A trio of panelists, including Pallawi Torka of Memorial Sloan-Kettering Cancer Center, Jeremy Abramson of Harvard Medical School and Kieron Dunleavy of MedStar Georgetown University Hospital, explore clinical practice changes for treating patients with lymphomas, including elderly patients with relapsed and refractory disease.
So with this in mind, we're gonna welcome our first speaker. So we have, uh, Doctor Kieron Dunleavy. He's a good colleague and friend of us. Um, he's the, uh, director of the hematology, uh, program in Georgetown University, and he's gonna be talking to us about, uh, the practice managed changes in patients with the LBCL in the first line setting. Karen, welcome. OK. Thank you very much Paco for the introduction and thank you to Paico and Matthew for inviting me to this meeting today. Um, OK, I just can't see my slides here, but that's OK, I guess. Um, OK. Um, so I'm gonna talk about, uh, clinical practice changes, uh, in the treatment of diffuse large B cell lymphoma and high grade B cell lymphoma, um, and, um, over the next 20 minutes, um, I'll talk about current understanding and classification of large B cell lymphoma biology, uh, standard approaches in frontline treatment. Approach to high grade B cell lymphoma and some other aggressive B cell lymphoma subtypes, and uh also I'll discuss the evolving role of MRD and uh touch on the controversy of CNS prophylaxis and aggressive lymphoma. Um, so there are a wide range of aggressive B cell lymphomas. Um, they really exist on a spectrum as shown here with diffuse large B cell lymphoma, NOS on one end of the spectrum and Burkin lymphoma on the other end, and in between those entities you have high grade B cell lymphomas, primary media sign of B cell lymphoma, um, transformed lymphomas, um, and, um. In terms of the treatment of newly diagnosed diffuse large B cell lymphoma for patients who have early stage disease, um, the treatment is usually typically straightforward. They receive 4 cycles of orHop therapy. There were 2 randomized studies, uh, 1 in younger patients, 1 in patients of all ages, and they basically showed that. You did as well if you got 4 cycles of workshop compared to 6 cycles of workshop. So for those early stage patients, the treatment is pretty straightforward. Um, it's a little bit more complicated for patients, um, who have advanced stage disease, um, and there are a lot of controversial questions. Um, is RCHP sufficient therapy? Um, which patients benefit from the addition of politizumab? What about high grade B cell lymphoma? Should that be approached differently? When should the CNS be checked and when should patients receive CNS prophylaxis? Um. And what about MRD? Uh, there is an evolving role for MRD in various, uh, parts of the management of these diseases. Um, so that's a very interesting area, um, currently. So, um, I'll start off with, with a case just to, um, illustrate some of these, uh, treatment questions, um, that arise. This is a, um, 68 year old male who was previously well, no past history, presented with a 4 week history of fevers, night sweats, weight loss, and bilateral neck lymphadenopathy. Um, all labs were normal other than an elevated LDH. He had an excellent performance status. Imaging demonstrated diffuse lymphadenopathy on both sides of his diaphragm. He had no extra nodal disease. Underwent a biopsy of a large neck lymph node, um, and, uh, this showed diffuse large B cell lymphoma. There was no follicular component. It was CD20 positive. Um, CD10 was negative. BCL-6 was negative. On immunohistochemistry, there was strong staining for MC and for BCL-2. Um, fish studies were undertaken and there was no evidence of a MC or a BCL-2 rearrangement. Um, both bone marrow biopsy and CSF analysis were negative. So, in summary, uh, this patient had diffuse large B cell lymphoma, um, non-German center B cell subtype, and he had an IPI score of three. Uh, so for this patient, um, how, how would you treat him? Would you treat him with 6 cycles of OrHop, um, give him or politizumab, glafeimab? Uh, what about the Smartop study, uh, dose adjusted epoch or, or would you treat him with orHop plus politizumab? Um, and I would probably treat him with archa plus politizimab, um. So over over 20 years ago, um, it was shown by gene expression profiling studies that diffuse large B cell lymphoma constituted several diseases. Most cases fell into the germinal centered B cell subtype or the activated B cell subtype, and there was also an unclassifiable type described as well. And since since that time we have really made significant advances in better understanding the molecular biology of diffusage B cell lymphoma. Now the GCB and the ABC subtypes can be divided into several genetic subtypes, and this is nice because these genetic subtypes harbor specific mutations which can be assessed and our hope is in the future that. We will be able to specifically target these molecular subtypes of diffuse large B cell lymphoma with various different strategies, um, as, as shown here. Um, interesting in diffuse large B cell lymphoma that as you get older, the molecular complexity of the disease increases. Um, so if you look at children with diffuse large B cell lymphoma. Uh, the molecular complexity of their tumors is, uh, typically pretty simple, and as people get older they acquire, um, a lot of aberrations such as MC and BCL-2 and various other, uh, genomic aberrations that are shown here, um. I think this slide's interesting. This, uh, is a slide from a study called the robust study which compared, uh, RCHP to RCHOP plus lenalidomide, um, and as part of that study there was gene expression profiling done of diffuse RB cell lymphoma from, um, around the world, and what this slide shows you is that the breakdown of GCB and ABC is very different in different geographical regions. Um, in the US and Europe, uh, the proportion of GCB is much higher, but that's, uh, reversed in Asian countries. And this of course is an interesting question for clinical trials. So what about the frontline treatment of aggressive B cell lymphoma? Um, the good news is that most patients, uh, with the disease have very good outcomes. Um, these are patients with stage 2 or higher, so patients with stage 1 disease even have a better outcome than this, where over 90% of them are cured. Um, but in the modern era, over 80% of patients with current immunochemotherapy are cured with diffuse large B cell lymphoma. Um, one of the big recent advances, uh, in the field has been the addition of politizumabvidotin, uh, to frontline therapy. Um, this was a, a trial that led to the FDA approving politizumabvidotin and relapse refractory B cell lymphoma where politizumab was, uh, added to BR and compared to BR alone, and there was a. Survival advantage in patients who got politizumab as shown here. Um, this set the stage for the Polari study which was conducted a few years ago, looked at over 800 patients with newly diagnosed diffuse large B cell lymphoma. They had an IPI score of 2 or higher, um, shown here are their characteristics which is typical of this patient population. And the primary endpoint of the study was progression free survival, um, and that's shown here in the curve on the left where patients who received politizumab uh with uh or CHIP versus or CHOP had a cure rate essentially of 6.5% higher, and there was not an overall survival benefit. There's been a lot of debate about the subset analysis of groups within the polaric study and which groups did better and which groups did worse. Um, older people did better in post-hoc analysis. Uh, patients who had the ABC subtype did did better and uh. Um, I think a lot of emphasis has been put on this post hoc analysis and. In terms of uh who we select for politisimab, there really are very regional differences in terms of uh who receives politizimab. In some centers, I think investigators confine politizumab to those with the non-GCB or ABC subtypes, uh, whereas in other centers investigators discuss giving politizumab to everybody with an IPI score of 2 or higher. Um, And this is data that was published a few months ago. This is long term data from the Polari study, and the results, as you would expect, are not quite as good as in the original publication, but the survival benefit of 5 or 6% for patients who receive politizumab remains in this long-term follow-up which was published a few months ago. Um, In terms of novel targets for diffuse large B cell lymphoma, there really are a number of different ways that the disease can be targeted. There are a number of FDA approved strategies targeting CD-19 like CAR T cells, uh, tofaciumab, longesttuximab, bi-specific antibodies are really rising in the field in terms of their. Their efficacy and they're being incorporated into upfront studies and are highly effective agents, and there are a lot of other, um, very interesting pathways in large B cell lymphoma that can be targeted. I'm just briefly gonna talk about a few recent abstracts um that were presented um at the Ash meeting. I wonder if there's any way I I could make this bigger because I'm just seeing a kind of a slide view. It's just a little difficult to. Perfect, thank you very much. Now I can read it much, much easier. OK, so this is a study, um, called the Smart Stop trial from uh MD Anderson, uh, developed by Jason Weston. There previously was a um. Uh, uh, uh, a, a, a trial that preceded this, um, and this is the latest version of that, and the trial looks at lenalidomide, tefaciumab, rituximab, and acaibrutiniblog and with combination chemotherapy in newly diagnosed diffuse RG B cell lymphoma. So, um, at the recent ASH meeting, an update on this study was presented. This is the Smart Stop schema. Um, as you can see here on the left, uh, patients, uh, receive, um, these agents, lenalidomide, tavaciumab, rituximab, Acaliber, so non-chemotherapy containing platform. They undergo CT DNA monitoring. Um, they then have a PET CT scan and assessment, and if they go into CR, they get two cycles of CHOP. Um, and continue the targeted agents and if they have a PR stable disease or progressive disease, then they get 6 cycles of CHO, um, with the targeted agents, um, and, uh, the results of this were published, uh, the approach, uh, was, uh, well tolerated. Toxicity data is shown here. Some of the high points, 57% of patients got grade 3 or higher neutropenia, um, 7% of patients got macular papular rash, um, and the primary endpoint of the study, um, was the overall response rate after the LTRA, that was the non-chemotherapy containing regimen lead-in. Um, and the ORR after that lead-in was 90%, so very interesting results with a non-chemotherapy containing platform. Um, and then primary endpoint 1B was the CR at the end of treatment, um, and this was 96.7%, um, and the PFS was 86.5% at 2 years, and overall survival was 98.4% at two years. Another trial that was presented at AS was a frontline chemoli Rpolarglow trial, um, and that induced high and durable responses in elderly and medically unfit frail patients with aggressive B cell lymphoma. Diffuse large B cell lymphoma is typically treated with R-CHOP or polar R-CHIP type treatments, but for those patients who are elderly and older, um, we frequently use our mini CHOP, where the cure rate is not as high as a standard R-CHOP or PA or CHIP. Um, so there's a real need to improve therapy for this patient population. This was the R pola Glo study design, um. As you can see here, there was a debulking phase, step up phase, then it got to target dose, and then there was consolidation, and the primary endpoint of the study was looking at the one year progression free survival. shown here are baseline characteristics of patients. Median age of patients was 80 with a range of 66 to 92, and 19% of patients were over 85 years of age and other. Um, characteristics are shown here as well as, uh, the simplified geriatric assessment, um, in terms of