-cell therapy if the patient was a good candidate before bispecifics in the third line.

Now, as you mentioned, it’s shifted. I mean, the question is changed because we have CAR-T in the second line and now we’re mostly doing CAR-T in the second line actually. We know that over 75% of patients will relapse early or be refractory to first-line immunochemotherapy, and therefore, go to CAR-T in the second line. It’s really uncommon now that we offer CAR-T in the third because most of the patients receive it in the second line. So bispecifics, as you mentioned, are only available in the third line. So the current sequencing outside of the trial setting would be CAR-T usually in the second line and bispecifics in the third line after CAR T-cell therapy in large B-cell lymphoma.

Paolo Strati:

ISo I agree with what Manali said and also Gloria commented on now overall the outcome of patients with aggressive B-cell lymphoma has meaningfully changed since cellular therapy has been approved by the FDA. The amount of patients that actually we follow on inpatient service is a complication from treatment as we use less and less chemo and we cure a higher fraction of patients is decreasing. Just as a reminder for everybody, when data from clinical trials that have brought the approval of CAR-T in large B-cell lymphoma being compared to real-world experience, if before the chance of cure for relapsed large B-cell lymphoma was close to 10%, it’s now 50% or higher.

Now, what I’ve learned as compared to Gloria where the reimbursement system has limited the utilization of CAR-T to second line only until recently, I’m very privileged to be where I am where CAR-T in second line has now been available for longer than two years. Like Gloria is currently doing in Spain, yes, we’ve been extensively utilizing CAR-T in second line for primary chemo refractory, for chemosensitive but overall transplant ineligible. We do realize that it’s really important to, though this sounds like an editorial statement, do the best thing as early as possible. As we all know, there are even ongoing trials trying to utilize CAR-T either to consolidate response to frontline chemo or to integrate with frontline chemo for patients who don’t achieve a complete remission after two to three cycles of chemo.

Actually, Gloria with a very highly cited JCO publication has shown that the treatment that we do before CAR, in her case bendamustine may impact the activity of CAR T-cells. So it would be ideal eventually one day to be able to utilize CAR T in the frontline setting, but we understand that the limitation of that is that in previously untreated aggressive B-cell lymphoma patients, the immune system is so strong and powerful that complications such as cytokine release syndrome or immune cell-associated neurotoxicity syndrome may be more concerning, but time will say and ongoing randomized Phase III trials may give us an answer in the near future.

To the sequencing question, yes, like Gloria, for the last couple of years we’ve been utilizing bispecifics, glofitamab and epcoritamab mainly in patients who received CAR-T in second line. When we started, we were very reassured by the clinical trial data. The initial narrative was bispecifics given after CAR-T work, as well as bispecifics given in patients who never had CAR-T before, but with longer follow-up we have realized that they may not hold true. That biologically makes sense that the patients who went through CAR-T that had lymphodepleting chemo, either fludarabine and cyclophosphamide or less commonly in bendamustine, so they don’t have… For a very prolonged time, the T-cells, they need to be engaged for the bispecific to work. So with longer follow-up, we’re seeing that actually lin the post-CAR-T setting, though still active and is still in my opinion, an option that should always be discussed with large B-cell lymphoma patients who relapse after their CAR, the activity may not be as good. So we are actually now trying, but again we are in a blessed setting where we can do sometimes more experimental type of approaches to utilize bispecific before CAR. There’s a chance that glofitamab in combination with GemOx may get approved by the FDA in second line later this year. Many of us are already going by the NCCN guidelines and are already utilizing glofitamab in second line. The biological advantage is that based on some translational work that has been published using bispecifics in an intermittent way as we do for glofitamab or epcoritamab, T-cell function can get better. So if anything, actually, CAR T-cell activity subsequently may also improve. But I think the new problem that we’re going to encounter in the near future as we will start increasingly to prescribe bispecifics as a pre-gene therapy before CAR T second line, what if a big number of patients achieve the complete remission before proceeding to CAR? Is there a cure? Of course, we don’t have an answer yet and that’s where real-world experience that Gloria mentioned also will be helpful in the upcoming future.

