Led by Roswell Park expert Francisco Hernandez-Ilizaliturri, joined by Julio Chavez of Mayo Clinic, Paola Ghione of Memorial Sloan-Kettering, Eliabeth Bream of UCI Health and Yucai Wang of May Clinic, hear new approaches for front-line management and treatment for relapsed/refractory mantle cell and follicular lymphomas.
Right, and for the sake of time I'm gonna go ahead and introduce our next speaker. Uh, it's my distinguished pleasure to introduce Doctor Yu Chai Wang from the esteemed Mayo Clinic, uh, number one hospital in the world. Um, I'm a Cleveland Clinic alumnus, so I'm, it's a little bit of a sore point for me. Uh, but, uh, Doctor Wong is a preeminent scholar in mantle cell lymphoma, and he's gonna talk about some of the practice changes, uh, in the frontline setting for that particular lymphoma. Doctor Wong. All right. Thank you, Matt. Uh, uh, would you mind swap the, uh, slide to the presentation? Thank you. So I'm gonna talk about frontline mantle cell lymphoma. Not a whole lot of changes, but just some review here. Yeah. How do I advance this one? Give me a click. This one. You could click up. Oh, here. OK, thank you. OK, my disclosures. So, uh, in front, frontline mantle cell lymphoma, the sort of fitness is still relevant, um, for older or unfit patients. Um, the ECO trial was changed the practice recently using acalabruib VR. Uh, still some question remaining is, is BTK inhibitor plus BR necessary for all of the patients? So this is the echo trial initially presented at EH 2 years ago. Uh, this is the trial with the Calabrnib BR versus placebo BR followed by maintenance. Uh, the trial met its primary endpoint in progression-free survival, and overall survival also shows a favorable trend with the Calabrum arm. So this got FDA approval just last year and, uh, it's being adopted into practice more and more. Uh, at Ash, um, they presented a longer follow-up. Uh, on the left you're seeing PFS and the right and OS again, the benefits confirmed with longer follow-up. Um, and Ash, their primary goal was to present PFS 2, from, um. first line therapy and then going to second-line therapy, basically time to third line. Um, here, you can see that the color BR still performs better than placebo BR when you look at the time to the third line therapy. Um, but here, we, if you think about it, you know, for the experimental arm, front line, you got a call BR. Second line, you got something else, possibly CART, possibly something novel, something different. But in the placebo arm, you're having placebo BR in the front line. Second line, most patients got BTK inhibitor. So here, if you think about a fair comparison, it's probably the PFS from combination of color BR in the experimental arm versus the PFS 2 from experimental arm where patients got BR and then BTK inhibitor. Basically, a question of combination versus sequential strategies of BTKBR therapy for mental self. Here, if you look at the PFS2 in the placebo arm, the median PFS 2 is 73.8 months. Uh If we go back to this. Uh, PFS endpoint. Look at the experimental arm. The PFS of the experimental arm is 72 months. So, with combination PFS 72, With sequential treatment, PF 2 is 73 months. So it's Numerically very similar. So, so that, the question is, again, are there patients who we can just treat with sequential BR versus BTK that avoids a prolonged exposure of BTK inhibitor in these older patients. Uh, we actually did a study, um, a multi-center retrospective observation, observational study looking at this exact question, BR front line, followed by BTK in the second line, and, um, the data is showing in the, in the, in the first two columns. Uh, the first column is all patients, second columns, those are older patients. If you look at the PFS 2 in the, in these first two columns, we're looking at 65 month median PFS 2. Uh, then you look at the experimental arm from Shine, the PFS is 80 months, and then from echoes 66 months. So, this is a real world population versus trial population. It's not too bad, right? With the sequential. Look at the survival, um, 5-year, 7-year, you know, survival rate, benchmark to shine echo. Again, it's not too different with the sequential approach. Uh, the numerical difference in the, in, in the real world series is probably also driven by the lack of maintenance reduction methods, which is less than 50% in this cohort. Whereas in the, in the trial, by design, you're required to have maintenance. So why is that, why does that matter? So. Although this very small maintained trial showed that maintenance doesn't really uh do much after BR, but in multiple retrospective studies we have seen benefit of Rituxan maintenance after BR. So this is the latest study from a multi-center study that we let, uh, 700 patients after BR without progression within 3 months, then they, you know. Either get maintenance or observation. You, you see on the right, you can see the maintenance, you know, dramatically improves both the progression and overall survival. So, so with this in mind, you know, with, with the prior sequential study, we only had about half the patients with maintenance Rituxan, yet the PFS2 and the OS is not too bad compared to the, um, ECO trial. So, so, so, at least for a subset of patients, we think, you know, sequential BR followed by second line BTK inhibitor would be reasonable. And this is also supported by the Shine tribes, uh, Eco tribe itself. If you look at the subgroups, some of the, um, Lower-risk patient does not necessarily benefit from, you know, sequence uh the, the, the combination treatment instead of a sequential approach. OK. Now, um, what about patients who are not fit for chemotherapy? So, this is not a, really an update, but, uh, just a refresher. The Enrich trial compared to, um, Chemo-free BK inhibitor with Rituxan versus chemotherapy with BR or R-CHO. The, for the entire trial, you know, it met its primary endpoint, the ibrutum Rituxan was better than BR or ARCHO. Uh, the problem is in the United States, we don't use ARC-CHOP for mantle cell lymphoma for these patients. Whereas in this trial, the primary benefit is driven by the eye chop patients. If you look at the BR, you know, folks, the IR versus BR is really the same. Uh, same thing for overall survival, and I mean, there was no statistical significant overall survival in the entire population anyway, but there seems to be a little bit of separation in the our child population with VR again, there's no difference. So, in, in uh Europe, um, countries, they, they, they highly regard this trial as practice changing because some, some countries use our CHO. In the United States, it's, it's, it's not quite practice changing, but it does give us another option where you don't use chemo immunotherapy and you can use uh BTK based chemo-free treatment. So Now, in older or unfit patients, one of the options, one, I think you can still use the traditional approach based on the PFS2 from sequential approach, both in the shine, uh, uh, both in the echo trial and the real-world data. Uh, I think it's very reasonable for, for low-risk patients or standard-risk patients. You use BER front line are maintenance for 2 years and then reserve your BTK inhibitor for the second line. For patients with, with high-risk features like bulky disease, OK, 67 high, high MP and stuff like that, uh, I think it's reasonable then you follow the echo approach to use a color BR and then you use, Maintenance indefinitely with the BTK inhibitor. Although in some scenarios, whether you can admit to BTK maintenance, uh, that's an open question. For patients who are not fit for chemo immunotherapy, in your mind, then BTK plus uh rituximab is totally reasonable. Now, moving on to young and fit patients. Uh, this is the pre-triangle era data where we do our chop. Uh, RRC based, um, uh, induction therapy based on MOC, MCL Younger trial. And then we take patients to ortho stem cell transplant and then follow that with three years of maintenance. As you can see, the evidence for hydrocepharabine and maintenance Rituxan, uh, are all strong with randomized phase 3 data, whereas the transplant data is very weak with, uh, only a small phase 2. Uh, the, the 3 important trials in the recent years, one is triangle in the, uh, in Europe where they compare ourH R rehab, transplant, and maintenance. Uh, versus the same approach plus ibrutinib in induction and maintenance, uh, versus the third arm where you add ibrutinum induction and maintenance, but then get rid of transplant. The trial has been presented a couple of times and published. Um, we all know that. Now, uh, ibrutinib added to the frontline therapy. Is there a new standard in, in Europe? You can add ibrutum to the backbone with the induction. Uh, and, and in maintenance for 2 years with that approach, you can safely omit transplant because you know, the two ibritum arms performed very similarly in terms of progression free survival, um. Uh, in United States, we kind of addressed the induction and transplant question in two different trials, the EA 4181 compared three-arm, uh, induction. Uh, BRR erRC was the standard, and then we add a, a calibrinib to that. And the third arm is adding a calibrnib but, but then get rid of high dose errorC. The other three arms performed very similarly in terms of induction success and short-term progression overall, survival with a shorter follow up at this point. Uh, in terms of the role of stem cell transplant, so EA 4151 took patients who are in CR with MRD negative status and randomized them to transplant versus no transplant. Folks with uh indeterminate MRD or the ones who have still positive MRD or non-CR uh got transplant by trial design. The majority of patients got a CR with MRD negativity. Uh, 500 patients there are randomized to transplant versus no transplant. You can see the two curves are overlapping. So, suggesting if you achieve a CR with antitectable MRD, there's no role for transplant. So, then, you know, with these newer trial data, again, there are probably at least two approaches. One, you follow the traditional approach or the ECOG approach where you use, you can use your choice of induction, including a color BR probably. Um, after induction, if the patient is in CR you can check MRD. If they are in MRD negative status, you can skip transplant. And then you follow that with your testing forms for 3 years. Here, you're basically uh Just de-escalate the transplant where you can still reserve BTK capital for, for the future. Uh, in Europe, they follow the triangular approach and a lot of centers in the United States also follow the triangular approach which is BTK plus R high dose ARC containing induction and then then you can skip transplant just based on the triangle trial design and then follow that with maintenance. Now, uh, There are still some open questions. One is sarabine. Is it necessary? From European data, seems like on our chop backbone, there's no question that, uh, uh, hydrose RRC adds to the induction success. Uh, you have the Nordic trial cross-tri comparison with or without hydro zero C and then the MBC or younger randomized trial. Clearly, again, on our backbone, the hydrozeroC definitely increases your chance of induction success. Now, on a BR backbone, that's less clear. Uh, if you look at the. EA 4181 trial focusing on this third and the second, and uh I mean third and the second arm, which is BRR RRC with a calibrnib and then a color BR. Basically, both arms have a calibrnib BR and then, and