toxicity, uh, the combination was well tolerated with no unexpected adverse events and a low treatment related mortality. Um, and then in terms of outcome, the one year progression free survival, uh, for the group was 84.6%, and the one year overall survival was 89.7% and with the immediate follow up time of 15 months, responses were durable and the one year PFS and one year OS rates were 85% and 90% respectively. Um, and then in terms of the key toxicities of ICAS and CRS which we see with bio-specific antibodies, um, these usually occurred in the early cycles as you would expect, and were low grade and completely resolved. Um, what, what about high grade B cell lymphoma, um. This, this is quite a complicated area. Um, most of these cases, um, have got a BCL-2 and a MIC rearrangement, and they are of germinal center origin. Um, important, uh, just to, to note that a very high proportion of diffuse large B cell lymphoma cases have got high BCL-2 and high MC expression, but they don't have rearrangements, and these are called double expressor lymphomas, and they have a worse outcome with standard therapies. Um, there has, there has been a lot of change over recent years in how we classify, um, high grade B cell lymphomas and aggressive B cell lymphomas. This was the WHO classification in 2016 where, uh, the entity high grade B cell lymphoma with MC and BCL2 and or BCL-6 was included and high grade B cell lymphoma NOS was included. Um, then in 2022, 2023, uh, the new edition of the WHO classification came out. There was also a competing ICC classification, um, and these were a little bit different. In the WHO classification, uh, the high grade B cell lymphoma cases, uh, were defined as having a MIC and a BCL-2 translocation, whereas the ICC classification included MCC and BCL-6 as. A provisional entity um. Uh, there have been a lot of attempts in the pathology world to try to make sure that there, um, are never two classifications again, that there are just, there's just one classification because it causes a lot of confusion clinically and it's a challenge for clinical trials, um, so currently there are efforts underway to make sure that the next lymphoma classification will be one classification, a unified classification, um, this is just a. A schema from 1966 of all of the various iterations of classifications that have um been around in the lymphoma world from the Rapaport classification in 1966 to at the other end of it hopefully a unified uh WHO6 classification um that that hopefully will be coming in the future. Um, in terms of, uh, the outcome of high grade B cell lymphoma, it, it, it has been shown to be, um, inferior to other aggressive B cell lymphomas. A lot of controversy about this. Different people treat high grade B cell lymphoma differently. Um, I think for me this is quite compelling data. This is flat iron data, um. It's retrospective. It looked at 800 sites of care around the US and included over 6000 patients. Um, and, uh, just, uh, for, for simplicity, just to guide you, so curve C, so the, the lower curve on the left is a comparison of patients who had double hit or triple hit lymphoma, and they received RCHHop or dose adjusted epochor. And uh the light blue curve are the patients who got dosage of Epoch R and the dark blue curve are the patients who got RHO. So you can see in this uh in this analysis, which is absolutely not a perfect study because it's uh it's, it's uh broad uh data from from thousands and thousands of patients, but I think that it shows you a very significant difference um. Between the two regiments in double hit lymphoma. Um, Then you know just a few other um updates uh this uh is the Zuma 12 uh study um which is which is published by by by Hugo Chavez last year in Blood um looking at giving um Axi cell to patients with um. With high grade B cell or or or with aggressive B cell lymphoma and uh really showed that there were excellent results associated with this um I'm not gonna talk too much about primary media sign of B cell lymphoma. It's a distinct clinical pathologic entity um, last year the IELSG study uh uh. Performed a large study, uh, and the question of that study was, if you have primary mediastinal B cell lymphoma, um, and if you get standard therapy, do you need to get radiation at the end? And they showed that you don't, um, so you don't typically need to radiate patients after frontline therapy for primary mediastinent B cell lymphoma. A lot of emerging questions in this disease, um, this is a study, um. Which has been completed now, um, uh, it included both pediatric patients and adult patients, um, approximately 250 patients with newly diagnosed primary mediastinal B cell lymphoma. It was led by Lisa Roth, who is at NYU, and, uh, the results of this study should be available at the end of this year. Um, the question of the study was, is adding nivolumab to immunochemotherapy. Um, going to improve, uh, progression free survival, so really, really interesting question for this study. Um, for the last 2 or 3 minutes, uh, there's, uh, always a lot of talk about MRD analysis in aggressive B cell lymphoma. Um, we have lots and lots of papers that show us that, um, MRD at end of therapy is more sensitive than PET imaging at at end of therapy. This is a study, uh, that was published by Mark Raszewski at the end of last year which really shows that if you look at the top two curves you see. Um, progression free survival as per pet, uh, negativity at the end of therapy and, um. On the, on the next curve, CTDNA, um, at the end of therapy and its association with progression-free survival, but you see that CTDNA is, is, is much more robust from these studies, but. A lot of work has to be done. Um, I think for, for a lot of us we use CTDNA in various settings, but, um, the last time I checked the NCCN guidelines, they say that you should consider doing, um, CTDNA in those patients with diffuse large B cell lymphoma who have a positive PET scan at the end of therapy, but I think that there's a lot of other, uh, really interesting areas to apply to. Again, this is a study from Ash uh from um the Hoven Group in the Netherlands and uh they. Um, looked at CTDNA in newly diagnosed aggressive B cell lymphoma patients in 50 centers across the Netherlands and really found that it was prognostic, um, at all of these different time points that they looked at it as, um, and in line with, with others showed that it was very useful and more useful than PET. Um, there is an ongoing study. Um, and I think there, there will be a lot of, a lot of studies like this in the future. This is, uh, an allergene study which is looking at patients who at the end of treatment for aggressive B cell lymphoma, um, are checked for MRD, and if they're PET negative and they're MRD positive, then they're eligible to. Either be observed or to uh receive some cell, which is an anti-CD19 CAR T cell therapy. So this study is uh is currently ongoing. Um, initial uh initial results came out a few weeks ago and, uh, there was an interim analysis and the study is, is moving forward. Um, and I think that that's going to be interesting. Um, just to conclude, as we always talk about this when we discuss high grade B cell lymphoma and diffuse large B cell lymphoma, um, we know that certain. Subtypes of uh aggressive lymphoma and and certain presentations have got a high risk of CNS dissemination, but the area is very unclear. Um, there are a lot of conflicting studies. A few large scale studies have not supported giving CNS prophylaxis routinely in patients, so, uh, it's a, it's, it's a challenging area, but I, I think for most of us, uh, we. Strongly consider some type of CNS prophylaxis, certainly for those patients with Burkitt lymphoma, uh, for some of the high CNS IPI score patients, uh, with diffuse large B cell lymphoma, and also for the high grade B cell lymphomas. Um. So in conclusion, uh, aggressive B cell lymphoma is a very interesting area. There are a spate of new agents. I think as we saw from Ash this year, we're certainly starting to move we're starting to move away from using anthracycline-based therapies and chemotherapy in the frontline setting and seeing really good results with by specific combinations particularly. So a lot, um, a lot of exciting developments in this area. Um, should high grade B cell lymphoma be approached differently? I would say yes, it's, uh, much, uh, or it's, it has features that are very close to Burkitt lymphoma, and it is a very highly proliferative tumor, um, and it really makes sense to, uh, to treat it more aggressively. Um, and with that, I thank you for your attention. Jeremy, so, and then, OK, so hi, thank you very much, and we'll have a Ky question at the end of the three lectures, so, um. We're gonna try to set up Doctor Jeremy Abrahams. Um, he's, uh, certainly a very well recognized, uh, lymphoma expert as well as car therapy expert, and he is the director of the lymphoma program at, um, in, uh, Mass General. Uh, Jeremy is actually joining us virtually, so we are in the process of getting him connected. Let me just text him, um. OK, we go. While we connect, Doctor Abrahams, um, I just wanted to, um, make another announcement that I forgot earlier, um, during the breaks, uh, please, uh, if you guys want to, um, visit, uh, the, the booths of our sponsors, um, this year we actually doing a, a, a, a raffle ticket price. So if you go there to each booth you will get a ticket and then you can win some Sabres or Buffalo Bills, um, prizes, so. Um, here in Buffalo, quite, um, followers of sports, so some of us maybe not as much, but, so, but a lot of people will appreciate that kind of, uh, compelled by savers now, but. Um, yeah, I think we're, we can hear you outstanding. Hello, good morning, Paco. Good morning, everyone. Good morning. Thanks. Well, we're gonna let you start, OK, Jeremy? Thanks very much. Are my slides visible to you? Yes, just swap. All right, swap. Well then, uh, good morning, everyone. I'm sorry that, uh, there were some technical snafus, and, uh, most importantly, I, I really deeply regret that I'm not there to be with you in person, um, in, uh, the great city of Buffalo, but I want to thank, uh, uh, Doctors, uh, Hernandez and Cortese and the organizers, uh, for inviting me to be there and I'm just wish I could be there in person. Please accept. The virtual background of magnificent Buffalo City Hall, uh, as, uh, as a weak, uh, substitute for my being there in person. These are my disclosures. Uh, it is a difficult challenge to follow, Doctor Dunleavy, but, uh, thankfully for me, the, uh, AV was not, oh, I'm being asked to flip. Presenter and Uh, let me see if I can change my view. Swap displays. All right, I swapped displays. Perfect. So hopefully now we're good. OK, um, these are my disclosures, um. And as we think about the management of second-line non-transplant eligible diffuse large B cell lymphoma, it's important to recognize where we came from. And where we came from was a time when for decades, our standard of care had remained unchanged. And that standard of care was quite simple. If a patient relapsed after front line chemo immunotherapy, we would ask a very simple question. We would ask whether a patient was fit for high dose chemotherapy or were they not. And if they were, we would take them to high-dose chemotherapy, preceded by platinum-based chemotherapy, and if they had chemo-sensitive disease, we would do an auto-transplant. And if they did not have chemo-sensitive disease, or if they were not eligible for high dose therapy in the first place, then we would treat them with palliative intent therapy with no opportunity for cure. And those patients, those previously incurable patients with non-transplant eligible disease are the so-called second line unfit patients, and you're going to hear about them far more effectively from Dr. Torka in the talk that follows mine. But in my talk, I'm gonna address these transplant