Manali Kamdar:

Yeah. I think the big question is obviously the advantage that CARs have with regards to CNS penetration, as well as being agnostic of tumor-antigen expression. I hesitate to give CD20 BiTEs if patient’s tumor doesn’t express CD20. If there is a concern that they may have a concomitant CNS involvement, there is very limited data that CD20 BiTEs can reach that space. But I completely agree that I think this discussion about sequencing is very soon going to move to second line where again a cure has been established with CD19 CARs and we have yet to find it or wait for longer follow-up with CD20 BiTEs.

But what Paolo was mentioning with regards to how we are going to start incorporating them, the biggest bane with CD19 CARs is the time it takes to manufacture and a majority of our patients are just not chemo-sensitive at that point because they’re typically early relapsing patients. If we were to apherese the patient, post-apheresis, does either of you think that a CD20 BiTE as a bridge to a CD19 CAR would be a good or a reasonable option given the time or the quick efficacy that BiTEs have, given they’re off-the-shelf. Paolo?

Paolo Strati:

Yeah. Maybe I’m going to start because we do have some experimental experience. And of course, I cannot yet disclose the data, but there’s an ongoing trial in my institution written by Dr. Jason Westin, our large B-cell lymphoma section lead, trying to answer this question where the bispecific in this case, glofitamab, is given before CAR and then actually even after CAR as a consolidation. As I mentioned earlier, there’s some translational evidence specific to glofitamab. The intermittent infusion of a bispecific may enhance overall the fitness of T-cells. So if anything, it may be helpful to even consider glofitamab before leukapheresis to strengthen the T-cell as much as possible.

But from a theory, so while we wait for efficacy data and safety data from the trial because of course, the question is also by increasing the fitness with CAR T-cell may toxicity worsen.. I think the one logistical clinical problem that we may not appreciate enough in a controlled setting such as a clinical trial, it may be more evident in real world is how many of those patients have based on the kinetic of growth of the lymphoma, the luxury of being able to receive just by bispecific before CAR because it’s true that by bispecifics also in my experience, in my hands, work very quickly.

But as a reminder, for glofitamab, technically we have to give one week before obinutuzumab to prevent CRS. So there are now data out there showing that we could escalate. We can start glofitamab little bit earlier and do the step up dosing a little bit at a faster pace. For epcoritamab, those data haven’t been made public yet, but I would think that we could do the same. So again, I think that I’m a strong supporter of using bispecific before CAR and specifically as bridging, but we need to work on the schedule in my opinion, because in the real world, those patients that we don’t see much in clinical trials with high tumor burden and quickly progressing disease exist. They are more than half of our patients and they’re hard to treat in between leukapheresis and lympho-depleting chemo.

Manali Kamdar:

Yeah, true. Well, that’s a great perspective. I think with the growing use of CAR-T and bispecifics across the world, where do you see the role of autotransplant fit in, Gloria?

Gloria Iacoboni:

That’s a great question. I think the number of autotransplants in large B-cell lymphoma is going to… I mean, it is sharply decreasing because we are already moving away from that for those refractory or early relapsing patients. That’s a question that sometimes we’ve had from other sites. If you do CAR-T in the second line and they relapse after that axi-cel in second line, some centers are like, “Should we reconsider the platinum-based salvage chemo immunotherapy and autotransplant?” The answer is usually no, but I think that question is still brought up by some sites. But I think the role of autotransplant now is mainly limited to those patients who relapse late beyond 12 months and are transplant-eligible. Technically, that would still be their standard of care.

In Spain, we have now, however, an open trial with axi-cel for late relapses from one to five years after first-time immunochemotherapy. It’s a single-arm trial where all patients receive axi-cel and it’s for late relapsing patients. So that indication of axi-cel may eventually extend not only to the refractory and early relapsing patients but beyond those 12 months. But until that happens, I think the role of autotransplant is mainly limited to the second line-setting. For patients who relapse beyond 12 months and are transplant eligible, then they would still do the classical salvage chemoimmunotherapy and autotransplant, but that’s like a 25% of the patients who progress after first line, so definitely numbers are coming down quickly.