the question of whether you need to see high dose ARC because all three arms perform the same, it seems like when you have a color BR. You don't need a hydroseroC on top of that. So on a BR backbone, especially when you have a BT inhibitor, the role of hydrozeroC may be diminishing. Second question is, in the induction. Uh, how much does BTK inhibitor add? In the triangle trial, the CR or the response was assessed with CT scans. So it seems like the addition of ributinib can increase the CR rate. Um, but, uh, if we use a PET scan, we're probably not so sure. And then back to the EA 4181 trial, you look at the BRRRC versus BRRRRC plus a calibrum. Again, they perform the same. So, if you have high dose RRC on a BR backbone, then calabrum as induction probably doesn't add too much. Finally a transplant. Is this, there's still a role of transplant. In the United States here following the 4151, we know that if you're MRD negative, you don't need a transplant. Uh, for the entire trial, for the ones, for the ones who are MRD positive at the end, they, they were given transplant. If they were able to convert to MRD inactivity, they do a little bit better based on the curves on the left side here you can see. But if, but put this into perspective of the entire 41, 81 population, probably less than 5% of patients benefit from transplant considering how many patients achieve MRD negative status. Uh. In the triangle trial in high risk subgroups, the curves seem to separate a little bit, but none of these reached statistical significance. So in a, in a Europe is my understanding that is, you know, while most most folks follow the triangle approach, some providers may still offer transplant in high risk groups, although the evidence is not very strong. And finally, BTK maintenance. We, we, we seem to think, you know, all the benefit in triangle from ibrin was from the maintenance part. And that's why we question whether you need an induction, uh, BTK inhibitor in the front line. Uh, here. You know, there's clear survival benefit. So it's hard to argue that, you know, you don't need a BTK for the maintenance because of the survival benefit. Although it's worth thinking that uh if we use, you know, second-generation BTK inhibitors, the data, would the data be the same? Uh, if we look at the sequential PFS, um, PFS 2 versus concurrent PFS, is that gonna be similar? We, we don't know. But, but as of now, before we have more data, I think the overall survival benefit, again, hard to argue that. So I think BTK maintenance in young and fit patients, uh, seems to be the standard right now. So approach, again, we reviewed the ECOG approach, any kind of induction followed by MRD guided transplant, followed by maintenance or the triangle approach and you decide from the very beginning using a BTK for both induction and maintenance and no transplant. There's sort of a hybrid approach here where you want to do everything you can for the patient, then you can use any kind of induction including BTK containing induction regimen. And then instead of skipping transplant for everybody, you can use MRD guided decision for transplant decision. And then everybody gets maintenance reduction and BTK inhibitor. Now, why do we mention echo approach here? Because if you remember, a color BR performed just the same as BRRRRC or a color BRR RRC in induction in that 4181 trial. So you can use that probably as a, as a, as a good enough induction. And then you follow triangle, no transplant, and a color our maintenance in the end. So, it's kind of a Some folks call it the North American triangle approach or it's just kind of a modified echo approach. So this is, uh, I think reasonable for patients where you don't want a transplant. They're kind of borderline 65, 66, you know, whatever, or you just don't like hydro, uh, based on extrapolation, although the all the trials, I think is reasonable. Now moving on chemo-free induction. Uh, mainly, you know, you can use BTK, BCL-2, sometimes thalidomide, different combinations, and, but, but the BTK BCL-2 CD20 triplet seems to be gaining popularity right now. So, uh, here there are some that approaches BTK based doublet and triplet, you know. Um, the most famous is the Bovine trial, initially tested for TP3 mutated patients, uh, triplet, Xanu obinnituzumab, and Ovinitoclax. Here, with this AAA induction regimen, you see very high response rate and very high CR rate, you know. Um, And then also very um high. Undetectable MRT rate at the end of induction. Uh, the most, uh, most impressive is the progression-free survival and overall survival in this, uh, historically very difficult to treat population. The two-year period is a 72%. Uh, historically, even you use hydrose ARC-based induction and transplant and everything for T3 mutated disease, the progression-free survival is probably 20-30% of the best. So, here with the chemo-free regimen, no transplant, no high-dose RRC you can achieve 72. So, that's a big deal. So, it's endorsed by NCCN and it's used widely. Um, so, at AS, this regimen, uh, used for transplant ineligible patients was presented by, uh, Doctor Kumar. Uh, you can see similarly very high response rate, overall response, um, 98 and 96% CR rate. And then on the right, Sany plot you can see within the uh induction at the end of the MRD negative rates equally very high and the progression overall survival is really, really high. Um. Uh, we can't really argue that, uh, you know, transmitting intelligible patient, uh, is, is a very, very high unmet need. So this, I don't know whether this is gonna be on NCC guide guideline, but nevertheless, you know, proof of concept triplet therapy works really, really well. Now, very similar approaches like this is from, uh, Mass General with AVO approach, a slightly different, uh, treatment schema, but the same concept of triplet. Of, uh, cohort B is high-risk patient defined as either TP23 alteration or transplant ineligible. Uh, here again, you can see very high CR rate and then on the right progression-free survival, overall survival. Again, really, really good. Uh, in this trial, lots of patients were actually T 3 mutated, uh, that qualify them to be high risk. And then you can see the two-yearPF 82%, you know, matching what we saw with Bovin. So this similar triplet, similar efficacy. And this trial also had a transplant ineligible, uh, eligible or TC wild type patients. And here the CRA 100% there's no event with short follow-up. So, again, maybe proof of concept, you know, even in younger patients, uh, typically wild type where you would traditionally consider high dose ARC based injection, um, or MRD guided transplant. Here with chemo-free approach, you're getting very, very good result. So these may be the, the, the, the future treatment that we, we, we ought to test against the current uh chemo approach. Uh, company trial from AstraZeneca AVR, uh, with induction and for MRD negative, they randomized to a calabrinib versus observation. Whereas if they are less than MRD negative CR, they get a calabrinib. So here we're only showing induction part of the results. Um, bottom line, very high, uh, MRD negative CR rate in the intention to treat population, 80% with, whereas in the evaluable patient where they have MRD testing, it's over 90, 90%. A response rate, not surprisingly, really, really high. And then what's encouraging is the induction success is seeing even in high-risk patients, including T3 mutilated patients. Now, with shorter follow-up here, progression, duration of response, progression-free survival, and overall survival. Everything looks very, very promising. So again, you know, BTK BCL-2, CD20 triplet induction looks really promising and uh we really look forward to see future uh triplet versus chemo approach to establish its role. Now, finally, just a few slides on the newest of fancy treatment moved to frontline, which is by Specific and CART. Questions, are we ready there? I mean, these are single-arm studies, uh, not prime time, but, uh, just showing some early data. Uh, Doctor Phillips presented a GLOVE trial, which is the needle class opin and glofumab and lenalidomide induction for, uh, mental cell patients followed by, uh, maintenance. Now, induction, they start with the needle class without any, without any debulking. So, and then straight to the 50 mg, pretty bold uh design. And then obintuzumab, um pre-dose, followed by golfumab, ramp up and then uh induction. Lenonomide was added a little late in, in cycle 3. And then in the maintenance part. The needle class will be continued for 4 cycles to finish 1 year of treatment. And then lenalidomide again, uh uh 6 cycles to finish a little over 1 year of treatment. And then clofumab is every 2 cycles, uh basically every 2 months maintenance for almost 2 years. So, this year, this data we saw at A is for the induction part. If you look at the green part or the, or the green uh stars, you can see the CR rate, MRD negative rate, everything is really high. Uh, just as, as we saw with triplet BTK BCL-2, CD20. So another approach. Uh, the, this is, there are, there are some concerns of toxicity. You know, there, there are 3 patients who died in this small study out of 27 patients. One due to disease during the Veninoclast ramp up. Uh, maybe, so some patients may still need, you know, some debulking like with the BTK BCL-2 approach, uh, where we can make ramp up a little safer. Uh, 2 patients did die of infection. So when you have needle plaques, when you have land, when you have glofinumab, so the infection risk is, is hard to ignore. So 2 patients dying of infection is a big deal here. Uh, PFCOS curve looks flat, but, uh, remember, all three events were due to death, 2 infections, one, due to disease and maybe ramp up of needle plaques. So, efficacy definitely looks promising. Uh, we just need to figure out a way how to use bicycles it's more safer. In terms of CAR T, this is a Windows 3 from MD Anderson, where they use BTK based induction. And then if they achieve a remission, they take them to a CAR right away. By the way, if the, if you put the patient on a color for too long, if they achieve a CR then they wouldn't be eligible for CAR in this trial. Um, here, they, they had to check the response pretty fast, you know. But, uh, after one cycle, median, one cycle, uh, almost every patient achieved a PR and then they take them to CART right away. And the response rate at day 30 is 100%. 