eligible patients, those patients fortunate enough to be able to be treated with curative intent in the second line setting for decades with a high dose chemotherapy approach. And that approach was based on data, honestly, from the pre-rituximab era, from the Parma trial, which showed us a study that accrued during the 1980s, the wonderful formative time of my youth, uh, and the golden age of pop culture, television, movies, and music, um, uh, that at that time, high-dose therapy could cure about 50 to 60% of patients. But the data that I'm showing you right now shows that those were historic and wonderful days of yore, uh, but don't represent how patients do today, if they proceed to high dose therapy. And in fact, in the modern era, patients who progress after frontline chemo immunotherapy, meaning our CHOP-based therapy, actually have decidedly poor rates of success with an auto-transplant. In fact, what you can see here is data from 3 prospective randomized trials conducted in the chemo immunotherapy era that the likelihood of a durable remission with a standard platinum-based approach followed by high-dose therapy for chemo-sensitive disease is probably less than 1/3 of patients. who are even eligible for a stem cell transplant. And if you look at patients who have primary refractory disease or relapse within 1 year, as shown on the far right-hand panel, the likelihood of a durable remission is probably in the range of 15%, showing us we must do better in the modern era. Now, as you know, uh, we have made great advances in the management of multiply relapsed DLBCL. Particularly 3 CAR T cells entered our treatment armamentarium and showed the ability to eradicate disease even in the third line or later setting where patients previously had no curative options. And so, given that context, no fewer than 3 randomized controlled trials sought to supplant high-dose chemotherapy with CAR T cell therapy in the second line setting specifically for these patients on the far right with primary refractory or early relapse disease. And two of those studies were positive studies that have truly transformed how we currently manage relapse refractory DLBCL in transplant eligible patients. Here we see the two positive trials, the transformed trial of Lisa cell versus standard of care on your left, and the Zuma 7 trial of uh AxI compared to the standard of care on your right. Both of these studies randomized patients with second-line transplant eligible DLBCL who Progressed or relapsed within one year of frontline therapy, and we randomized 1 to 1 to Lisa cell or axi cell on your left or right respectively versus platinum-based chemotherapy followed by high-dose therapy and stem cell rescue for patients with chemo-sensitive disease, and both were dramatically positive studies. On the left-hand panel, the transformed study showed that Lysa cell induced a CR rate of 74% compared to only 43% on standard of care. That reflected a dramatically improved progression-free survival with a nearly 60% reduction in risk of progression or death favoring Lysa cell over standard of care. Um, And a trend in favor of overall survival, though, uh, with, uh, as you can see here, um, a clear separation of those curves, but not statistically significant, um, likely reflecting a built-in crossover on this study, uh, and the smaller, um, uh, number of uh sample size. Uh, the Axis cell studies, Zuma 7 on your right, showed a 50% reduction in risk of progression or death favoring Axi cell over standard of care and a similar, um, uh, separation of the survival curves for overall survival with actually a nearly identical, uh, uh, difference, uh, in, uh, overall survival. Uh, and this did meet statistical significance likely reflecting the larger sample size. Both studies showed improvement in quality of life for CAR T cells, uh, compared to standard of care. And one thing we recognize in these studies, as we have in studies in the third line and later setting, is that there is really a, a quite significant difference in the toxicity profile between Lysa cell, A 41BB co-stimulated CAR T cell and Axi cell ACD28 co-stimulated CAR T cell. What you can see is Axi cell on your right has a CRS rate of over 90% compared to just under 50% with Lysa cell. The severe CRS rate is 6% on Axi cell, only 1% on Lysa cell, and perhaps more strikingly, uh, uh, the neurotoxicity rate was 6%. % with axi cell, severe in 21%, meaning 1 in 5 patients have severe neurotoxicity, which is the biggest challenge that we manage. Uh, whereas neurotox only occurred in just about 10% of patients of any grade on Lisa cell and severe and only 4%, and those were all grade 3, no grade 3 or 4 events. Now, I was asked to address both high-grade B cell lymphoma and diffuse large B cell lymphoma, so I will note on the Zuma 7 trial, uh, that, uh, these, um, uh, data apply both to high-grade B cell lymphoma with, um, uh, rearrangements of uh NC and BCL-2 and or BCL-6. Uh, as well as DLBCL not otherwise specified, so you can see a substantial benefit for, uh, CAR T cells over standard of care on Zuma 7, in patients who had double hit lymphoma, uh, just as in DLBCL, not otherwise specified. Uh, now, if we look at the subset analysis, uh, on the Lisa cell study, we see the same thing. When we, uh, do a subset analysis for high-grade B cell lymphoma, and these were all double-hit lymphoma patients, we again see, uh, uh, A substantial improvement in favor of Lisa cell over standard of care. So even in the high grade B cell lymphoma patients, these patients are substantially benefited from CAR T cells in the second line setting compared to historic chemotherapy-based approach. Now, if we take a deeper dive into the Lysa cell study, I noted that unlike Zuma 7, all patients on this study had built-in crossover. What that means is unlike Zuma 7, all patients on Transform underwent leukaphereis and car T cell manufacturing prior to randomization. What that meant is patients who were randomized to standard of care, where they failed by the standard of care arm as the The Majority of patients were, uh, they could immediately cross over and receive Lysa cell, whereas patients on Zuma 7, if they were failed by standard of care, which the majority were, they would have to come off study, undergo leukaphereis of T cells that had just been exposed to second line therapy, uh, undergo manufacturing and receive CAR T cells from commercial supply. So we adjusted for the impact of crossover using a two-stage accelerated failure time model for you statistical geeks in the audience. Uh, and when we do that statistical uh um smoke and mirror, we do see a significant improvement in overall survival. The other question that comes up from a lot of folks is saying, look, transplant works pretty well in patients who achieve a CR to platinum-based chemotherapy. Now, uh, the important point is most patients don't achieve a CR to platinum-based chemotherapy, only a minority did on both of these pivotal trials. But the question is, for those who Did. Do they do just as well with, with an auto-transplant? Maybe we should give everybody platinum-based chemotherapy um for the minority that achieve a CR and take those complete responders to transplant and take the rest of CAR T cells in a third-line setting. And I want to show you two lines of evidence that tell you that's a terrible idea. So first, if we look at just the complete responders on your right, what you can see is that complete responders for Lisa cell in blue compared to uh um uh standard of care in gray, uh still have a separation in their duration of complete response curves, showing you that patients on a Lysa cell are likelier to have a durable complete response compared to patients on Standard of care. So not only are complete responses likelier on CAR T cells, they are more durable. On CAR T cells with substantially more complete responders staying in complete response. At 70% on the Lysa cell arm compared to only half on the standard of care arm. Furthermore, among patients who cross over or receive CAR T cells in the third line setting from commercial supply on Zuma 7, they simply don't do as well as patients who are randomized to receive CAR T cells in the second line setting. Now, if CAR T cells work just as well when you receive them, uh, if you didn't, uh, uh, have a complete response on platinum-based chemotherapy, then you should be rescued with CAR T cells in the third-line setting and do just as well. But that is simply not the case. If you take patients who are randomized to standard of care and then give them a CAR T cell as a third-line set. Uh, therapy, even though these are identically matched patients due to randomization, the CR rate, progression-free, and overall survival to third line CAR T cell is substantially lower than those patients who were randomized to receive the identical CAR T cell in the second line setting. CAR is simply more effective when used earlier. Now, I've shown you that duration of complete response is better for CAR T cells in the second line setting and that patients who cross over and receive CAR T cells in the third line setting don't do as well. Now, what that tells us is that we're simply getting a better depth of remission from CAR T cells compared to platinum-based chemotherapy, and this is not a surprise. We are treating patients by definition with chemotherapy, refractory, or primary or early relapse disease. When we give chemotherapy to a primary refractory early relapse patient, we are giving chemotherapy to by definition, a chemotherapy resistant patient, and we are throwing good money after bad. Which means chemotherapy doesn't work as well. They are already chemotherapy resistant, and indeed, if we do phase-eek analysis, the best uh uh MRD assay we have, um, 62% of patients on Lysa cell achieve uh MRD undetectability compared to only 38% on standard of care. And if we take complete responders who are MRD undetectable at the end of treatment and look at their event-free survival, guess what? Even among MRD undetectable patients on standard of care, they still don't do nearly as well as patients on the, on the CAR T cell arm with Lisa cell, as shown in the event-free survival on your left. And that's because on your right, what you can see for Lysa cell patients in the upper right-hand panel, none of the MRD undetectable patients actually develop uh recurrent MRD as opposed to the majority of patients on the standard of care arm uh revert to MRD positivity in follow-up showing us that those remissions are simply not nearly as durable, and we should stop, stop giving chemotherapy to chemotherapy refractory patients. Now these of course are patients all treated in the rarefied setting of pivotal randomized trials. Uh, so let's look at some real-world data that tell us how these patients are doing in uh with commercial supply. Now, these are data from the French Descartis registry. Descartes, of course, is a famous artist and philosopher from France, and so the aptly named French Descartes Registry, um, uh, for those um uh erudite among you, which I know is 99.9%. I know the 1.1% among you, uh, who is not familiar with. Descartes, but here the French Descartes registry captures every single patient in France treated with a commercial C T cell. So this is an extraordinarily valuable real-world registry. There's no selection bias here other than being French. So every patient in France is enrolled on this register if they get a commercial CT. And they looked at their patients who got a second-line CAR T cell uh in France. Now, there are far more patients who with Axill than Lisa cell because Axiel was available earlier as it was here in the United States. Uh, and there's a bit of selection bias. If you look at who's getting Axi cell versus Lysa cell. The median age is a bit older with Lysa cell at 71 versus 63, slightly higher proportion of patients with high. Grade B cell lymphoma, though