Manali Kamdar:

True. You clearly talked about a clinical trial that’s happening in Spain for late relapses with CD19 CARs. Paolo, what are you most excited about in the field of DLBCL in general with regards to clinical trials that are ongoing? There’s obviously a lot of data bringing bispecs and CD19s second line upfront. What are you most excited about?

Paolo Strati:

What I’m the most excited about is how we are trying to do clinical trials to address unfortunately new problem that is happening at a faster pace than I was expecting. As we got an autologous CAR-T targeting CD19 approved in second and third line and a bispecific targeting CD20 in third line, maybe soon in second line, of course, everybody was thinking about the possibility that with time, we would increasingly select clones which are double negative CD19, CD20, but I thought this would have taken much longer. But unfortunately, I would think that your experience is the same, our clinics are filling up with patients who are relapsed after both CAR and bispecifics and tend to be double negative.

So for those patients, most of the agents approved out there like loncastuximab, tafasitamab-len, they would not apply. I agree with what Manali said before, no matter what industry says, I would not give an agent whose antigen is not expressed. Target antigen is not expressed. We could use polatuzumab, the target CD79B. Most of the patients have already received polatuzumab as part of the frontline regimen. It remains to be answered whether it will still work subsequently. To your question, I’m very excited about either allogeneic cellular therapies, non-T-cell based like allogeneic NK or NK-CAR targeting antigens other than CD19 or CD20, like CD70, for example, we have ongoing trials across the US.

Personally, I’m very excited also about autologous macrophage-based therapies. So there’s been a lot of interest, of course, over the last few years in manufacturing and engineering T-cells, more recently NK cells, but it’s very recent the focus on macrophage-based treatments and these include agents activating macrophages like anti-CD47, anti-SIRP-alpha, now bispecifics activating macrophages and more recently autologous macrophage-based cellular therapies. I think that those, because to the point that you just may tend to be really antigen agnostic and they just rely on the anti-tumoral potential of the innate immune system, may help the high-risk population that we’re increasingly seeing in our clinic.

Manali Kamdar:

True. True. Okay. Well, in the interest of time we will move across the next subtype. Shifting gears, I was going to talk about what’s happening in relapsed/refractory mantle cell lymphoma. Year after year, the data keeps telling us very valuable novel inhibitors such as BTK inhibitors that were previously used in relapsed and now we have brought them upfront based on the existing label, not just for transplant-eligible, but also transplant-ineligible patients. To transplant or not to transplant is no longer the question. I think majority of us would not transplant patients anymore based on the TRIANGLE study. So why don’t we divvy this up into two cohorts? Let’s first talk about patients who are TP53 wild type and get your programmatic approach at your individual sites in patients who are fit and unfit.

TP53 mutation has really emerged as a very valuable marker. If somebody has it, that means they’re chemo-resistant. You technically try to keep them away from chemo treatments. Today, if somebody gets diagnosed with mantle cell lymphoma, in the frontline setting, we are checking for TP53 mutation because it has implications. So let’s first talk about fit patients. Fit patients, Gloria, coming to you. I’m going to be agnostic of age. I don’t want to be ageist. So fit patient coming to you, TP53 wild type I’m going to say needs treatment for frontline mantle cell lymphoma. What is your approach at the site today?

Gloria Iacoboni:

That’s a great question because it’s actually shifting, as you mentioned, very rapidly. We are still starting to have access to BTK inhibitors combined with immunochemotherapy in the first line. That’s not so straightforward yet for all patients. So until very recently and technically still today, our standard approach would be immunochemotherapy R-CHOP or R-DHAP or R-DHAOx plus autologous stem cell transplant, which of course, as you mentioned, is starting to be removed from our protocols and that is still what we would offer upfront to this profile of patients. We are starting to have the possibility of adding that BTK inhibitor ibrutinib to the immunochemotherapy if we request especially for certain patients, but it’s not so straightforward to do it for all yet. We’re still struggling to understand if we remove the autologous stem cell transplant completely from our protocols or try to decide which subgroup of patients could still benefit from it.