95% of patients was in CR with a breast cell. Um, two patients progressed, one at 6 months, one at, uh, one at 12 months. But all other patients are having ongoing CRs. So the efficacy definitely looks, you know, very, very promising. Uh, this is a progression free, so well, like I mentioned, 2 patients progressed off the car and everybody is living. Now, what's the concern with this one? So first of all, they only include high-risk patients. It makes sense that you want to give the toxic therapy only to high-risk patients so that it may be worth it. But the issue here is the grade 3 or higher uh neurotoxicity. Um, Here, 45% of, 45% of the patients had a grade 3 or 4 neurotoxicity in, in the front line, which, which is very concerning, right? And then so many patients got into the ICU for, for different um Uh, reasons. So, just like the glofumab study, you know, efficacy is definitely there. No question about it. And it, it's just how can we make the therapy safer so that it's worth it. Uh, so in summary, the standard of care and frontline treatment has been evolving. Um, but, uh, at the moment, it seems to be complicated for both older, unfit or younger fit patients cause you have so many different options. Whether you use BTK, how to do the maintenance, whether to do transplant and all that. Um, older patient options include BR with or with colorbrib or chemo-free approach with BTK inhibitor. Younger patients, you kinda need to decide your intent for transplant and BTK maintenance upfront, and then you choose your different paths. I think to make all these complex regimens, um, sort of easy again or simple again in the future, we hope, you know, BTK BCR2-based triplet therapy can beat all the chemotherapy approaches. Uh, so that uh just like a CIL it becomes simple again. Um, biosophisticated and CART are promising in moving to frontline, but, uh, we need to figure out, you know, what's the best population to try these high stakes treatment. Right. Right. Thank you. Fantastic talk, doc. Thank you so much for doing that. Um, uh, next I'd like to introduce, uh, for those patients who unfortunately relapsed with mantle cell lymphoma, uh, Doctor Julio Chavez coming all the way from, uh, Florida, uh, Mayo Clinic Jacksonville. He's an associate, uh, consultant. I, I would say associate professor slash lymphoma rock star, uh, former Buffalo trainee as well. Doctor Chavez, thank you, sir. Yeah. Thank you, Matt for the nice introduction. So I was in Buffalo here. I did my training about 20 years ago. So we're kind of like a little, getting old. Um, now, um, um, I'm in charge to talk about, uh, rela refractory mantle cell lymphoma, and it's kind of like a challenging always talking of after Yuchai won. So he always bring all the frontline. Options to patients and what is left is kind of like uh the next step. So I'm gonna skip this because I know Doctor Wang went through this, but you know, in mental cell lymphoma is a heterogeneous disease and there are, there are several alterations that leads to uh poor prognosis, you know, epigenetic alterations, complex genetics, TP15 mutations. Um, uh, those are kind of like, uh, in the molecular level in real practice, you know, I kind of, and I'm sure many of us do this, we look at clinical factors like BP score, some molecular sites like a TP53 mutation, KR67, and morphological findings that leads to prognosis. When you put all together, you know, you have, uh, if patients had, um, all these factors, the survival is very poor. So it's important to, uh, like as Doctor Maya mentioned in the in the lecture before, to kind of personalize treatment depending of, of the risk of patients. So, now that we have we have 3 randomized studies that shows that kind of BDK inhibitors are becoming more and more part of the frontline setting, you know, some may still use uh in standard chemotherapy followed by transplant, which is not wrong. However, uh we will see more in the clinic. So I've seen at least personally in the in the in the community, more community doctors are integrating PTK inhibitors into the frontline uh setting. Even though that it's not definitive word but it has to has to be the the case but it's, it's happening and most likely in the relapse relapse setting in mental cell lymphoma, we'll see patients already exposed to cobalt MBTK inhibitors. So that's what I call rela refractory mental lymphoma for those who speak Spanish. Dorispaco, I know he's, he's there. And Matthew, Matthew also speaks Spanish. So abalo loque Sobra Los Prisonerros was a very good group, uh, uh, very good group, rock group from, uh, Chile, uh, in the 80s, you know, I like the Jeremy Abramson broke the 80s. It was very vibrant. A lot of music. So they were uh making songs against the dictatorship in Chile that lasted until the early 90s and they call this song El Valle de lojesoran, the dance of tho of those left behind. So reflecting the lack of opportunities, discrimination, lack of access to good education, etc. So that's what happened with rela refraremental cell lymphoma. If we put everything in the front line, if we can put chemotherapy, we can put BCL2 BTK inhibitor, even by specifics and even CAR T what is left. So as a doctors we have to make sure how are we going to uh play with what is left for patients and treat and see if we can get them into long term remission. So, I just go for a few cases I've been seeing over the years and, and how I personally manage. I'm not gonna go kind of read the whole slide, but essentially this is a patient 68 years old that had been amassing 6 cycles without maintenance, you know, is whether you say it was wrong or right, but you know, who knows. But you know, a relapse, he had a good remission, 6 years and then kind of relapse. And these were the treatment options at that time, you know, we can talk about Kovalin, non-covalentBDK, Benetolas cartel. So I, I, I picked uh BTK inhibitors because it works very well. Especially in a patient that has kind of like a low risk indolent disease with no um high risk molecular factors. And And that's proven by in clinical trials. This is kind of like uh obviously no longer we have available in the lab refractory setting, but we have two that has already long term follow up. So we had a uh a reasonable progression free survival. Whether you do Acala or or or sandurutinib, both are equally effective, and you can pick your, your preferred option. In, in the simpatico trial that compare, you know, ibrutini Benedoto lax versus ibrutinib in relax refractor at least one line therapy, it showed that significant improvement in progression of free survival but no overall survival benefit. However, who benefit from this, the high risk patients, you know, high risk patients, as Doctor Wang mentioned, looks like they benefit more from adding. Uh, uh, other agents, targeted agents in the frontline setting. It's like you, you, you, you receive ibrutrino cracks, you have a better overall survival than if you did placebo and ibrutinium. That highlights something else, you know, that probably patients with high risk factors may, may not benefit or may have a short duration of response with uh BDK inhibitors in the lab setting. Most recently, uh, this study was actually presented at at A, but and also just recently published the summa to the cohort 3. So was Brexucatagen Alu cell for patients with BDK naive relapse refractory mental cell lymphoma. It's a, it's a good size, uh, uh, study, 86 patients. Uh, good proportion of patients had P50 mutation and also, uh, a high K 67. And they saw actually a very good response. The PFS was not reached. However, there's a cost, you know, a cost of toxicities. They saw ICAS 21%, you know, uh, grade 3, 20, when I talk about grade three, ICAs of neurotoxicity grade it means that patients stay in the hospital for at least 22 weeks or 3 weeks, require physical therapy, probably is going to rehab, probably has side effects from the steroids and infections, and there were, as I mentioned, grade 5 infections, 5 patients, 5% of patients die. So, keep in mind what is is a is a very good therapy that is available, however, there is a cost of not only toxicity, potential toxicities and also utilization of resources, you know, hospitalization, medications to mitigate toxicities. Uh, this is another case. In this case, 65 years old, you know, patient was treated with BR cytarabine, is a regimen that is, is reasonable, well tolerated at that age. The patient declined autologous transplant, then the patient had relapsed within 6 months of initial treatment. So it's kind of an early relapse patient. In this, in this case, uh, you know, we, we have these options Cal MBTK, non-coval MBTK, cortisol therapy, or BTK, Benetoclax, and another option. So, so I, I picked cortisol therapy. And just to kind of mention the importance of the timing of relapse in mental cell lymphoma is important in several types of subtype of lymphomas and is also in the in mental cell. So patients who had a what we call the POD 24, relapse within 24 months, they associated with several factors including elevated LD LDH, older age, high care 67, high tumor burden in general. So, um, in regards of outcomes of patients in the lab setting, mental cell lymphoma with BTK inhibitors, doesn't seem to be that good in the, in, in patients with high risk factors like you have blast morphology, P53 mutation, high KI-67, and then you combine, you have early relapse and P53 mutation, essentially patients don't respond. And we see those cases actually in, in, in the clinic. So is BTK the right approach for those patients who had high risk features at relapse. Uh, this is very interesting, uh, study, uh, by Doctor Villa. Uh, it was, uh, published a few years ago that they actually they developed like type of like a normalmogram looking at factors that are such as KSD7, MP. And also, uh, the, the, the timing of relapse and the timing relapse had the highest uh hazard ratio of death and also the highest probability of no response to BDK inhibitors. So there were there were three groups of patients, those patients had a low risk, low. Group patients that have no, no points, the intermediate group that may benefit from BTK inhibitors, and then the, the red one that have no benefit or very limited benefit from BTK inhibitors. It doesn't mean that we shouldn't use it, so on those patients, what I do is I kind of trying to transition to a BTK inhibitors a bridge to CART if possible, in that case it's very effective. Uh, in the Sumatu had data for, uh, uh, Braxo, sorry, I apologize, it's no rexus for large fragmental cell lymphoma, but that shows that, you know, patients benefit regardless of the mutation of the status of KST 7 values. However, it's not clear if this uh that replicates in the real world setting. This is uh uh data from Doctor Wang. That published the uh kind of large number of patients with a large fragmental cell lymphoma that received Brexo cell. Uh, there, there was a a trend of patients who still had PVC aberrations or that couldn't benefit. However, the POD 24 may still have a benefit, but not, not as much. But they still, I, in terms of you see, you see the, the, the me and PFS, it seems superior to BDK inhibitors. Third patient, in this case, same patient, you know, had the VR, then, uh, we put them on a calabbrutinib and then, uh, progress within a year of treatment and then the, the options obviously we don't have a covalent anymore, but we have non-covalent cartio Benetoclax. In this case, again, I prefer Carti cell therapy and I'll tell you why. So, unfortunately outcomes post post uh beca inhibitors are poor, so treatment options are needed. Um, Peter Rude has a very good activity in this in in the last refractory patients, particularly on those patients who had um a prior, um. Uh, on BDK uh Kent BDK naive but has activity also in patients who had, uh, had been exposed to. And it lasts us the, the, uh, longer follow up data was presented and again this confirms the the fact that best benefit from Pertoglutin was of those patients who were BDK cover and BDK naive as opposed of prior BTK still works, but the, the production survival is about 5 months and the over survival is about 23 months or so. And again, once again confirming that the high risk patients subgroups uh has a little hard time with uh a non-covalt MBTK inhibitors. So, lower, lower PFS and OS if you have P50 mutation or high uh high high values of KR 67. Um, going back to Brexit cell that is, this is, this is a kind of like an older data, higher response