the incidence is low in both uh CAR T cells, slightly higher primary refractory disease and early relapse disease, and interestingly, more patients with a poor performance status, which with Lysa cell than Axi cell, probably reflecting the more favorable safety profile with Lysa cell than Axi cell. So providers are saying, you know, I've got an older, frailer patient. I'm a little likelier to give them a Lysa cell than Axi cell. And so based on this, they conducted um um uh stabilized inverse probability treatment weighting and propensity score adjustment to adjust for the difference in baseline risk factors so that you're looking at apples to apples, instead of apples to wilting oranges. And when you do that and match for patients based on on baseline risk score, what you can see is identical efficacy between Axi and Lysa cell in the second-line setting. The CR rate was 65% for Axi and 69% for uh Lysa cell. Uh, the overall response rate, 78%. For Axi cell, 87% on Lysa cell, so slightly higher response rates and CR rate for Lysa cell compared to Axi cell, but identical progression-free and overall survival, as you can see here. So identical efficacy between Lysa cell and Axi cell in this real world comparison. Where the real-world comparison showed a difference should be no surprise to all of us, which is in safety. You can see the incidence of CRS was dramatically higher with Axiel compared to Lysa cell. Uh, and this is exactly what was seen in the pivotal trial, remarkably enough, 90% of patients had CRS on Axi compared to 49% on Lysa cell and identical rates of severe CRS at 5% and 1% for Axi cell and Lysa cell respectively. But CRS is pretty easy to manage. We give ketosillizumab and steroids, it turns around. You know what doesn't turn around quickly, quickly is neurotoxicity. And here, more than half of patients on Axiel developed neurologic toxicity, severe in 19%. Again, identical to what we've seen on the pivotal trial. Compare that to Lisa cell where neurotox occurred in only 9% of patients and severe in only 1% of patients. Uh, and so this was dramatically better tolerated. That reflected, as expected, in far less ICU level care. More than 1 in 5 patients on Axiel needed to go to an intensive care unit compared to less than 3% on Lysa cell. And toxicity matters, and toxicity matters in terms of non-relapsed mortality. If you are pounding patients with prolonged steroids for prolonged neurologic side effects, you're going to see more severe. Late adverse events and more non-relapse mortality. And in France, uh, we see a higher non-relapse mortality rate for Axi cell compared to Lisa Lysa cell. 3 times as many patients died from getting Axi cell than Lysa cell from non-relapsed mortality, despite having identical rates of progression, showing similar efficacy, much more toxicity, and this is why I favor Lisa cell in the second-line setting compared to Axi cell in the majority of patients. Let's turn our attention to third line and later and reflect for a moment on where we came from when CAR T cells entered our treatment armamentarium. Now, these CAR T cells were initially approved in 3rd line and later in patients with a median of 3 prior lines of therapy for DLBCL, which means most patients were treated in the 4th line and later setting and had no curative options available. Those data Uh, showing us from the scholar one study, we remember that their likelihood of a CR to existing therapies was probably only in the range of 5%, and their likelihood of overall survival was a median of about 6 months. Uh, now look at the 5-year follow-up data for both Lysace and Axi cell for that population. With 5 years of follow-up, remembering more than half of patients achieved a CR in this context, fewer than 50% of patients have died from lymphoma at 5 years. That is mind-blowing. Compared to a population that previously had an overall life expectancy of 6 months or less, now fewer than half have died in the third line and later setting, validating the transformative nature of CAR T cells, not only in the 3rd line, but as I've just shown you in the 2nd line setting. Furthermore, we demonstrated early on that the benefit still applied to patients with high-grade B cell lymphoma, uh, with, uh, high rates of response, and in fact, we showed in the progression-free survival curve on your upper right-hand panel that patients with high-grade B cell. Lymphoma actually had a better outcome compared to patients with DLBCL not otherwise specified. In the second line setting, we did not show that they did any better than DLBCLNOS. If anything, they didn't do quite as well, uh, but they still substantially benefited from CAR T cell therapy. And we have real-world data in the second line and later context. This is recent data presented at the ASHH meeting in December 2025 from 15 academic US centers looking at both Axi and Lisa cell in the second line and later setting. Most of these patients were treated in the third line and later setting with Axiel or Lysa cell. And what we can see is substantial. I, uh, high rates of overall, and complete response rates, um, uh, in, uh, both, uh, 2nd and 3rd line with slightly higher rates of, um, uh, response, uh, in Lisa cell, similar rates of CR rate. Um, but what you can see once again is dramatically higher rates of CRS and neurologic side effects for, um, axi cell. Compared to Lisa cell. So in the real-world setting, in the third line setting, we're again seeing a much better safety profile for Lisa cell compared to Axi cell and specifically in the third line and later setting, we're seeing that nearly 80% of patients had no ICAS and half of patients had no CRS, uh, whereas the majority of patients with Axill had both CRS and IAS. If we look in that real-world analysis, and again in mostly third line and later patients, once again, no difference in progression for your overall survival for patients treating Lsy cell or Axi cell. So validating that Lsy cell appears to be equally effective, uh, but a safer product for patients. And that's validated uh with a, a meta-analysis uh uh in this multi-center study showing similar rates of overall and complete response rate and similar rates of duration of response, progression-free, and overall survival between Axi cell and Lysa cell in relapse refraction. DLBCL. But, uh, when we do a meta-analysis, looking at, uh, multiple studies uh across uh different uh regions of the world, uh, we see substantially better LISA uh uh safety favoring Lysa cell and Axi cell. I want to turn our attention a bit to real-world data looking at the impact of CAR T cells in double-hit lymphoma and high-grade B cell lymphoma, saying, are these patients just carefully selected in pivotal trials or are they really doing uh as well uh with CAR T cells? And these real-world data shown here from the United States, US Consortium, Academic Centers, 80 patients with double-hit lymphoma. Doing just as well um uh with uh CAR T cells than patients without uh double-hit lymphoma who are also getting CAR T cells. So this is true in terms of both progression to survival and your overall survival, um, on your left and right respectively, uh, that patients can have durable remission and cure, uh, uh, with double-hit lymphoma getting CAR T cells in their relapse refractory setting. This is an Italian multi-center analysis, also looking at high-grade B cell lymphoma and isolating out the MC BCL-2 double-hit lymphoma patients compared to high-grade B cell lymphoma NOS and other patients. And what you can see is Also identical rates of progression-free and overall survival, with about 40% of patients having a durable progression-free survival, and most of these patients were treated in the third line and later setting, which is what we would expect then for patients treated with um uh uh with DLBCLNOS. So again, validating that CAR T cells should remain the treatment of choice for relapse refractory patients with second-line and later DLBCL. Now, I'll close with a sobering point, which is that most patients who should get CAR T cells don't get CAR T cells. Dr. Torka is going to tell you about all the great advances, uh, other than CAR T cells for non-transplant or frail patients. Uh, but more patients should be getting CAR T cells. Now, there are a lot of reasons patients don't get CAR T cells. Now, most of the patients in the world don't get CAR T cells because CAR T cells aren't approved or reimbursed in most countries in the world. But here in the United States. Where CAR T cells are fully approved and are paid for by the majority of patients with private and public healthcare insurance, still don't get CAR T cell therapy. Now, there are a lot of reasons for that. Patients have rapidly growing disease and clinical deterioration related to progressive DLBCL that doesn't always allow the time it takes to create a CAR T cell, let alone be referred to a CAR T cell center, undergo the manufacturing process, etc. Patients don't always have the ability or wherewithal to travel 3 to 4 hours and relocate near a treating center um uh in a major city like Buffalo or um uh Boston. Um, or New York City, uh, um, and so, uh, they need treatments that are available closer to home. Um, now, uh, how many patients in the US who are eligible for a CAR T cell actually get it? Well, this is really strikingly, uh, disturbing data, um, that shows that in the second line setting, uh, patients who are considered fit and eligible for a CAR T cell only receive a CAR T cell in only in about 25% of cases, uh, meaning three quarters of patients who should get a CAR T cell in the ideal setting, um, don't get it. And that again, is due to multiple obstacles. Those data are even more concerning when we look in the multiply relapsed or in the, um, excuse me, Medicare claims data, which is, is looking at older patients. And so older, frailer patients only get CAR T cells in the most recent Medicare claims data of less than 10%, even though these patients have the highest cure rate reported with CAR T cell therapy in that context. So we obviously need to do better. In my practice now, if a patient relapses, I ask if they're a primary fracture or early relapse. If they are, then they should get a CAR T cell with either Lysa cell or Axi cell in the second-line setting. Now, if they're not, then I give those patients glofinumab, gemcitabine, oxaliplatin because I know they're gonna do terribly with a high-dose therapy with primary refractor or early relapse disease. So even if they're transplant eligible, I'll give them an off the shelf immunotherapy. Therapy approach if they're not a candidate for CAR T cell therapy, there are other options available there as well. For patients who relapse late, if they are young and fit, those are still the zebras, the uncommon patients who should still get platinum-based chemotherapy and go to an auto-transplant in the second-line setting. But most patients are either transplant eligible or or have primary fracor early relapse disease. But for those patients who are young, And relapse late, those are patients who should still get platinum-based chemotherapy and go to auto-transplant for chemo-sensitive disease. If I have a late, uh, relapser who is non-transplant eligible or non-chemosensitive, I favor CAR T cells for that patient in the second-line setting as well. Um, uh, but, uh, offer Glowfit Gemox to most of those patients if they're not CAR T cell, uh, candidates or have access to CAR T cell therapy. So I will conclude by saying that CAR T cells, now Lysa cell or Axi cell, are the preferred therapy for the vast majority of patients with relapse refractory large B cell lymphoma in the second line and later treatment setting today. Lysace and Axi cell have analogous efficacy, but the safety favor uh profile clearly favors Lysa cell, including any great and severe CRS and neurotoxicity and the lower non-relapse mortality rate for Lysa cell compared to Axi