So we would definitely still do immunochemotherapy R-CHOP or R-DHAOx upfront, and then potentially as we are still shifting in our protocol, discussing our lymphoma tumor board, the possibility at the beginning we discuss the possibility of adding a BTK inhibitor and our discussions help them get the approval from the pharmacy department. Then when we’re moving towards the moment of transplant, also discussed that in our lymphoma tumor board, depending on the response the patient has achieved with chemotherapy and the patient profile and how he’s tolerated treatment. At this time point where we’re shifting from one protocol to another, we have those two discussions. Should we upfront add the BTK inhibitor when we are starting therapy and then towards the end should we still move forward with our classical protocol of consolidation depending on response achieved and tolerance of therapy.

Manali Kamdar:

Got it. Yeah, they say if you go to three institutions, you will get three correct answers for mantle cell lymphoma because there’s just so much heterogeneity. I will say at our site, if patients are fit and they are TP53 wild type, we typically have done the TRIANGLE regimen and then we don’t have any access for ibrutinib in the US anymore for mantle cell, so we replace it with a second generation BTK inhibitor for two years. That’s been our approach. In the unfit patient population, if they have been TP53 wild type, I think the bigger discussion is around the SHINE data. The SHINE data talks about bendamustine-ritux versus bendamustine-ritux followed by acalabrutinib forever or until it stops working. There’s obviously a PFS benefit. I don’t know if I’m still a big fan of using BTK inhibitors upfront for TP53 wild type in my relatively older patients. So we still stick with BR unless obviously someone has a blastoid morphology or a pleomorphic variant, then of course, we are using the triplet upfront. Gloria, is there an access for unfit patients to get BTK inhibitors upfront with BR like how the SHINE was designed?

Gloria Iacoboni:

No, not currently.

Manali Kamdar:

Not currently. Okay. With relapsed/refractory mantle cell lymphoma, previously the pathway used to be starting patients on BTK inhibition followed by then CAR T-cell therapy, made an advent there with initially brexucabtagene and now we have the ability to go with lisocabtagene, then we have pirtobrutinib. So I think now that in the upfront setting we have patients who may or may not have been exposed to covalent BTK inhibitors, when a relapsed patient comes to you, what’s your approach been at your side, Gloria, if they have seen a covalent BTK inhibitor?

Gloria Iacoboni:

That’s, I think, a very important question moving forward, but currently, just to set the context, we only have brexu-cel available regarding CAR-T constructs. We do not have liso-cel. So the only construct would be brexu-cel. Patients have to have received two prior lines of systemic therapy including a BTK inhibitor. We haven’t done really that many patients with a TRIANGLE scheme up to now, so straightforward first line immunochemotherapy, second line ibrutinib and third line would be brexu-cel. For patients who are doing ibrutinib as part of their TRIANGLE scheme in the first line, then we’re trying to access pirtobrutinib in the second line.

Interestingly, as another nuance of the Spanish system, pirtobrutinib, it’s reimbursement, it has to be for patients who are not CAR-T candidates. So technically it has to go before CAR-T. I know it’s kind of strange, but that’s how it is. Everyone was surprised, even I think the pharmaceutical company. So we technically can offer pirtobrutinib to patients who are not CAR T-cell candidates. It’s not a post-CAR T, let’s say, option. So it would fit in well for those patients who have received immunochemotherapy plus ibrutinib in first line and in the second-line setting received pirtobrutinib, and then they would access brexu-cel in the third line.

Manali Kamdar:

Got it. I think it’s been for us at my site, pirtobrutinib frequently gets utilized, especially in refractory mantle cell lymphomas as a bridge to CAR T-cell therapy. I think it’s always a question with regards to brexu-cel or liso-cel. Paolo, at your site, obviously, Dr. Wang has a lot of clinical trials for patients with mantle cell lymphoma, but between brexu-cel and liso-cel, is there a way you tease out the data, which is your favored CD19 CAR, especially with the advent and not yet approved glofitamab, but some of the really good data with glofitamab in relapsed/refractory mantle cell? How do you really pitch CD20 BiTEs, CD19 CARs for your relapsed/refractory mantle cell lymphoma patients?