rate with, um, uh, Brexit captaging in this patient population, you know, and in the summa 2, keep in mind it was specifically for patients who were BTK refractory or most patients actually were BTK refractory, but they all had prior BTK. And we'll see the, the, the media, the media PFS 25 months with a progression is about almost 50 months on this patient population that's confirmed with the kind of like a long term follow up, almost 5 years when you put the summa 2 and summa summa 18, which assumma 18 was the expanded access, uh, protocol. Transcend is another um in C19 card cell therapy, lysoce for BTK refractory. Almost all of them had prior exposure to BTK had a very good data, uh, however, and, and as I mentioned in the, in the discussion, the LBCL, uh, what stands out for lysoce is the toxicities. So grade 3, only 9% as opposed of, of Brexit that is close to 30%. It's particularly the, the neurotoxicity is the main problem. With Gardasil therapies. Well, third case, the same case, well, let's say, um, you know, patient had, you know, BR, then Acala now had progression with Carti cell therapy and Pertaruri. Now we, we're left out to maybe Beneto clocks or novel approaches, and my personal, um, uh, my personal approach is, is considered novel approaches and see what we have so far, and again this is a dancehall of what is left behind. Unfortunately, um, fortunately, you know, Brexit is being studied real life large databases including the one that was presented at Wong, the DSCRT and the CIBMTR. Very good outcomes, but also with high rates of of of ICANN's 30% grade 3 in the CIBMTR and in DCRT 15% uh ICANNs. However, prognosis is poor on patients who progress of the CART. The survival is about not even 6 months. Whether you do in, in, uh, in our in our US multicenter study and also the SCAR team, uh, publish their data, poor survival for those patients. So what is next? Soglofitumab, as I mentioned, was a stu uh is, is, is, is, is being originally studied actually and published in rela refractory mental cell lymphoma. One of the things is that happens with, with, with bi-specific antibodies is the toxicities. You can see higher rates of CRS, higher rates of, um, of neurotoxicity as well. However, that can mitigated by the doses of, of, of venotuzumab. It appears the higher the dose of venotuzumab prior to the specific antibody kind of improve, uh, outcomes in that regard. But it's effective therapy and we use it, uh, commonly. And you see responses regardless of of the risk factors whether you P53 or blast morphology or K6C7. Obviously the patients have less uh risk factors, they have better responses. Uh, another kind of recently published, um, study, uh, Mozumpola, uh, was just published, I think like a few days ago, uh, 42 patients, they actually had all patients were, uh, BTK, uh, naive, and the standard dosing of zum mozunatuszumab polotuzumab, in this case is a subcutaneous, uh, mosun, not the IV, um. That show high response rate regardless of, you know, whether the patient had prior CART or high KS6C7 or more or PVCT mutated and what they stand out actually from the most important is the toxicities, you know, they were grade 3 CRS about 43%, and then they didn't see any grade 3, we didn't see any grade 3, icons in this study, so it's a promising, uh, approach, uh, most important, the two options in patients who had progressed to. Uh, BTK inhibitors, whether it's non-covalent or covalent and CI cell therapy, that's my, that's my approach on those patients. So, uh, again, you know, the, uh, Doctor Wang mentioned the bipo study that you put all together Obino, prednisone, ibrutinib, len Benetoclax, all, all, all together and has an efficacy even if patients have been exposed to prior BTK inhibitor. I haven't used honestly this regimen a lot, but, uh, the data presented by the NIH shows a reason and it's a time limited actually regimen. So some, some shows a reasonable response rate, a reasonable um toxicity, so this is something that you could do in patients who you don't have availability of by specific antibodies, for instance. Just to kind of like a summarize, um, er, this is a table to summarize all the, um, uh, treatment options that we, we discussed and why I prefer, um, particularly on the, on the patients who are BTK exposed, why I prefer CAR T on those, on those patients as opposed of, of non-covalent BTK is kind of the duration of responses and, and, and the progress of resurvival that we see. obviously there is no, you know, head to head comparisons, but it's important to kind of at least look at the phase two data together and. Make the decision And, and more, more recently, actually there's been like what we call the BTK degraders, uh, here I'm just not gonna talk about more about, um, uh, about the mechanism, but basically using different targets, targeting one of the molecule called the serum that kind of activates the predispose the BTK to be degraded by the proteasome and there are several uh BTK the greatest investigator in an investigation. And one is the uh the BDK, the BGB 16673. I think it has a name already, right? You can try, um, but it shows interesting activity, particularly mental cell lymphoma and also low grade lymphomas. So that's being a studied and, and soon we have more like a longer follow up data, but it's coming. Another one is the some rotoplax is a novel BTK, uh, uh, oops sorry, no no novel BCL-2 inhibitor in the last refraimental lymphoma that was presented in AAS. Um, Uh, uh, important patient population of prior CAR T, prior transplant, 100% patients were exposed to, uh, BTK inhibitor. Most patients were refractory, and they, they saw a response a reason as a single agent, so rotoclax BCL-2, so they, they saw a response rate of 50% to 16% or 15.5% of, uh, CRs, um, in. Whether that's different than Benetoclax, you know, we use also Benetoclas as single agent mental cell lymphoma, but it's a different patient population, you know, in Beneto class didn't have, or actually didn't have any or very few patients had prior exposure to to BTK. This patient had prior exposure to BTK. So that's what it's interesting to see single agent data that can be combined and actually was combined already in. The IA was presented last, um, last year, uh, in Madrid. The combination of of Soro and San Brutin BTK and BCL2 high response rate, duration of response is important. So still, um, this was kind of like a more like a second line, um, kind of simpatico kind of uh uh regimen. It was important, uh, efficacy and probably will have, will know more in the future, and there is actually a randomized clinical trial comparing this approach with versus uh sanorutiny alone. Um, other options for, um, car cell therapy delivery, this is the centralized C19 CRT Atlanta one presented at Ash as well. So the idea of this is doing manufacturing in the site, and with a kind of close, close, closed system that allows uh shorter manufacturing time that on average was 7 days to main time, and they presented mantle cell lymphoma. high response rates almost 100% on all, all patients, the PFS 83% and 9 months, very short, um, follow up, but what's interesting is the rates of, of CRS grade 3 and ICAS, 4% IA grade 3 and no grade 3 CRS. So very manageable on patients who were, uh, you know, they, they, um. We tested for MR were tested for MRD 90% MRD negative disease. So how is it gonna go in the future, apparently we, we don't know, but it's interesting that they have a different kind of way of manufacturing CARD cells. Another product actually that we we're working also at the Mayo Clinic is the buff, um, buff R. Buff is a, is a, um, surface receptor that is specifically for, uh, B cells, and in this case is a humanized buff, um, with a 41B stimulatory agent for patients with different type of C-19. Um, uh, B cell lymphoma and, and also on patients who had prior, uh, card cell therapy or those who had C-19 negative, uh, relapse disease, and, uh, it's it it was a very preliminary data, but what caught my eye was the efficacy in the, in the four patients with mental cell lymphoma, they all responded, and they all had prior prior CART. So interesting, I mean, I know it's still early, but it looks like, uh, the more patients we see, we'll see more, more activities, and also, uh, the, the toxicities, you know, toxicities, low grade mostly, you know, no grade 3 icons, no grade 3 CRS. So that's an important, uh, another, another potential option for patients with the relapse refracturemental cell lymphoma. So, uh, this is my last slide. So that's what I do, um, uh, for patients of rela refractory mental lymphoma in, in 26. So it depends what Doctor Wang did at the beginning. So I had to look what he did to the patient. I had to figure out what we can do first after. So, um, uh, I, I recommend all patients to go for CART evaluation, you know, you never know, you have a patient who, especially those who had high risk. You know, early relapse, blast morphology, you know, I kind of, my bias is to do CART with a bridge to BTK, but if they, if, if they don't have those risk factors, probably the patient will, will, will do well. Um, with a non-covalent BTK or even a column BTK, it was not exposed or those who were the BTK exposed, my, my, my, my bias is CT, CT first, and then pages don't respond, the progression, then maybe no a Perto. Sometimes I, I do Perto breach and those pages have like a highly pro uh they're like bulky disease trying to kind of cool them down while they're waiting for a manufacturing, so it's not an option. It's that's an option in the third line setting again, it depends on what you did at the beginning. If patients had no prior CRT in the second line, so CART obviously the next step, but the patient had prior CAR T and prior noncoval MBDK. So I prefer a novel approaches over the clinical trials available, but by specifics look look, the data looks very good. So my, my choice is Mozumpola. But other options like Ln or Len Benetolax rituximab, I don't see a lot of activity as oppose as, uh, by specific antibodies will be the option. And finally, the gradients are coming more. Uh, into the play, I may, we may see actually trials in combination or an earlier lines as well. Fantastic talks for mantle cell lymphoma. So now it's time for follicular lymphoma, the most common slow growing lymphoma. If you don't like lymphoma, today is not your day. I just have to say, but, uh, it's my pleasure to introduce, um, Doctor Paula Gioni, our former colleague here at Roswell Park in Buffalo. Uh, welcome back. Um, so she's coming from Sloan Kettering Hospital, um, where she's, uh, assistant attending of lymphoma and a lymphoma expert. She's gonna talk about, uh, practice changes in the front line for follicular lymphoma. Doctor Gioni. Thank you so much. Thanks a lot for the nice introduction. It's so nice to be back in Buffalo. Um, so, um, As you may have seen at Ash and and the presentations from last year, um, there's been a, a proliferation of novel frontline options for follicular lymphoma and especially those, um, including by specifics of, of which I'm gonna focus a little bit more today. Um, and, but I was gonna start with a little bit of a provocative set of slides. Is new always equal better, um, and this is, um. What I wanted to show you guys is everybody, you know, uh, whatever we give to frontline follicular lymphoma usually works. It has a good, uh, complete remission even if you use, uh, chemotherapy-based treatments. Uh, uh, the CR rate is around 7. 