cell. Platinum-based chemotherapy followed by high-dose chemo and auto-transplant still remains appropriate for a young fit patients who have relapsed disease more than 1 month, uh, more than 1 year, uh, from frontline chemoimmunotherapy, though that is a very small proportion of patients we see today in the second-line setting. But the big elephant in the room is that access to CAR T cells remains a huge problem in the United States and more so worldwide, and we need to improve access to these life-saving therapies. Thankfully, bio-specific antibody-based combination approaches, which I think you'll hear more about from Doctor Torca, are highly effective in the second-line and later setting. Um, as of today, they've really only been validated as second-line treatment for non-transplantation. And eligible patients. Uh, however, um, uh, they're substantially better than traditional chemotherapy, uh, in the second-line setting, uh, including in primary fracture and early relapse patients. And so I would consider it an option for those patients, uh, if they have primary fracture and early relapse disease and that's unlikely to have a durable response from, uh, just more chemotherapy in patients with proven chemotherapy resistant disease. With that, uh, I will thank you very much for your attention. If we have the ability to do questions, I'm delighted to do that. I'm also delighted to join your question and answer session if that's, uh, feasible as well. Thank you very much. I Thank you Jeremy. So we'll keep you kinda connected for the Q&A session after. So, and I'm gonna just, uh, in the lieu of time I'm gonna introduce Doctor Torca. So she's gonna be talking to us about what to do with elderly and frail patients with large lymphoma. Doctor Torque is coming back to Buffalo like she's an attending at Memorial Stone Catherine Hospital. Certain she has developed a career in how to manage elderly patients with large lymphoma, how to navigate all these options. Paula, we welcome again. So thanks. Can you switch this to, um, presenter mode, this presenter mode, here? Good morning. Thank you so much, Paco and Matt, for the invitation. Uh, I always look forward to this invitation every year because it's my opportunity to come back home to Buffalo. So thank you so much. Uh, without further ado, um, let me share some thoughts about evolving treatment strategies for elderly or frail transplant ineligible patients with relapse refractory DLBCL and high grade B cell lymphoma. I didn't make this title up. This was given to me by Parco. OK, so we'll start with the case, um, a 79, and this is a typical case that you see in clinic, a 79-year-old woman with a history of hypertension, type 2 diabetes, hyperlipidemia, chronic kidney disease, stage 3, DLBCL, ECOG PS1, um. Sorry, CKD stage 3 ECOG PS1 was diagnosed with non-GCBDLBCL stage 4 IPI4. So how do you treat this patient in the front line? So we heard a lot from Dr. Dunleavy, and I agree. I would also treat this patient with polar chip for 6 cycles. Uh, and this patient did have a complete response. But at 12 year mark, the patient had disease relapse. So what would be your preferred second line treatment for such a patient who's 79, so a little bit on the older side and has a bunch of comorbidities, but nothing that might preclude the patient from curative treatment. Uh, sorry, but can you switch it back because the font is really small on this. So this is the treatment algorithm, which is just in a different format, but very similar to what Dr. Abramson just shared, and, um, I acknowledge Dr. Frank Morhauser, um, who presented this at his presentation in Ash 2025. So, uh, I would like to bring your attention to the second line treatment. Let me see if my cursor works. I don't think it works, but, um, at the, at when a patient has disease relapse, the first question is to ask whether the relapse is within 1 year, is it early relapse or primary refractory, or did it happen more than 12 months, but because that's kind of our clue to whether the patient's disease is chemo sensitive or not. And then that's when the next question that you ask is transplant eligibility or CART eligibility. So in the past when we did not have CART cells, then it was just transplant eligible versus not. But now there are two questions to ask. One is transplant eligibility and CART eligibility. So if the disease relapse happens within 12 months or the patient has primary refractory disease, we do not consider a transplant. CART is the treatment of choice. So, so that's one question already taken care of. And then that's when we look for whether the patient is CART eligible or not. And if the patient is CART eligible, then we go for CAR T cell therapy. And if the patient is not, then we have a plethora of options that I'm going to share more about today. Uh, and many more were added last year to the benefit of our patients. If the disease relapse happens after one year, then we ask ourselves the question, is the patient's transplant eligible or not? If they are, then platinum-based therapy and autologous stem cell transplant is still under consideration. If they're not transplant eligible, the next question is, are they CAR T eligible? And then we go through the same algorithm, which is CART versus all the other new options that we have. And then coming to third line, there are again a ton of options available which we'll talk about a little more today. So before we go further though, you know, all the data that comes out is not exclusive to older adults. So the first question to ask ourselves is, can we even apply this data to our older adults? Are we doing a good job enrolling our older patients in clinical trials? And that's important because the median age of diagnosis of DLB. PCL is about 65 and one third of our patients are over 75, so we looked into it a little bit. We looked at clinical trials for the past 10 years that led to FDA and EMA approvals, and good news is that we are actually doing a good job. Over 50% patients, which is represented by the line in the center. Are over the age of 65 in these trials. The exception is the initial CART trials, but as I'll show you, the companies did trials exclusively in older patients for CAT cell therapy, which gives us a good sense of how CART performs in older patients. And the other, um, kind of plot on the, uh, on the right is looking at the trial eligibility. in, uh, these trials, even if the trial states that we're going to enroll older patients, sometimes there are barriers to their eligibility criteria, for example, creatinine clearance, which is just a feature, which is a feature of getting older and older patients can inadvertently get excluded because of creatinine clearance cutoffs. So this is kind of a representative of how these trials performed. And it looks like overall, except for again, the CART trials, most trials were quite permissive to enrollment of older patients. Um, so based on all the data that we have available, let me start with where we were. How did we start to get to where we are now? So as Jeremy had alluded previously, till about 2016, 2017, I think that's when, um, um, the first party approval came. Our treatment algorithm for when I was doing my fellowship, our second line treatment algorithm was transplant eligible, yes, which is about half the patients, and they would go for high dose chemo and autologous stem cell transplant. And if they were not transplant eligible, they would just go for low intensity chemotherapy. But what were the options available for these non-transplant eligible patients? The first one, which is still used as a control arm for many of our trials, is RMMox. In the original papers, the complete response rate with RMMO was 44%, with a median, with a 5-year median PFS of 12.8% and median OS of 13.9%. And this data was again refreshed and published very recently by Doctor Sam Yangshom, who's going to be one of our speakers today, who showed that it's still the same one, in fact, 1 year overall survival for with Gemox based treatment was about 10 to 15%. So clearly this is not good enough for our patients who were transplant ineligible. The next advance in the field was addition of polituzumab to to bendamustine and rituximab, which was another, um, chemotherapy-based option. So addition of polatuzumab did improve outcomes. The complete response rate went up from 40% from 18% to 40%, so a little bit better, but again, not a slam dunk. The median OS was still around 12.4 months even with polar BR. The next advance in the field was tarafacitumab and lenalidomide, and this was great because it was a non-chemo based option, better tolerated. Few caveats about the LMI study which led to the approval of tafacitumab and lenalidomide. Was that they excluded patients who were primary refractory or had bulky disease, so the highest risk patients were excluded from the trial. This was reflected in the outcomes, which actually looked very good. The complete response rate was 40%. And not just that, the median overall survival increased to 33.5 months for these patients. Um, I do, I would say that in terms of tolerability, this is a very tolerable regimen. I actually have a 93 year old patient who's, who's been getting it for 3 years and still in remission. So this was a nice advance in the field, but clearly not enough, uh, for our patients who were ineligible for transplant. So in this setting, CAR T cell therapy in the 2nd line was evaluated specifically in transplant ineligible patients in two trials, Alicante study for Axi and pilot study for Lysoce. And looking at these data compared to what I just showed you, it was, it was remarkable progress. So the best CR rate with both with AxisL was a little bit better than, uh, Lysoce, but the one year progression free survival was similar at about just short of 50% for these patients who were otherwise transplant ineligible. So we are going from somewhere of a 1 year progression free survival of. About 15% tops to about 45 to 50%, which is, which was, which is pretty unprecedented in this group of patients. So, um, I think with that the landscape of second line relapse refractory DLBCL shifted significantly to changing the question from transplant eligible to CARD eligible. So when I see an older patient or a frail patient who has, um, who has a disease relapse for DLBCL. Uh, one more thing to remember in the pilot and the Alicante study was that they did not have that primary refractory caveat. It could be disease relapse even beyond 12 months of therapy, especially in the pilot study. So based on that, if a patient, if a patient relapses, um. With their first relapse and their transplant ineligible, I asked the question, are they CART eligible? And if yes, my preference at this point was CAR T cell therapy. And if no, then we had all these other treatments to go to. But that's where, you know, by specific combos or chemotherapy could make a difference. Um, so let's talk a little bit about this CAT eligibility, transplant eligibility, and such. So just so that we have a good idea of what we're talking about here, so. Just to remember, patients could be transplant ineligible, but CART eligible, and both transplant and CART ineligible but still eligible for bi-specific antibodies. Why? Because the age limit in general for auto transplant is about 70 years in most centers for CART and bi-specific, at least in our hands, we don't have an upper limit. Um, we transplant patients who are 89, 90, sorry, we perform C T cell therapy even on patients who are pretty higher up in age, octogenarians and such. Um, for ECOG performance status, again, for transplant, you really have to have great performance status. CART 0 to 2 should work, especially with some prehab, but for bi-specific antibodies there is no upper limit. Similarly with the comorbidities, there's a spectrum, and for transplant you really have to have, um, very few comorbidities to be eligible for