Paolo Strati:

I’m going to start by saying, and I hope you don’t think I’m biased because of the place where I work and the amazing PI that you just mentioned, Dr. Wang, but I think we all agree that when it comes to relapsed mantle cell lymphoma, it doesn’t matter what’s the morphology, it doesn’t matter what the molecular signature looks like, it’s still hard to make the statement that we can actually effectively cure those patients with currently available standard treatments. So I would always consider a clinical trial for relapsed mantle cell lymphoma. But if we look into standard options, to your specific question, how do I look into clinical trial data to make a decision between liso-cel or brexu-cel? Again, we are told that in the field we should never do inter study comparison because of interesting bias and differences in baseline characteristics and treatment patterns.

Of course, the progression-free survival looks better for brexu-cel. The toxicity profile looks better for liso-cel. I would say at this time, differently from large B-cell lymphoma where really if efficacy see looks similar or follicular lymphoma as we’ll discuss later and where I can make the decision to be more mindful of the toxicity profile, the mantle cell lymphoma whenever possible, I do try to go for a CD28 costimulatory domain as we have in brexu-cel because again, as I mentioned before, it’s a potentially incurable condition and I want to try to give to my patient the best possible chance.

Now, keeping this in mind, we know that our patients, by the time they get to third line brexu-cel, they can be deconditioned. One thing that we are increasingly seeing with the use of brexu-cel in mantle cell lymphoma is actually treatment-related mortality is quite high and morbidity is also significant. This patient may end up in rehabilitation for months. The cytopenia that we see in mantle cell lymphoma, it’s way longer and greater than we see in large B-cell lymphoma, follicular lymphoma. So keeping all of those things in mind, there are selected patients where I would rather go for Breyanzi, understanding that the efficacy may not be as good as with brexu-cel.

To the second question that really alludes to the sequencing with the upcoming potential approval of new agents, I’m also very impressed by the activity of an anti-CD3xCD20 bispecifics in mantle cell lymphoma, particularly in combination also with polatuzumab, like mosun-pola data are very interesting. Yeah. We’re in the United States differently from Europe many times, either based on NCCN guidelines or publications. We sometimes get approval from insurance of non-FDA-approved combinations. I’ve tried personally mosun-pola as a bridging strategy before CAR in patients that I was unable to control with any other standard regimen including chemo radiation with really impressive results to the point that I started asking I achieved CCRs and I was wondering should I still proceed with CAR? I eventually did because the data are not there. This is data-free field, but I think that maybe not a single agent bispecifics, but bispecific combinations like the mosun-pola that I just mentioned may change in the near future the way we think about relapsed mantle cell lymphoma.

Manali Kamdar:

Gloria, you’ve published so much work on bispecs. I’d love to hear your take on bispecs in mantle cell.

Gloria Iacoboni:

Well, I think as Paolo was mentioning, I think they are a very exciting treatment option and I think they’re even more relevant in this disease entity than they could potentially be in others. Given some of the points that Paolo just made, I think we kind of all agree that probably the curative fraction of CAR-T in mantle cell lymphoma, it’s much lower. I mean, there’s always some patients will be cured, but the fraction will probably be much, much lower than in large B-cell lymphoma. We continue to see those late relapses as follow-up is extended. Therefore, when you take away you know that concept of CAR-T’s are curative, then definitely the field breaks wide open for bispecifics to compete with CAR-T.

These patients are many times very, very aggressive. I mean, the most difficult to manage patients I’ve had are mantle cell lymphoma patients, even more than large B-cell lymphoma patients definitely. Something that’s readily available off-the-shelf that you can give immediately and do not have to wait for those manufacturing times, that becomes even more of an advantage in the mantle cell lymphoma setting. So I think the availability, the efficacy with even single agent. We’ve had some trials with glofitamab in mantle cell lymphoma as well and the efficacy definitely is very, very encouraging. Given the toxicity that we see with brexu-cel, that was also mentioned by Paolo, not only the mortality but the morbidity, I mean, when you give brexu-cel, practically all patients would have some degree of CRS, some degree of ICANS close to perhaps 15, 20% will require an ICU admission.

So when we weigh the efficacy, the toxicity, the lack of curative potential perhaps in general for most patients with either option, then I think bispecifics become really relevant. Then I think as the body of data increases, bispecifics in monotherapy in combination, they have the potential to perhaps be equal to CAR-T in the setting of relapsed/refractory mantle cell lymphoma in the future when we have more data, real-world data to support the efficacy in the trials, but I think they have the capacity of being a real competitor.