76%, uh, progression-free survival at 1 year is 90% and 73% at 3 years. Uh, these are data from the Gallium study, um, which, um, which has, uh, a follow up of more than 15 years right now, um, and so there's a very high bar for novel agents to, uh, come into the front line therapy. Um, and then there's this other, um, nice, uh, paper that came out just in February, uh, that, um, is the update, uh, the update results of the SWA 0016 trial, uh, which compared RCHHP versus RCHOP radioimmunotherapy, uh, with no maintenance, and you can see that the, um. I wish I had a nice pointer, but on the, on the curve up to the far left, uh, the incidence of relapse after our CHP, um, chemotherapy is, is much higher in, um, between 0 to 5 years, and then it gets basically down to 0.6% between 15 to 20 years where. They actually mortality from other causes starts ramping up for these patients. So, um, these authors did a nice cure modeling estimating the proportion of patients that are cured from the disease, and you can see that the overall cure rate is around 42%, um, with higher cure rate around 47, almost 50% in the low or intermediate risk follicular lymphomas. Uh, but obviously chemotherapy comes with a lot of safety considerations, right? Like we all know that especially the BR combinations have, um, uh, high incidence of infections, and here you can see a table where the infections that required admissions are listed and within 9 months of treatment initiation for BR, so, you know, while you're still getting treatment. Uh, the, the incidence rate of admissions for infection is around 22%. Um, it's a little lower for our CHOPRCVP. That's why I kinda, that's my favorite chemotherapy to go, um, but within 3 years of treatment initiation, um, this, the rate is still pretty high, you know, 38% for BR and 32% for our CHOR CEP. Um, and then another very important thing to consider is the rate of, um, secondary malignancies, you know, the chemotherapy-based, uh, regimens, um, that are in the first two lines of the table are the ones that have a higher, a longer follow-up, right? 15 years of follow-up, um, and the rate of AML and MDS is around 2.6% for the RHCHP and. Uh, 3.7% for RHO plus maintenance, um, and these are the secondary malignancies we know are probably related to the treatment. The other ones can be, you know, prostate cancer, any other cancer, uh, but they are still quite high, 22% and 13% respectively. So we love, uh, you know, the chemo-free options because we think that usually these are a little bit easier to give and they may have less, um, long term side effects although we don't have that long term follow up that we have for chemotherapy, right? So these are the trials that are ongoing without by specifics. I didn't wanna leave them behind, so they're in this, in this slides you can see that. You know, ibrutinib, uh, obinuttuzumab, and the combinations with Zanuacala, um, do reach pretty good overall response rates and CR rates, um, and, um, pretty good progression-free survival of 80% at one year and 79% at two years. Um, so, before we jump into the Ash, uh, results, these are the trials that are ongoing, uh, in frontline for the Phay trials that compare, um, basically by specific combinations, uh, with chemo immunotherapy, and you can see that the first two lines are, um, trials that basically are R2+, um, or, uh, lenalidomide plus uh by specific antibody. And the other trials are, uh, basically the, um, single agent by specific or by specific plus chemo, um, and the soundtrack is the only one that uses a CD19 by specific, uh, versus um. Most of the, uh, most of the control are, uh, are chemotherapy, uh, with or without maintenance. But you can see that all these, um, All these experimental arms have a pretty long uh treatment duration. You can see that the, for example, the morning light has a 30 months treatment. Uh, the odor next toma kind of similar thing. It does odor maintenance, um, so are those the real schedule we want to bring in the first line for follicular lymphoma. Oops. So let's move on to and what we saw at Ash and maybe some, some were presented a little bit earlier at Lugano. These are all combinations of um either by specifics uh with rituximab or single agents or by specifics with R square or um or zanabrutinib, um, and you can see that most of these clinical, most of these trials, um, included high flippy score and bulky disease, um, and Personally, what I've been trying to do with these trials is, is really enroll patients that would, I would otherwise have given chemotherapy cause, um, otherwise I don't, I don't see really the, uh, the point of enrolling a patient in a clinical trial if it doesn't, if otherwise I wouldn't have given, you know, the standard of care chemotherapy. And so regarding efficacy you can see that this is stunning for most combinations and single agent uh versus you know single agent with a tiny bit of rituximab. I'm gonna go a little bit more in the details of the ones that were recently presented, but you know overall response rates are around 90%, even more than 90% for most of them. Um, the complete metabolic response rate is slightly less but still stunning. Um, the, I would say the only, the only result that is a little bit out of the chorus here is the morning sun study, but this might just reflect the fact that this study was done mainly in non in academic centers. And so the first thing that we noticed about all these frontline trials is that the rate of infection is still very significant, you know, um, you saw the percentages with the chemotherapy, and these are patients that got at least 8 months of treatment and the, the grade 3 infections are pretty significant. We also have to say that some of these trials were run during the COVID era. Uh, so that was a specific particular time, uh, but you can see that the non-related mortality is also, um, significantly high, and that's something that we would need to work on in the future for sure. So let's start with kind of the studies I like more, uh, so the single agent by specific or or just rituximab by specifics. Um, so you can see that, um, the, uh, our EPCO study is the one that was recently presented but there's also Bic one. Uh, with Moon single agent and the morning sun study, um, so the, the MT one showed is a very good progression-free survival now at 30 months, uh, the, um, Our EPCO study was very interesting because it used rituximab really just to lower the rates of CRS and you can see that the results, the response rates are, uh, great as uh, as shown before. The basically everyone responded, right, to our EPO. There was one patient who did not respond. And he had a progression of disease um with uh with a biopsy that showed transformed disease so probably this was already transformed um at baseline um and then among 4 patients that had PR basically 3 converted to a complete metabolic CR um and no, no patients have relapsed yet. And then 4 patients discontinued for adverse events and 1 patient and 1 for patient uh preference. And you can see that the more, the, the adverse events are mostly hematologic toxicity and um infections. So this is what we have been talking about before. Um, the CRS seems to be more important when you actually reach the full dose of the echoriamab, but it seems to be all grade 1 or 2, so nothing that's not manageable, um, really mostly outpatient. And the infections are distributed through the treatment stages. There's no, there's no real, um, you know, um, there's no real time where the infections are more or less, especially the grade 3 infections, the severe infections. And infections were present in 60% of the patients. Um, and then this is another thing we really pay attention to the the immunoglobulins level, the IgG levels, um, there was, uh, there was always a pretty good level of IgG in all the patients, uh, but we now know that the, the level of IgG doesn't really, um, doesn't really mean the patient will not, uh, develop infections. Sometimes we give IgG even if the levels are decent. Um, and then let's switch on to the lenalidomide-based combinations, um. There was, uh, the, there were 3 studies, um, analyzing these combinations the EPCOR LEN, um, the EPCO R2, and the EPCO BR. Um, you can see that the overall response rate and the CRA are kind of similar to the other studies actually. Um, you know, the overall response rate for Ecole was 100% CR rate, 96%, which is fantastic, but then we here we, um, we start to see rashes that we didn't see with the single agent by specifics, and that's probably related to the lenalidomide, um, and some hematologic toxicity and infections as before. Um, in the EPOR2, um, there were two arms. AM 6 was the frontline follicular lymphoma, um, EPOR2 combination, and the arm 7 was actually maintenance after whatever you got in the front line. Um, and you can hear the, the results and the toxicities again great response rates, great PFS so far, um, but quite a lot of neutropenia, um, I have to say this patient, these, uh, studies were particularly heavy on COVID-19 patients, uh, so maybe in the non-COVID era things would look better but still, you know, it sounds like a pretty heavy treatment. And not to mention EPCOBR, uh, which was kinda, uh, the, uh, combination with the more, um, with the higher incidence of adverse events and, uh, again done heavily. Uh, influenced by the COVID era, uh, but, uh, basically every patient had an adverse event and great more than 3 in 92%. Um So the combinations instead with other drugs than lenalidomide um are in my opinion, maybe even more interesting but we still, you know, have to look at that in detail and they're still kind of early on. The Mozun pola is ongoing, um, and unfortunately the Mozuntas was closed because of the Tazametta that was um um removed from the market for the for the secondary malignancies in the chemotherapytas, uh, study. So, um, what remains and and has been. Uh, presented at, at the last, uh, Ash meeting is the MITI 2, study that is, uh, evaluating Mozun together with Seanu. So Mozun was given for a full year and, uh, uh, sorry, Bozun was given for 8 to 17 cycles depending on the response rate. So if you had a CR, you would only do 8, cycles of boson, and if you, if you actually achieved a partial remission. Um, you would, you would add, uh, some more cycles and get to 17 cycles, and there was 1 year of xanobrutinib together with all that. And the rationale for adding xanubrutinib, besides adding, you know, activity to the bi-specific, which is kind of questionable, is that maybe Xanu, um, could mitigate the, the T cell exhaustion and so kind of stimulate the T cells to go after to, to work together with the bi-specific again, um, and, um, and increase the muscle mediated tumor killing. Um, kind of similar profile to. Before, uh, here again we, we see some more rashes, um, I'm not sure because the with the, with the zanobrini they're not really, uh, documented so much, but with the combination probably there are a little, a little bit more rashes and then the, the number of infection is, um, significant and, uh, although they were all grade 1, most, mostly were grade 12, uh, there were a couple of infections that were grade 3 and then. The LFT elevation, which is something a little bit newer. And here the CRS was really predictable and we'll see um in the first uh infusion and mostly grade 12 we did not see any icons with these patients. So the other big question of