transplant. Another important thing to remember for transplant is that patients have to have chemo sensitive disease and the best outcomes are if they're in complete remission before they go for transplant, which can be a challenge in the relapse setting. And as, uh, Doctor Abrahamson had pointed out, both for transplant and CAT, you really need referral to specialized hospitals which brings down their availability to many patients definitely in the world, but also in the US which by specific antibodies have no such barriers, so. This was a recent um review that was published in Blood by Doctor Daniel Wallace, um, where the question was this was specifically review in older patients and the question was the algorithm that I showed you earlier, does that differ a little bit in older patients or not? And actually it did not till last year so. CART was considered curative and everything else else was considered non-curative, but the question in 2026 is, is CART still the best option in our older patients with DLBCL, especially the patient case that I showed you, who's 79, has a bunch of comorbidities. Should I just send the patient for CART or should I be thinking of all the other advances? So let's look at some data that came about last year. So I've divided it into chemotherapy-based new combinations and non-chemo based combinations. So the 1st, 1st, trial that was presented was the Polargo study, which was addition of polartuzumab to our favorite strawman backbone R Gemox. The other one was the Starglow study where glofumab was added to Gemox, and both of these were. Sorry, both of these were randomized phase 3 studies, and then Ecorriumab Gemox was also presented. This was a smaller study. It was a phase 2 study. So I would like to point your attention to the survival curves here, which shows that, um, not only the complete responses got better, we are hitting that car T cell territory now where our, uh, complete response rates are about 50%. But look at the 1 year progression free survival and the flattening of curves in some patients. So 1 year progression free survival with Polargo was slightly lower at 37%, but with addition of bi-specific antibodies in the second line. Um, so either glofumab or equariumab, the progression free survival was able to touch about 50%, which was similar to the early Alicante and pilot data that we had seen, which tells us that at least for some patients, this, especially where access is an issue, these might be really good options which could, um, which could be used. Even more impressive is the non-chemo based data, so combination of bi-specific antibodies with antibody drug conjugates and such. So 4 data sets to note here. One was equariumab with lenalidomide. So the thought is that lenalidomide is an immunomodulator, so it boosts the, uh, efficacy of by specific antibodies. This was, um, a smaller study. Phase 240 patients, but looks like the complete response was about 51% with addition of lenalidomide. However, it did come at the cost of higher risk of CRS and ICANS. Um, this has not been, this was, uh, presented about two years back and I haven't heard more about it so far, so I'm not really sure if this is something we'll be able to really use it in the future. Um, bringing your attention to the Sunmo study, which was the largest data set among all these four that are up here, this was again a randomized study where Mozunpola was compared head to head with our remarks. Uh, there was fair representation of older patients in many of these studies. Again, complete response rate about 50% and 1 year progression free survival, about 50%. And similarly, glofumab and politizumab, so basically we're just swapping the bis specific antibody and keeping poletuzumab, had similar outcomes. The best data in this setting is with the combination of glofumab and longest tuximab. So longesttuximab, as you all know, is an anti-CD19 antibody drug conjugate. And that led to the highest complete response rate of all these regimens at 87%, which is great, but we do not, we have not seen survival data with this yet. I think it'll be presented this year, so it'll be important to see if these high CR rates amount to prolonged, uh, duration of response, um. One thing to remember about these is adverse events. So even though we are not using chemotherapy, they're not without side effects. There is less cytopenia, but there is long term, um, immunosuppression and risk of infections, and there are special considerations with longcetuximab. So even though the response rates are highest with this, I think we have to be cautious about using low-fit longer. In our elderly frail patients, my go to at this point is either mozunpola or glofumab polizumab, although glodumab polizumab is category to be in the NCCN guidelines, so it's kind of hard to get for most of our patients. Um, with this, um, landscape, I, we had a study open at, uh, MSK where, um, we thought it might be a good idea to combine equariumab with lealidomide and add tafacitumab, which is an anti-CD-19 monoclonal antibody, so you're kind of boosting the CD20, uh, by specific antibody and also adding CD19. Um, it was a great idea, but, um, because of the changing treatment landscape, we were not able to enroll patients on this trial, uh, and it was closed. So I just brought this up because this is because of all the advances and CART and all these combinations. Second line DLBCL is a hard space to develop new drugs at this time. Um, so what did we do for our patient going back to the case? It seems like even though there is great data coming with other treatments, you know, at this time, CAR T cell therapy is still king just because we have more, um, long term data. So we chose to give this patient Rgemox bridging followed by Lyso cell. Uh, of course, I think for these patients formal geriatric assessment based optimization, what we call prehab is very important to, um, to increase their chances of success. Um, I don't know how much time I have, but I would like to briefly touch upon third line treatment for our patients. So giving, um, so this poor patient, she had Lysoce, however, she experienced another disease relapse at 6 months after treatment. Now the question is how do I treat this patient? So to remind you, first line polar chip, second line lysoil, which is what we do in many of our patients. So treatment menu in 2nd and 3rd line plus relapse refractory diffuse large B cell lymphoma is rather broad. We have a ton of treatment options. I would probably divide them into single agent options like longcetuximab. Orroneximab is not approved in the US, but it is approved. In Europe, Ecorriumab and loutumab, and what I would like to point your attention to is the complete response rates. So they range anywhere between 20 to 40%, but the real world data looks worse where the response rates are anywhere between 20 to 25%. Um, another option that we have, uh, to use is rituximab, lenalidomide lenalidomide, rituximab, which was a randomized phase 3 trial compared with lenalidomide rituximab. It did lead to a complete response rate of 40% compared to just 20% with LNR, um. It is supposed to be agnostic of CD 30 to use brain LR. I hardly use it in my practice, um, because it is not an easy regimen to give because of the neuropathy and the cytopenias, and I really do believe if you're going to use a directed therapy against CD30, you should have CD30 on the, on the target. Um, again, all the regimens that I talked about in the second line, EPOLn, Mozunpola, Gloy Pola, Gloy Lanka are available in the 3rd line setting to use. You see, the data looks much better than single agent, but to be remembered is this is a combo of 2nd line and 3rd line data. In most of these presentations, they did not separate out second line and third line plus, so I still don't really know what is their activity in third line, but it is to be believed that of course they'll be better than using single agent drugs themselves. The problem with these mostly is expression of, uh, CD-19. For example, if I, if I want to use glofriumab with longest tuximab, I need the disease to have both CD20 and CD19. And what usually happens is after you give them car T cell therapy, especially if they have early relapse, many of them lose their CD-19, so you can't use some of these combos, and you've already used polattizumab in frontline with polar chip. So then what benefit are you getting by adding polatzumab again in this setting? So another sobering figure is this where this is just the survival plots of all these treatment regimens, uh, up here for, uh, visual inspection, and you can see that overall, these probably benefit about 20 to 25% patients. So in the third line setting, we are not curing 75% of their patients, uh, when they get there. Um, lastly, real world data. So this was a presentation by Doctor Shweta Teruadam, um, looking, collecting data from the Cubic Consortium. Do by specific antibodies hold up in the real world? And thankfully for our older patients, actually the outcomes are even better than our younger patients in the real world. The CR rate was 40% versus only 27% in patients less than 65. Um, looking at the survival, the same pattern was mirrored. Doesn't matter if your patient is older or younger, you should be able to invoke and use by specific antibodies, with just ensuring that they have good, um, infectious prophylaxis and liberal use of IVIG to avoid infections. So for what did we do for our patient, I had all these grand thoughts of using some of these combinations, but her disease was CD19 negative, so I resorted to single agent glofumab. She did achieve remission after two cycles, which is a very good prognostic sign, and she still continues on glofumab. It's time-limited therapy, but she has not reached the end of her, um, six months. So in summary, I think today in 2026, CAR T cell therapy is still the favored second line option in most older patients with DLBCL, even if they're transplant ineligible by definition. By specific antibody combinations are challenging the paradigm, and I'm getting more and more comfortable with bringing them in, but I would love to see some more long term data before really deciding, um. Among the bi-specific anti antibody combos, I think my favorite ones are non-chemo based combos that hold the most promise, but I think the need of the R is to really develop non-CD-19 and 20 dependent therapies because that's where the field is going. We're using up these targets earlier and earlier. Um, there are many, uh, trials that are awaiting readout like the Skyglow study where, um, by specific antibodies are going to be used in first line. And then we would be left with, we won't have these targets to use later. So that's where the push in the field is to develop other targets like CD22, CD79B, and such. Um, but hopefully we are doing good and we will be able to conquer lymphoma together, um, with our older patients. This is my attempt at using chat GPT to help me with some slides. Thank you for your patient listening. So, OK. So let's start the session. So I think we can make. Uh, if everyone has, uh, any questions, please feel free to come to with the microphones. Um, hi, uh, great talks, everybody. I'm not sure Jeremy is still on, but Jeremy, great talk to, uh, he's here, awesome, uh. Cool. Maybe can you hear me? Yes, we can hear you and we can see. I'm so great, um, so hi, uh, Sammy Amshon from, uh, NYU Lingon. So great talks all three of you. Um, we, we, we saw a lot about, uh, by specifics and CAT, um, kind of sequentially, um, what. That what I've been seeing a lot recently in my practice and I'd be curious to actually hear all three of your thoughts on is that especially in in the second line we're actually kind of seeing them almost almost concurrently where either by specifics are being used as bridging therapy after apheresis or patients are getting by specifics as kind of holding therapy, uh, right before