Manali Kamdar:

That’s amazing. Lack of curative options. With that, I’m going to lead into an incurable chronic treatable, maybe curable with all the new agents, which is follicular lymphoma. Clearly, there have been significant advances, especially with the data that got published at ASH at the late breaking with tafa-len-R in follicular. Now we have three constructs that are approved here in the US, liso-cel, axi-cel, tisa-cel for third line relapsed/refractory follicular lymphoma. We have mosunetuzumab, epcoritamab approved for third-line follicular lymphoma. We have odronextamab approved in Europe for follicular lymphoma as well in the third line space.

So I think this question about sequencing has never gotten more pertinent and real than for follicular lymphoma because I think we are still talking about a chronic incurable condition. So maybe PFS matters. Maybe some of the risk factors matter. So maybe I will start with Paolo. Paolo, when you have a relapsed/refractory follicular lymphoma patient, how do you really sequence or how do you think through with that patient if the patient is currently needing treatment in third line? Because you clearly have so many options. Now, just to make sure that the conversation with regards to third line is easy, let’s assume the patient has been exposed to benda-ritux. Let’s assume for this question the patient has also been exposed to R-squared, and now has high tumor burden disease, has not transformed. How do you decide between CAR-T or a bispec?

Paolo Strati:

I would first like to say that I’m so glad that at least you mentioned the possibility of curability for follicular lymphoma. As somebody who’s seen a lot of follicular lymphoma for living, I hope we can work together to change the narrative. It’s true, I acknowledge if you’re looking into all literature, mostly chemotherapy-based, the narrative that has been pushed so far is that this is, as you said, an incurable chronic disease. You just kick the cane down the road and you will treat relapses over and over. But I think that long-term data from the frontline trial, so chemo and immunotherapy, are giving us some hints that we may start changing our conversation with our patients.

So with that in mind, answering your question, I think yes, I mean, the scenario that you described is probably the most common scenario in clinic in third line. So most of patients have received chemotherapy in frontline. A lot of BR in the US, I’m hearing more R-CHOP in Europe and in second line R-squared. How do we pick between options? Let’s remind ourselves that options beyond bispecifics and CAR in the US are also tazemetostat an oral EZH2 inhibitor and more recently the combination of zanubrutinib, a BTK inhibitor and obinutuzumab.

Now, most of times the selection between bispecifics and CAR-T is made by the patient profile. Differently from large B-cell lymphoma, our follicular lymphoma patients tend to be older and frailer, and so it’s not very common to prescribe CAR-T for FL. Just to share numbers, in my institution, over the same timeframe, we prescribed 600 CAR T-cells for large B-cell lymphoma, but 35 for follicular lymphoma. So the young and fit patient who fit the profile for CAR-T in third line are not as many. They exist though. So if I do have in clinic a young patient, maybe POD24, I would consider CAR-T.

One caveat is based on the data that we mentioned before that Gloria published showing the bendamustine exposure may overall affect the chance that those CAR T-cells may work. And because we know that CAR T-cells are a one-shot option, so we have to bring our patients to CAR T-cells in the best possible setting with a low tumor burden, with very fit T-cells. If bendamustine exposure has been very recent, I will probably think of other options just to give time to T-cells to recover and maybe look into CAR T-cells subsequently. My point is that I’m definitely doing as I think most of my colleagues between US and Europe a more extensive utilization in third line of bispecifics as opposed to CAR-T.

As you mentioned, there are two bispecifics approved by the FDA in the US, epco and mosunetuzumab. It’s very hard looking at the clinical trials to say which one is better and which one is safer. They really look the same. In my personal experience, it ends up being driven by the schedule. The schedule is much easier for mosunetuzumab. It’s weekly for the first three weeks, but then it’s once a week, once every three weeks for eight to 17 cycles. So it’s a fixed duration. On the other end though, from a patient perspective, even if epcoritamab is given more frequently and until progression or unacceptable toxicity, many patients do value the subcutaneous injection also because the chair time is much shorter. So particularly those patients who receive treatment in the community, they like that they can go quickly in and out as opposed to an infusion that takes a couple of hours. As for the other two agents, and I’ll complete my answer that I mentioned, tazemetostat and zanu-obino, I definitely use those in the very common older patients where I really know that I’m just trying to prolong as much as possible the time without disease and what I’m not aiming for a potential cure. I’m going to use again the C word.