bringing by specific in the front line is what's the impact on subsequent treatment. Uh, so first of all, the CD20 laws, you know, we know that it's a little more, it sounds to be a little bit more than what happens with the, uh, with the CAR T cells. So depending on the studies we have percentages of, uh, CD20 loss around 30 to 50%. Um, so are the subsequent immunotherapy gonna be still effective? What are, what are we gonna choose after a bi-specific antibody if the patient doesn't have that marker anymore? Um, and what is gonna be the safety profile of relapse refractory treatments when the T cells are exhausted and how can we prevent this, right. Um, So I think that all this um excitement around the device specifics and their and their role in the front line is absolutely justified by the great results but it's still but we still need to um focus on what's important for the patients with follicular lymphoma meaning the quality of life and um you know the duration of treatment which will be very important. So in conclusion, um, this, this novel by specific combination might have similar efficacy and PFS curves related to our chemo, so they really might, um, challenge the, the frontline treatment for follicular lymphoma. Um, the key immediate side effects that we are seeing with by specific antibodies is not really the CRS, but. But for the infections that seems to be um still important and then um. The phase two trials are still ongoing so we'll see if really there's a there's a big benefit there, um, but it's important to figure out while these trials are ongoing if that's really the tools are really the schedules we wanna use for these patients or if you wanna maybe just abbreviate the treatments a little bit more the intensify maybe using MRD or other type of um you know, uh, monitoring or schemas. And thank you all for your attention. This is just to remind you that today is April 25th, and it's Italian Liberation Day from Nazi fascism, and this is a photo of me, uh, in that day, um, celebrating Italy. Thank you so much, Doctor Gioni. It's wonderful to see that image. I'm an Italian American myself, only a quarter of Cortese, but. It's a great day. Uh, the next speaker, um, needs no introduction. He's, uh, literally the face of the meeting. I'm just kind of the co-face, I think. Uh, so Doctor Francisco Her Hernandez Eliza Laturi is a professor of medicine and, uh, lymphoma, uh. Yeah, here he is. We need to cut down the title. Thank you. Thanks for the introduction and, and I'm sorry I jump in too soon, so, but, um, but you know, thank you. So, well, um, we're gonna talk a little bit about what to do with patients who they have relapsed refractory follicular lymphoma, um, and again this is certainly a very interesting topic because whatever you say is a right and you are never wrong, which is great. So these are my disclosures, um. Just briefly again, follicular lymphoma is certainly the 2nd most common type of, uh, B cell lymphoma that we deal in our common practice and something that we know from ages is that subsequent lines of therapy, they work but they don't work as good as the first one, so we do know that, you know. Um, what sets the tone of what's gonna happen to the patient is really how long your remission lasts the first time around when you actually require treatment. So we always know that what they have been tons of models to try to prevent outcomes, um, incorporating clinical parameters plus minus molecular studies. I think to me the practical thing is that every remission, if your remission lasts less. Than 2 years you are in bad shape, especially if you are in the younger spectrum in your 60s plus, uh, everyone else you're gonna do well and unless the doctor gives you a very toxic treatment you should be OK. So and I think that's one of the challenge, uh, in why do we consider, uh, you know, when we select treatments for patients with relapsed refractor follicular lymphoma. The landscape is changing so much, not only in the relapse setting but in the first line setting, and the changes that happen in the first line setting, they are going to reflect what we do next for those patients. So it is very important that every time that we see a patient that has relapsed follicular lymphoma, especially those one that progress very quickly or that the clinical presentation does not make too much sense, is to re-biopsy these patients, ideally with a PET directed biopsy. Because in a lot in a, it's a significant number of patients you will find transformation. I would say half of the patients who they are POD 24 at the institute, when you revise them, you end up finding a follicular lymphoma grade 3B in in those patients, and they will be moving to a different treatment algorithm. I think it's also very important that we look at the prior treatments that the patient has received for their cancer or other cancers because sometimes patients that have had prostate cancer, they have radiation, etc. we had to look at the comorbid conditions, the organ function, the life expectancy, the social support, you know, because there are all very important parameters that we have to put together to come up with the magical choice for the patient, you know. Because again I think in relapsed follicular lymphoma, we do have many options, um, and I think this is like a little card that I kind of create that I had to re-edit, uh, because certainly new treatments that I didn't put here are coming up like the role of the drug conjugators in relapsed follicular lymphoma. As well as there are drugs that are coming out like taemetostat that unfortunately lost their um the FDA level and the company decided to pull it out of the market, so it's no longer available for patients with follicular lymphoma. So certainly this is a very, very old story that was looking at evaluating Rituxan versus Rituxan and lenalidomide. It's a very important story to remember because a lot of the changes that they are coming now in the second line and eventually the first line setting are building by incorporating by specific antibodies into R square. So this is an original old trial looking at relapse refractory follicular lymphomas. That basically uh randomized patients to lenalidomide and Rituxan versus Rituxan and placebo, and again, uh, they had to have more than one prior line of therapy, um, and again, it's very important these patients should have had Rituxan refractory disease, you know. Again, the story showed that the combination of Rituxan and nalidomide was better than Rituxan alone, uh, in terms of progression for survival and overall survival. Um, I think this is one of the reasons that we have been using RSquare as a platform to compare to other new regimens, um, and again I think we had also become more familiar to using RSquare in patients so they have more resistant or aggressive forms of lymphoma that when this original trial was conducted. Um, again, at the beginning, we were kind of not based, we're skeptical about this R square in patients with bulky disease, etc. Um, and this is just looking at the response rate. Again, that certainly was better, so. And, and again, so as I said before, uh, new clinical trials has been built up in adding a third immuno immunotherapy agent to RSquare. So the first one is basically adding tafacitumab to RSquare. This is the in-m story that was a randomized clinical trial that was looking at patients with relapse refractory follicular lymphoma. They have been over the age of 18 and again they had to have more than one prior line of therapy including an anti-C20 antibody and again they were not supposed to have prior R square um and again patients were randomized to either tafacitumab and R2 or placebo and R square. This actually was a double blind, uh, clinical trial and uh we're part of the study, the study of the institute. Again, the primary endpoint basically was progression for survival, but there was other secondary endpoints which are quite typical for this kind of uh trial designs. Um, this is kind of the patient distribution again, the study enrolled close to 548 patients, and again, patients were randomized to both studies and again when we look at the clinical characteristics, we can see that the treatments were well balanced. Again, the median age of these patients was around 64 years of age. It is very important when we look at the FLIPP score, which is the tumor burden. You know, we look at it, you know, the FLIPI score was like 3 to 5 in half of the patients, which again, when you look at the R square document trial, patients with a high FLIP score was actually much lower, you know, and again, uh, it did include follicular lymphoma grade 1, grade 2, or grade 3A, and again, um, when we look at the number of patients with POD 24, it was around 30% in both groups, you know. Again, most of these patients, they have prior bendamustine or accolatein treatments, prior Rituxan, some of them are CHOP. This was certainly not in the car therapy era, you know, or. Now when we look at the response rate, uh, in this particular trial, and again this has been presented at the ASH meeting published recently this year, and again we can certainly look at the response rate was certainly better in, uh, the deficit to map R2, you know, when we got the PET negative there was at least like a 10% improvement in response compared to, um, R2 alone, you know. Now, uh, when we look at the progression for survival, you can see that there was clearly, uh, an improvement of by adding tafacitum up to our square, and again, um, this is one of the reasons that the combination now is, is approved, you know, to be used in the relapse, uh, setting, um. This is looking at the benefit was really observed, you know, the duration of response was positive, um, as you can see as well, um, and again, the benefit of the combination was seen regardless of any baseline characteristics of the patient, so POD 24 or not, whether you have prior antracycline therapy or not, etc. Uh, when we look at the overall survival, of course it's too early to kind of see that there's no difference in overall survival, so that's one thing. Um, another thing that we, that this study was looking at was the loss of CE-19, especially because in this kind of setting some patients may move to CE-19, car therapy directed treatments, and again in general, um, uh, negativity was kind of rare to see in this kind of patients, so. So in terms of toxicity, really adding tafacitumab to R square, there was no significant changes in terms of side effects, um, so that's something that is kind of encouraging as we're gonna be reviewing what happened when you add a a specific antibody. Um, not surprisingly, this story was done during the COVID, um, lockdown, and of course there were some more COVID infections in the patients that received the triple therapy versus the dual therapy, but in general there was no major like signal in terms of safety, um. Now, certainly parallel to this clinical trial, there was another clinical trial that again was recently presented at the meeting and recently was published as well, uh, this a couple of months ago, and it was the EO uh follicle lymphoma one trial. It was looking at combining Ecorrithumab and R2, you know, with the rationale that by adding a third immunological agent you may be able to have a better response than just R2. Similar eligibility criteria, there were patients with relapsed refractory follicular lymphoma, priorlyin aging therapy, prior