they're referred still with the intent to go to CART in the second line. So I'd be curious actually because I this is something that I've been seeing a lot in clinic and kind of struggling to to tease out timing etc. how you think about the timing uh in in terms of uh apheresis and the bridging for patients who are uh either already getting by specifics by the time they're referred to CART or who are planned for by specific bridging after apheresis and kinda how you think about the timing of, of those two. Uh, I'm happy to start, Sam. I think that's a critical question and, and honestly an unanswered one right now. Um. And I'm, uh, I don't favor a bi-specific immediately prior to C, uh, presently. Um, I think there's, I know a lot of people are doing it, um, but we really don't have data validating the efficacy, and um, my biggest concern is the theoretic risk of actually altering the curative intent magnitude of the CAR T cell therapy, which is the definitive therapy in this context. And the reason for that. Uh, is because if you give a bi-specific antibody in the bridging setting, um, uh, or even in the holding setting, um, but if you give it in the bridging setting, then when you're giving the CAR T cell, the bi-specific antibody will still be in circulation when you're re-infusing the CAR T cell, uh, based on the half-life of the bi-specific antibody. Um, and we just don't know if that's gonna, uh, cause a problem. What problem could it cause? Well, a bio-specific antibody is going to engage the CAR T cell, um, through the CD3 domain, um, and that could theoretically lead to CAR T cell exhaustion. Uh, and CAR T cell exhaustion is the number one mechanism of CAR T cell failure, right? The majority of people who progress on a on a CAR T cell still have CD-19 on their surface and still have CAR T cells in circulation. The dominant mechanism of resistance to CAR is exhaustion and immune is immune exhaustion and immune um intolerance. So, um, So that is my biggest concern. Now, we all know that the best predictor of cure with CAR T cells, independent of that, or at least I won't say independent of um but um uh without looking at immune exhaustion, is tumor burden going into the car. Uh, and so it may very well be that my theoretic concern about inducing carci cell exhaustion by engaging with the bi-specific at the time that you're asking it to do the heavy lifting is offset by the fact that if bi-specifics effectively said to reduce patients, that maybe it all comes out in the wash, and it's still better to do that and then give a car. And the answer is we don't know if that's the case. So my pitch is to study this prospectively. I think, uh, my hunch is it's probably fine. Um, this is basically a, a roundabout pitch to say we're about to study that very question, Sam. We're launching a study of bridging Glofit Gemox. Uh, we're using an accelerated glofumab ramp-up, uh, in concert with Gemox, um, prior to, to, um, Uh, CAR T cell. Uh, and so that study is gonna go live. It's gonna be a multi-center IST and I'd encourage everyone, uh, if you, uh, uh, first of all, we'd welcome additional sites, but second of all, uh, we'd welcome your referrals, um, for that study. It's not yet open, but it will be. Um, and I think that's going to be an important thing. The other, uh, highlight that that issue, that, that, uh, points to is that using a bi-specific and bridging in the currently available approved approach is not all that feasible because of the three-week ramp up it takes to get the full dose, which is really too long in a bridging setting. So, I use other bridging options if I have them available, um, and, but we're going to formally study it. Um, uh. Is my very long answered approach to that. I think we need more data. Yeah, I mean, I think it's, I think it's a really interesting question and, uh, you know, certainly in our practice over the past 6 or 9 months, it has become a huge issue, um. And as, as Jeremy said, I mean, I think we need to learn a lot about it in terms of, um, efficacy, you know, potential impact on, on CT, timing, timing of apheresis in relation to it, but Um, but it seems over the past few months I've had a lot of very resistant DLBCL patients who are primary refractory or have CNS disease where I've used a bio-specific approach with a plan to go to car. I think one of the questions or the big questions is how long do you continue with the bi-specific approach, because if you see people doing really well and going into remission. Uh, you know, do you give 6 weeks, 8 weeks, 10 weeks, or, or continue it, or when do you, when do you, um, do the car? So, I think it has opened up a lot of really, really interesting questions that we have to figure out. Yeah, um, at MSK we, our policy is that if you're going to use a bi-specific for bridging, we do it after pheresis because actually Jeremy brought up a very interesting point about the bi-specific binding to the car. I hadn't thought of that, but we were more concerned is that the T cells that are engaging with the bi-specific are exhausted and they're not good T cells to manufacture cars. So let's manufacture and then give the bi-specific. I think your concern is stemming from the data data set, I think from Gloria Gloria Yacuboni which showed that patients who get by specific before CAR, they did worse compared to patients who did not get bi-specific. But of course that data is biased because why did your patient require bi-specific before car anyway? They probably had worse disease and that is a huge confounding factor and that's what we are seeing in. Our practice too is if you have had to resort to buy specific before car they have bad disease like primary refractory disease. I, I have a patient right now who has double hit lymphoma who got epoch primary refractory, and now I tried to bridge her. I'm trying to bridge her with Mozun and Pola, but like, you know, she's going to go for car and I know she'll probably, you know, like this is a tough situation. So anyway, to answer your question, I, we are using it cautiously, but, uh, prospective studies is always welcome. And just, just quickly to the patients who are, who are already kind of gotten it as holding therapy or we, we have a similar policy where ideally we also, we have the same concerns with with caution. When you're getting referred for CAR T, sometimes they're already coming in on my specifics. Do you guys have a, have a, a like a mind watch out? No, because it doesn't matter. It's, it's in the system for a long time. Right. Yeah, um, I have just a brief two questions if you don't mind. Doctor Levy, if you can comment more about the MRD, uh, how do you use it during treatment, uh, per cycle or at the end? Or this, um, CT DNAs are specific to that patient only? And the second question is the, uh, if anybody doing trials for off-shelf C T cells using a um donor, healthy donor T cells which are modified, if any were in trial going on. Yeah, I mean I can, I can answer the first question. I mean, obviously it's a hugely evolving field where we have a lot of, you know, really good research looking at MRD at various time points. End of therapy, um, in, in the middle of treatment in, in diffuse large B cell lymphoma particularly. Um, so, I mean, we use it at the end of therapy where the PET scan is, is, is, is, is positive and Um, it, it can be very helpful and, and the NCCN guidelines endorse that. Um, I, you know, I think, I think most of us also use it in a lot of other settings, um. And it's, it's hard to give kind of like a laundry list of those because we come across situations where it can be incredibly helpful, where imaging um just does not give us an answer, is ambiguous, or So I've used it in different settings. I mean, I, you know, I don't use it in the middle of therapy to predict outcome. I mean, we know from retrospective studies that if you do it after cycle 2, that if you're MRD negative, you've got a very good outcome. You know, I don't do it then, but there really are so many settings where it can be used and in patients, for example, who get CAR T cells. I've used it a lot where, you know, we see these kind of um ambiguous scans that go on forever and it can be very helpful. So, um, yeah, yeah. Yeah, that is a great question and that is going to be very, very, um, relevant more so in the future. The problem right now is that we have 3 commercially available MRD tests. One is regular flow cytometry, which is not good enough. Then we have clonoseq, which is based on your, um, you know, IGH IGGBH. That's for DLBCL. That's not good enough. Then the last one that just became available is Cigna Terra. Um, all the data that we have, which is great data, is with Face Seek, which was through Foresight, which was bought by Cignaera, but that's not the test that's available right now. So the test we have is the Cignaera which has very limited data. So we are, so that is the problem right now is we are, I, I've started to send the test a lot, but that's just so I can understand the kinetics and the performance of the test. Hopefully in the future when we, when we have Phase seek, which is the best test, then I do hope to use it for the end of treatment determinations and. Perhaps first use it in the research setting to kind of de-escalate treatment are there are many trials ongoing with escalation of treatment and then use it in clinical practice, but I've just been sending a lot of it just to understand, just to get familiar with it right now. Yeah, we have this, um, you know, we we have this allergen study which is ongoing, which I'm sure a lot of people are involved in that and that's. Um, you know, that's a really interesting study in that it's, it's, it's, it's really questioning whether being MRD positive at the end of treatment means something and if you can intervene and if you can treat somebody who's MRD positive and if you can improve their outcome. Um, so that trial is ongoing at the moment. Um, I will say one thing, we don't find that many patients who are PET negative and MRD positive at the end of therapy for diffuse large B cell lymphoma, but, um, but it's, you know, it's a really interesting trial. I, you know, I think, I think in the future as well with all the data that we have with interim MRD after two cycles. Uh, we really need to start constructing more studies where if patients are MRD positive after two cycles, then we, um, come in with some other type of therapy because we know that that those people do pretty poorly if they continue the same therapy. Yeah, yeah, and I think, I think the important thing is to maybe see what the clinical trials will show in, in terms of how to integrate this new technology. I think right now in common practice there are very few settings and. I think there's also regulations that they are different between each state. I think in New York state we only have available the clonic, so the other, um, yeah, you can also send signataire now. I, I agree with, with my colleagues. I think there's a very limited role for MRD today. I think the place where it's the most useful, maybe the only place that's useful clinically right now is adjudicating these sort of equivocal PET scans. There are some settings. where I found it's particularly helpful. Primary mediastinal lymphoma patients always have these, you know, Devilleos at the end of treatment, this dense inflammatory thing, and you try and biopsy them and you just get this inflammatory, you know, schmutz, and you don't know if you've caught the lesion or not. Um, primary bone disease is often PET positive due to remodeling. Um, the issue with this is, you know, you need a baseline tumor biopsy. Um, And sometimes these patients don't have, you know, their initial block has been exhausted and you can't generate the signaera assay on them. So, there are real-world obstacles. You know, the, the alpha 3 trial blends the two elements of your question, um, Algene Carr