Manali Kamdar:

Yeah. Gloria, how do you look at a third-line patient? Let’s assume the patient has received rituximab, three years of remission, bendamustine-ritux, three years of remission, now comes to you and how do you look at it? Fit, has great social caregiver setting, insurance is not an issue. So how do you-

Gloria Iacoboni:

In Spain, it’s not… Yeah.

Manali Kamdar:

So how do you manage that patient? The patient has bulky tumor, biopsy proven to be still follicular lymphoma.

Gloria Iacoboni:

Yeah. In Spain, and I always feel that the contrast and it’s more striking, but we have access just to put in context to bispecifics in the third line, only mosunetuzumab has reimbursement, not epcoritamab, and we only have access to CAR-T in the fourth line for follicular lymphoma because axi-cel specifically, at this moment, we do not have access to tisa-cel or liso-cel for follicular lymphoma. So only access in the fourth line because EMA approval is in the fourth line. So our decision is kind of made for us in the sense that we have bispecifics in the third and CAR-T in the fourth line. But if both the patient is a fourth line potential patient or both were available, the decision-making process would follow what Paolo mentioned.

It is true that I would perhaps also favor CAR-T just to add something new. Patients where I had a suspicion of potentially transformed disease, if it’s a large tumor mass and perhaps there are some areas with high SUV max haven’t been able to biopsy, even if what I did biopsy was follicular lymphoma, but I still had this suspicion, then I would perhaps consider offering the patient axi-cel, which is the CAR T we have available, or even if I do believe it’s follicular lymphoma. I have had some patients with even an aggressive behavior, large masses. To be honest, the efficacy I’ve seen with CAR-T and follicular lymphoma is really quite amazing, just patients who had very large abdominal masses and they’re in a CR at one month post-CAR-T. I think that’s perhaps much stronger, let’s say, or faster, quicker than what we see with bispecifics.

So just trying to add to everything that Paolo mentioned, which I completely agree with, those are the things I would consider patients with bulky masses and aggressive behavior with or without a suspicion for transformed disease, those patients I would consider for CAR-T, axi-cel in this case. Even if I had tia-cel available as well, I would favor axi-cel if the suspicion was for a transformed disease. I don’t have much to add, I think, to what Paolo mentioned. I think both are great options. Just to again put on the table that the bendamustine issue, which you both mentioned, I think the interesting thing is we have data in the CAR-T setting. We know it has a negative impact they recently exposed before leukapheresis, but we also have data in the pre-bispecific antibody setting.

We presented that at our ASH in ’23 and ’24, and not only our data, but also data from other colleagues and other groups which support the concept that recent bendamustine exposure does not seem to have on the contrary sets a negative impact prior to bispecific antibody therapy. One of the reasons might be we know bendamustine has a special impact on CD4 counts, not as much on CD8 and some bispecifics. There was data presented at ASH here at ’24 from the epcoritamab colleagues, bispecifics at least epcoritamab, which was their data seems to rely more on the CD8 cells. So perhaps bendamustine is impacting the CD4 fraction and that is why look at certain for an explanation, that is why perhaps it does not have such a negative impact.

So I think it’s interesting to be aware of the impact before both T-cell redirecting strategies. I think in summary they’re both great options. It comes down to the patient profile, discussing with the patient the pros and cons of one and the other, discussing the specific disease behavior of that patient and moving forward with what we believe is the best decision for that patient.

Manali Kamdar:

We keep hearing about recent benda exposure and there have been a few studies. But in your practice, what has been your cutoff for when you say, “I will not offer a patient CD19 CAR”? Is it six months? Is it 12 months?