anti-C20 based therapy, no R2 exposure, and again, patients, they needed to fit criteria for retreatment, you know, and again, um, patients were randomized to R2 as a standard doses of equareumab and R2. The EPO again, it was given as a step of dosing, you know, uh, in the first cycle and then cycle um 2 to 3, they were every week and then after that, it was every 4 weeks, so. Again, the primary endpoint was again response rate, progression for survival, and the second the endpoints were overall survival. So this is kind of just to kind of highlight just the step of dosing, you know, just to mitigate CRS in the first cycle and again, um, recently there have been safety data that we can dose this, uh, by specific antibody in the outpatient setting, so certainly that will, uh, decrease the, uh, resources utilizations in the healthcare industry and hopefully it will be allowed to implement this in the community setting as well. Um, these are just the distribution of the patient demographics. I know a busy slides, but pretty much it's just the median age of these patients was 60. Again, it is very important to highlight that both studies, the DA R square and the R square, we are looking at a younger average patient age. Again, uh, remember the median age of patients with follicular lymphoma at diagnosis is around like 68 to 70, so, um. Um, it's very important to kind of notice that again, flip it 3 to 5, again was seen around like 30% of the patients, kind of similar to the DARSquare trial, and again, um. When we look at um the POD 24 in this particular trial, it was pretty much the same. So. Now when we look at the uh response rate, you know, we can see that basically the um patients that they were randomized to EPCO R square they tend to have a better response rate when we look at there was um less risk of progression, you know, um. The CRA was around 83% for patients that were randomized to EPCO R2 versus 50% to R2 alone, um, and again, uh, when we look at the progression of survival, clearly you can see a big split in the curves. Um, when we look at the overall survival, we do see also a difference and again the same thing about the direction of the response in the manuscript there's also a positive curve looking at the time to next treatment. So patients who were randomized to FR square, uh, they have certainly an improving outcomes, um, you know, in the, in, in pretty much from PFS duration response to OS, um. Now when we look at adverse events, and this is very important to be aware of it, yes, ecorithumab is certainly a more powerful partner to add to our square, but we have to also be concerned that this comes to an increased toxicity, primarily CRS, you know, and infections, so that certainly was more evident and um. R2 and uh curriumab that when we look at the safety data from um D R2 uh so I think it's very important to balance both um when we start looking at the data from these trials some of the original comments was that how come the R square arm in these two trials performed worse than the Augment trial, but that has to do with the amount of patients with bulky disease and tumor burden. That you know, again the Augment trial was done um when we were kind of more skeptical about the the significant activity of R square in follicular lymphoma of patients that they were enrolled in that particular trial, they didn't have a lot of high risk features that now that we're more comfortable with R square, um, we're using this combination and you know. And the second thing when we look at, you know, the Gulf criteria, so the really the patient demographic was slightly different and that kind of explained why R2 in these two trials didn't do as well as a main trial, you know, I think overall, you know, adding tafacitumab to R2 or EPO R2, they had led to an improved outcomes. I think it's, we don't know which one of the triple therapy is better because they have not been compared one versus the other one. I think we have just to be mindful about the toxicity profile of the combination and the patient that you have in front of you in your office and see what may be better for them depending on comorbid conditions, age, family support. Clearly to, to do a by specific antibody, you do have to have a patient that has more family support, access to, to uh a tertiary care and care significant CRS, etc. Some of our patients with uh DLBCL, sorry, that with follicular lymphoma because they're elderly, they may have some cognitive impaired problems that sometimes we don't quantify very well in practice, and that can be challenging when we're prescribing a bi-specific antibody and how to monitor, uh, ICAS. So certainly, um, I think we're gonna be learning how to incorporate these two regimens in the 2nd or third line setting of follicular lymphoma. Um, there is a third, um, by a specific antibody or, uh, kind of like an immunotherapy for patients with follicular lymphoma that relaps I think that is coming up. This is looking at adronexumab and enalidomide in patients. Relab refractory follicular lymphoma. This is just presented at the meeting. It's just the early presentation of the phase one safety run of the study that was looking at patients with relapse refractory follicular lymphoma or margins of lymphoma, and the patients were basically, uh, they are gonna be randomized to either uh by specific antibody enalidomide versus R2. However, so far the data that we have is with the um by specific antibody aenalidomide. And again, um, there were two, dosing levels of the Biospecific. Eventually was settled down to do just one, which I think is the 80 mg, and again, um, I'm sorry, uh, what we can see here is that the response rate actually was quite impressive. Uh, it was 88%. It was overall response rate. The CRA was around 67%, so. Certainly, it is a very important um alternative regimen that is coming up. On the plus side, you don't have to maybe add Rituxan, so you just do not need to do 3 drugs with just 2 or 2 biological agents. So I think it's too soon to see um how this is gonna do compared to the other two combination regimens, so. Now, um, of course, we have other regimens that we have been using now for a while. This is just the results from the phase two data looking at combining sanobritinib and obinotuzumab in patients with relapsed refractory follicular lymphoma. And again, uh, this is basically a randomization of sanobreumib and obintuzumab versus obbinotuzumab monotherapy. Um, this has been presented in abstract for and published. This is just looking again patients with relapsed follicular lymphoma, kind of similar demographic these days when we look at the POD 20, 4, as well as the, uh, median age of these patients. Um, so when we look at the response rate, you know, combining a noriumabobbinutuzumab led to an improve in, uh, response rate to around 70%. Certainly, um. You know, was better than ovinotuzumab alone, you know, um, when we look at what kind of patients may benefit better from the combination, pretty much I think any kind of patient population benefited from the combination, the bulk of the disease, the performance status, the PLD 24 status, etc. Um, of course, the duration of the response was better than the combination, and again that's another option that we have, I think in terms of safety this is certainly a quite safe regimen to use, um, so, and again, yeah, maybe the, the, the PFS scores are not as high as with a bis specific based antibody or atafa R square, but you know, certainly it's a regimen that has less side effects and it's a little bit easier to administer. Um, is again looking at the PFS as well, sorry, and the OOS as well, and again there was certainly an improvement in overall survival by using this combination. So, um, this is just looking at some of the side effects and again, so as I say, for most of the side effects are grade 1 and grade 2 because they look blue in the curves and again these are things that in general whether you do the combination or the single agent there was no significant differences in toxicity so. And of course, you know, then we are moving to options that maybe are a little bit kind of more, maybe a little bit more challenging to administer, more toxic, so we're looking at, I'm gonna go a little bit faster through the slides because we want to present the mature data, but this is the transcend data which is the phase two clinical trial looking at car therapy in patients with a lapse refractory uh follicular lymphoma. And again, um, When we look at the number of patients that have POD 24, again, this is certainly, it was kind of more enriched for these kind of patients, around 65, 60% of the patients, they actually had um POD 24, and again they were given car therapy in the second line or beyond, you know. And again what was presented at the ASH meeting was the 3 year follow up and you can see that the overall response rate to car therapy was 97%, uh, the CRA was 94%, and really the duration of the remission has not been reached. Around 70% of the patients, they're still free of progression at 36 months, so that certainly looks quite, uh, impressive, uh, especially for patients who they have POD 24. Um, and again something that you can accomplish with one single treatment, um, but again we have to be just concerned about CRS, uh, neurotoxicities while most of the events in CRS and ICAs are like grade 1 and grade 2, again, there are a couple of patients, they develop, um, significant, um, uh, CRS and neurotoxicities that we have to be aware of it, you know, so as I said before, this is kind of, you know, um. Kind of more data that which is on the prior cartoon. Um, there's another trial that was presented at the meeting was the 5 year outcomes of the LAra trial looking at different car therapy product in patients with relapsed refractory follicular lymphoma. And again, this is a kind of very important to kind of, um, highlight that again included patients with POD 24, again 60%. So when we look at the car therapy trials compared to the By specific and R square, around 60% of the patients, they have POD 24 in the um by specific Cortafa plus R square is like around 30%, you know, and, and again, um, when we look at the overall response rate again it was like an 86% overall response rate with 68% achieving a complete remission and again then at 5 years, the duration of the response has not been reached again. I think what is very important when we look at the 5 years, um, always around 64%, you know, and again, um, when we look at the PFS, you know, yes, you know, the PFS at 5 years is around 35 to 40% of the patients depending on the FLIPP score, the POD 24 status of the bulky disease. So at least with car therapy I would say that. You know, we, we may get like a, a 5 year disease control in 40% of the patients, which again I think it's kind of important to kind of be aware of these um results. So when we're picking a treatment for a patient, we have to factor that into the age of the patient and the life expectancy because again, not every option is good for a given patient. Uh, and again, I think it's very important about toxicity here because again, the more that we follow these patients we're aware that patients are developing secondary malignancies, um, and again, or infections, so it's very important to notice that around 24% of the patients they die from, um, from complications after car therapy. So I think we have just to kind of be aware so. Um, personally, if I have a patient