and MRD. So Karen mentioned, you know, that trial is taking patients who are in an MRD detectable complete response and randomizing them. To standard of care, which is observation versus um Cmacatine and Seidlusol, which is an allogeneic car. And their initial data is showing that you do eradicate MRD in the majority of patients who get it, it's almost 60%. Um, so, it is effectively erasing MRD in the majority of patients in that context, which is great. Um, will that translate into an improved progression-free survival is what will remain to be seen. That's the primary endpoint of the study. We have that study open. We also have, um, another, um, uh, allogeneic car, a, a UCA 2022, a dual targeted allogeneic car available, um, and are soon going to launch an in vivo car. Uh, study as well. I think the key question is that these, these owl cars have not had the same degree of persistence as auto cars, and that's generally translated into shorter progression-free survival. So I think we still have room to move on the technology and I think that shows that maybe the MRD clearance approach, uh, where the degree of persistence might not be, uh, uh, as necessary, uh, is a really great strategy for the allergen folks. Uh, we'll see where that translates into the development of ongoing alloe cars as well as these in vivo cars, where we have a proof of principle in myeloma that you can drop light chains and drop IGM, but we have no durable progression-free survival data to know whether the persistence is adequate with an in vivo product, uh, to induce durable PFS. So there's a lot remaining, but I think these are valuable ongoing studies for us all to participate in. Just one point. After what Jeremy said, that this is something that I discovered recently. So the Cignatira assay does require tissue, but the foresight assay can use peripheral blood at the beginning, so it doesn't require tissue to look at MRD. We're eager for that for for Nora to make, to get foresight commercialized. Uh, Obviously it's not yet. No, no, no, I was just saying with the assays. I know it's a very complicated with company. And I don't think you need a baseline biopsy either for the foresight, you don't need a baseline biopsy. They use a library to compare your. Well, it's tricky. They, they, it, you get better results if you do have a baseline biopsy, but, um, uh, but they can do it without, it just doesn't have quite the degree of sensitivity if you don't have a baseline biopsy. So it's still helpful even with phase C, but not absolutely mandatory. Paul, you have a question. Hi, um, yeah, I have another question on MRD for Kieran. I'm Paula Guire from MSK. So, uh, to me, like, once we have that essay, right, like the, the foresight, would you be comfortable from the data we have for the patients that are MRD negative, PET negative at the end of treatment to not, um, do this surveillance scan or not do surveillance at all. I and I'm asking this because I have a lot of patients that travel from away like very far away, etc. they wanna go back to their own country. Is that something, and that's something that came up, uh, on their questions like can I just do this essay and then, you know, don't not be be observed by my primary care physician or something like that. Yeah, I mean, you know, I think we're not at the point yet where, uh, we can, we can just do the essay and not do any imaging and assume that somebody's in complete remission, right? Like the last one, of course. I just do the surveillance. Not, not do the surveillance imaging every, every 6 months, just do the MRD, yeah, yeah. So I mean I, I mean hopefully in the future we will be able to do that. It just hasn't been, it just hasn't been validated yet, I guess. Um, yeah, I do kind of, you know, I mean there are situations, I mean, as, as you know, um, Jeremy said. You know, for example, primary mediastein of B cell lymphoma at the end of therapy where you have, where you have diseases where you have really, really, really minimal amounts of disease, um, I don't know how much, uh, investigation has been done to. Look at the um sensitivity of MRD in some kinds of clinical situations where you really, really have low levels of disease, but it could be very important in terms of, you know, the disease may need to be treated, but is MRD always going to pick up very, very, very low level disease and uh you know, these are, these, these are questions that have to be looked at and studied, yeah. Well, there was a recent, uh, just pre-published in Blood. There's a Capsiq, the predecessor to Faiq, not quite as good, but still pretty darn good. In primary mediastinal B cell lymphoma, I think it's from a French study, uh, prospectively studied, looked pretty darn good in primary mediastinal large cell lymphoma as a subset. So that's, um, kind of a Appealing. You know, Paula, I, I would say, you know, there's a lot of institutional bias around how imaging is utilized, but um, to address your question at a broader level, you don't have to do imaging on those patients at all. Uh, with modern data, even without MRD, right, there's never been an overall survival benefit. Um, demonstrated with surveillance imaging, um, there are centers that never do MRD, uh, that, excuse me, never do surveillance imaging and only follow clinically based on the lack of validation, um, you know, uh, uh, including some very major centers, uh, and so, you know, I typically do it, uh, you know, CT scans once patients are remission every 6 months for 2 years and then stop imaging. Uh, but the NCCN guideline says up to every 6 months for 2 years, but you don't have to do any. So if a patient of mine says they don't want surveillance imaging, I'm like, fine. Uh, we know that the vast majority of relapses, if they happen, and there's nice data from Memorial that shows that, um, that you don't improve outcomes, uh, you might find disease a little bit earlier, but you don't actually substantively change their outcomes if you find it earlier. Um, so I would still say that surveillance imaging based on the available data is optional, even though most of us do it, not everybody does. I mean, I would say that there are some diseases where I do think it is critical to do it, like for example, Hodgkin's lymphoma and primary media standard B cell lymphoma if you don't give radiation because If you do have a recurrence, it's gonna show up on imaging. Somebody's probably not gonna be symptomatic, and you are going to be able to intervene and potentially cure somebody that I think is one situation where it is helpful to them. I think immuno cell lymphoma is something you can salvage a patient with radiation therapy. You cut them earlier, but other than that, I think there was a randomized study in France that compared aggressive imaging versus no imaging. In people with the LBCL at that they were in CR by PET at the end of treatment and there was no difference in outcome, so I think there's enough data that patients who are comfortable not getting imaging studies, you can say you're PET negative, you're MRD negative, you're good to go. So. Um, Paco, yes, hi, hi, everybody. Uh, my question is the role of transplant at this time, like now and in the future with somebody getting carti, like Carti moving off, what would be the role? And if they are getting CAT at this time and if we can collect stem cells and save for the future, how, how does that work? Yeah. And when you mean transplant would be auto and allo transplant. I mean, theoretically we do in the algorithms it says that if a patient has chemo sensitive disease relapse beyond 1 year, then auto is the standard of care, but those patients are very rare because most relapses do occur within 2 years. Patients are older and such. I don't remember. We're sending any patient for auto in the past since like past 5 years, but yes, if you had a patient who had DLBC will come back after 5 years, they'll go like I, you give chemo and if they go into remission, then theoretically they're a candidate for cancer. Yeah, I always find it bizarre that uh if a patient with diffuse large B cell lymphoma relapses within 1 year, they get CAR T cell and then if they relapse like 1 year and a day, they get older and it doesn't make a lot of sense and. I don't know. I mean, hopefully there are studies ongoing that are going to address this, but yeah, um, I'm curious to hear Jeremy's, uh, attitude or opinion about that. Exactly, yeah, well, again, we're gonna challenge out in relapse disease at one point. So because it may be if, if the outcome is better in the primary refractory, could the outcome will be better in the relapse. And maybe there's less toxicity because the toxicity from beam or CBD is certainly more than dealing for the pollution that we do for cars. So I don't know, Jeremy, what do you think so. I'd always rather give a car than an auto transplant. Um, my, uh, general feeling is that auto transplant has always been the medical oncologist's folly. It's never made good sense. It was maybe the only thing we had available for a while, uh, but giving more chemotherapy to A chemotherapy resistant patient, which is by definition, any relapsed large cell lymphoma is always throwing good money after bad, and it's, uh, it's barbaric and overly toxic. Now, in, for patients who relapse later, they can do well with that approach. They are more chemotherapy sensitive. Uh, and so, uh, as we've repeatedly pointed out for that young late relapser, We still do it. Although my bias is that CAR T cell probably works better in that context. Um, now, um, I guess it, the, what gets to the question is, who's transplant eligible? Um, and that's been a moving target, right? I mean, before we had CAR T cells, I transplanted. Some patients in their 80s. I'm not proud of it. Uh, but, you know, when that's all we had, we would assess fitness more than things like age. Now I'm using age as kind of a get out of jail free card, and, you know, where do I draw the line? You know, if patients are over 60, you know, I'm saying, all right, I'm not considering them transplant eligible, and if they're relapsing at 18 months or 2 years, I'm going to give them Lisa cell. Um, because I've got an FDA approval, uh, and data to support giving CAR T cells to a patient, uh, who I call transplant ineligible. I think for somebody in, you know, who's young, it's hard to make that argument that they're transplant ineligible. It's hard enough to make it if they're 64, 65. Um, but I do it because I generally think CAR T cell is a better therapy, but we haven't truly proven that in the late relapsing patient. It's certainly better tolerated. I think CAR T cell as an uh autotransplant has a minimal and a dying role. I think the real question is where do we use an aloe today? Um, I still think there's a minimal role for aloe. There's always been a minimal role in large cell lymphoma. If I have a patient who's relapsed post-car, and I get back into remission, uh, with a subsequent line of therapy, um, you know, if I get, if they relapse post-car and I get them back into a CR with, um, You know, a glofumab-based regimen, I'll consider an aloe, um, you know, uh, in that patient, if, if they're a candidate, uh, if they're multiply relapsed. Um, but even then, I think bis specifics have the goal of, of, um, uh, of, uh, you know, curative intent, even in the third line and later setting. Uh, certainly, if they're beyond, uh, car and have relapsed post. Uh, post by specific, if I can get that patient back into remission, I'm definitely considering an aloe if they're aloe eligible. Again, this is a really small subgroup of patients. Thank you, thank you, Amy. Thank you. Well, thank you. I think we're gonna go, uh, in lieu of time we have to take a break for a couple of minutes and then we'll move back to the next session. But Jeremy, thank you, Kieron, Valerie, thank you very much.
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