Gloria Iacoboni:

That’s a great discussion which I think is open. In the study we published, in large B-cell lymphoma and — cutoff was nine months, it was mostly directed by our statistical analysis, which we finally settled for nine months. That was in the supplementary. We looked at six months and we looked at 12 months and we still saw the negative impact at six and at 12. Did the same propensity score matching analyses and still observed significant differences in terms of progression-free and overall survival. So we did all of those cutoffs. The cutoff for the ZUMA-2 data for mantle cell lymphoma, six months. The cutoff for ZUMA-5 follicular lymphoma data, six months, what’s published in the papers. Then in the mantle cell lymphoma setting, there’s also data for 24 months when you look at the US lymphoma CAR-T consortium data. So I don’t think there is a single cutoff. I think it’s kind of a dynamic, the further we are, the better kind of behavior. Six months seems reasonable, but probably 12 months is even better. Our thought is CAR-T is the best option for that patient with a big difference regarding other options, even if the patient has an exposure to bendamustine in the last six months and we still think that CAR-T is definitely a much better option than other treatments, we will still move forward with CAR-T. Now we think that there are other options which are in the ballpark regarding efficacy, then we would consider other options before CAR-T because of the bendamustine exposure. But I think it’s important not to take CAR-T off the table completely if we’re lacking other therapeutic options for that patient.

Manali Kamdar:

One final question, Paolo, if someone is POD24, there’s clearly data that shows CAR-T looks better, especially if you look at the liso-cel data with POD24 patients. The PFS at two years is 85%. Of course, long-term follow-up is awaited. We have seen something similar with the ELARA study looking with tisa-cel where POD24 actually impacted PFS. But I assume POD24 patients, majority of these have received benda-ritux. At least in my hands I’ve seen them, if they were to be POD24, they are actually POD12. They have relapsed within the first one year. So taking the same conversation forward, how do you really approach your patient with POD24?

Paolo Strati:

Going back to what Gloria said before, I think that we have the luxury of making all these considerations about prior bendamustine exposure if we have alternative options. Unfortunately, it’s not a luxury that we experience much in large B-cell lymphoma, but that we may in follicular lymphoma. So we do have the luxury. We have all the options that we mentioned before. When it comes to second line, now R-squared has been incremented. You quickly alluded to the inMIND data with doubling of PFS by adding tafasitamab. Now, in the US actually because tafasitamab R-squared has been included in the NCCN guidelines, we can already do it. The same day, another agent target CD19 has been added to the guidelines loncastuximab in combination with rituximab, so we can even do that in follicular lymphoma in second line.

For a young patient and fit that has a POD24, if I do have alternative, I will still try first in second line all of these immunotherapy options if there’s been a recent exposure to bendamustine. For the older patient, again, it’s an easier decision because it’s unlikely that I would use CAR T in this patient population. But one thing that we have to keep in mind is that we’re very focused on bendamustine, but also other agents that we use in lymphoma, anthracyclines, platinum-based chemo in aggressive lymphoma may impact either T-cell number or function. So I think that what we really need for those cases where we have no alternatives and we have to make a decision whether it’s the right time to do CAR or if we have to make an effort risking a lot to delay, we need some sort of surrogate markers.

That brings to another problem, which is that currently, when it’s time to apherese patients, there’s not really a universally agreed on rule on, let’s say, absolute lymphocyte count that we need to have or lymphocyte phenotype that we need to have and how this is impacted by prior treatments. Our institution, I mean, we follow rule of the thumb where patients have to have at least 0.10 of ALC and not having been recently exposed to corticosteroids or chemo, and when I say recently, I mean two weeks. But I think we can work all together and utilize our large registry strength to understand if there’s a specific threshold of lymphocyte count or a specific phenotype of lymphocytes, no matter what treatment you had before, they would also associate with good outcomes after CAR T-cell infusion and they may help in the decision-making process.

Manali Kamdar:

That’s great. Well, this has been a fantastic discussion. Thank you both for your valuable insights and thanks to our audience for joining. The field is evolving at breakneck pace and I think it’s an exciting time to be involved in lymphoma research. So looking forward to more breakthroughs and more conversations with both of you. Thank you so much for joining.

Paolo Strati:

Thank you all. Nice to see you.

Gloria Iacoboni:

Thank you.