that is in the younger size and they are cycling to treatments more often, I think we're gonna be talking about car therapy sooner with them. If we have a patient that is more in the elderly side and they have a long intervals of remissions, we're not gonna be talking about something less toxic. So, and I think that's something that is a little bit different when we look at. The application of car therapy in more aggressive histologies in which you have to go through things in a very straightforward. I think follicular lymphoma is kind of like a very sig zagging. Um, This is looking at the this also was presented at the meeting at Ash was later the long-term follow-up for patients treated with mocetuzumab in uh with relapse refractory follicular lymphoma. So this is a bi-specific antibody that can be given 100% in the outpatient setting and again it's given for a 1 year duration of remission. It was in a standard phase two clinical trial designed for patients with follicular lymphoma in the relapse refractor setting, more than 2 lines of treatment. And again, uh, these are a total of 90 patients. Again, going back to the median age is in the 60 range, you know, and when we look at the POD 24 in this particular patient center, so they were basically 50% of the patients, a little bit higher but not as high as the car therapy studies. And again when we look at here at the median duration of the response is around 46 months, you know, when we look at the 5 year progression for survival is around 36, uh, so it's around, um, 36%, so it is kind of maybe a slightly compatible to what you get with a car therapy product, um, so, and again it's something that can be done in the community in the outpatient setting. And, and again, um, it's very important that the response rate, it was really quite high regardless of your POD 24 status, and I think that's also very important when we look at the median progression of survival. If you were a POD 24 with abi specific, it's a little bit short it's only 21 months. So again, so to me when I try to put a lot of these things together. I will tend to be more aggressive towards a POD 24 patient and I will tend to use car therapy sooner compared to a patient that um has not progressed that quick, you know. And again, this is just the, the mature data in terms of side effects, which again we're we're familiar with them, CRS ICAs, and infections, but again, really most of the side effects were like grade 1, grade 2. Um, so, and again, I do think that the field in follicular lymphoma in the relapse setting continues to change. I know there is another treatment that is combining Rituxan noncatuzumab, which I didn't have time to add in the slides, but the activity certainly is quite active in, in a significant number of patients. Adding a drug conjugate has a different toxicity profile. But I think it's, it's good to have too many options. I don't think there is a, is a straight pathway to follow for every patient. I think for equal lymphoma in the relapse setting is a condition in which the patient and the, uh, and the doctors, they really have to sit down together and figure out what is best for the patient, and a lot of this has to do with the duration of the prior remission and the side effects and the logistics of the treatment. That we want to implement so and we said we'll stop so thanks. All good. All right, well, we have one more talk before lunch if you need to stretch your legs briefly and, and, uh, use the restroom, please feel free, uh, but Doctor Elizabeth Bremm, you don't wanna be gone too long, is a fantastic speaker, flew all the way from Orange County, uh, California, so she's a little bit jet lagged, but I'm sure she's gonna crush it no matter what. Uh, Doctor Brem is an associate professor of, uh, clinical associate professor at UC Irvine. Um, she is the vice chair for clinical operations and she's a proud, uh, Buffalonian, uh, North Buffalonian I believe. Uh, went to college, in medical school. You were neighbors with Ryan Miller, I think I saw in your, your introduction. It's pretty sweet. You know, um, but Doctor Bren, without, uh, further ado, uh, please join us to talk about LPL and MZL management. Thank you. So I talk fast, so I should get us to, uh, Q&A and lunch pretty, uh, efficiently. All right, so I get to talk today about Waldenstrom's and marginal zone, and, um, I often don't get to talk about Waldenstrom's in particular, so I'm kind of excited about this. Um, so I'm gonna start with a patient case because this case really tested the limits of my creativity period. So I think it's an interesting one to talk about. So this gentleman was in his late 70s. His, um, LPL was actually found by his prostate cancer doctor in the setting of anemia, and she noticed there was also an elevated total protein. He was MYD 88 negative and CXCR4 wild type. He was originally treated by one of my colleagues who started ibrutinib for anemia and elevated viscosity. Um, but his hypertension actually got worse faster than you would expect with ibrutinib, but nonetheless, he got changed to xibrutinib. He was on that for about a year, and then his IGM and his viscosity started trending up again. He went on a trial of a non-covalent BTKI, um, but withdrew consent pretty much immediately as his hypertension got worse again, and he had a pretty, um, dramatic episode of atrial fibrillation that involved a hospital stay. So I am curious. I'm gonna make you be awake and show me by, uh, hands who, what you would do. So, um, we can give a proteasome inhibitor-based therapy. Anybody? No myeloma docs in the crowd. All right. Uh, bendamustine-based therapy. All right. Off-label Purdo. No, off label then. All right. Benda for the win. Um, OK, so not much has really changed a ton of upfront therapy of LPL or Waldenstrom's, um, but most people would give a covalent BTKI or a bendamustine-based therapy. You can see the other options there. They have not fully died, but they're still there. For relapse refractory, basically, you can do what you didn't do in the first line. If you didn't give your, um, covalent BTKI you can do it there. And if you didn't give your bendamustine, you can do it there. And then there's a number of other things listed, um, including pertabrnib and including Venneta Clax. So one reminder is to think about checking. Um, I think we all, most people will do MYD 88, I think, for a suspected LPL case, we tend to use that to try to differentiate Waldenstrom's from, um, say, marginal zone lymphoma. Sometimes there's a lot of overlap and it's hard to tell. Um, but don't consider checking for CXCR4 mutations as well. Um, as you can see in the rare situation where you have, um, MYD 88 wild type and CXCR4 wild. Type, you tend not to get a ton of response to your BTK inhibitor versus on the flip side, the more common presentation where you do have the MYD88 mutation and your CXCR4 wild type, um, most patients have an excellent response to ibrutinib. So it doesn't mean you wouldn't necessarily consider using, um, a BTK inhibitor in sort of those middle cases, but at least it sort of sets your expectation and kind of sets the stage for what kind of response and duration of response you're going to get out of your BTKI. So this gentleman, um, we ended up starting the bendamustine. Um, I always sort of planned I was gonna add the rituximab later, but his IGM like came down but kind of just sort of stayed there at like 4000 and I got a little nervous. So we decided to give the world's smallest dose of rituximab, and he flared just from that. So we were done. No more rituximab after that. Um, so we then gave him some Beneta lax, which I'll talk about in a moment, which did work. His IGM down trended to about 2000. Then he started to develop lower extremity edema and he told me he was quite sure it was the Venetta lax. It was not, um, but we decided to hold it anyway. Um, but even off therapy, his IGM just kind of hung out at 2000 and I think it's almost been 9 or 12 months since we've stopped it, so we're just observing him off therapy. He's got a lot of other stuff going on. Um, but we've actually known Venetta Clax is a potentially a good drug for Waldenstrom's for quite a while, even going back to the original phase one of Venetta Clax and all non-Hodgkin's lymphomas. So that light blue line all the way to the right, those are the Waldenstrom's cases, which I get it. There's 3, but they did all respond. So we kind of have always had this little early signal for BCL-2 inhibition in, um, LPL. And just a quick, uh, shout out, a little detour down memory lane. I did a lot of work on the BCL2 family as a resident and a fellow, and that started with the project that I was, projects I did here as a medical student, um, that led to my, uh, med student thesis and, um, my 1st, 1st author publication. Um, so subsequent studies have been done looking at Venetta Clax in, uh, Waldenstrom's and LPL. This is from a publication a couple of years ago. You can see the breakdown of the patients here. Most of these patients had two prior therapies. Most, all of them in this data set, um, did have an MYD 88 mutation, and about half of them had a CXCR4 mutation. And you can see the response rates here for all patients. The overall response rate was 84, um, uh, 84%, and you can see the different breakdowns of the different disease, um, subgroups. I don't want to spend a ton of time here for the sake of time. Uh, medium PFS was 30 months, and there was only one case of tumor lysis syndrome. I think when we talked. One thing, uh, one of the reasons I wanted to put this in here is I feel like when I have a community referral for Waldenstrom's, this is one of the drugs they haven't really considered. I don't think they think of it as a drug for Waldenstrom's, and I think there's still a lot of fear of tumor lysis syndrome, but at least in this data set, there was only one case of TLS. Happened to be grade 3, but it was only one case. And if you want to look at the PFS curves, there they are for you. In terms of ash abstracts, there wasn't a ton going on in Waldenstrom's this year, but there was a couple of things worth taking note of. Um, there was follow-up of the Bruin study looking specifically at Pertabrtinib in the Waldenstrom's patients with a very high overall response rate, and you could see the breakdowns of the types of responses there. There was also a study of Ven plus Perdo, um. Of the patients who had an MYD 88 mutation, they had a 100% overall response rate. They did have two patients in this data set who, um, were wild type for MYD 88, and both of them actually progressed very quickly, just as a reminder to consider checking that early on to help you kind of gauge where you're going with this. So in summary for Waldenstrom's and LPLs, there's a lot of options. So I think there's a lot of room for individualized care, as was kind of mentioned for follicular lymphoma. Um, do consider checking for CXCR4 mutations. Um, do remember the IGM flare with rituximab because if you are not prepared for it, and you don't have your pheresis team on board, it's a bit of a struggle. Um, don't sleep on Vennetalax as a potential tool for this disease. And just a reminder that sustained PRs are OK and honestly the most common outcome. It's relatively uncommon to get a CR in this disease. So now I'm gonna switch over to marginal zone. Um, not much has changed in upfront marginal zone. We're still doing a lot of our bendamustine, rituximabs, um, or, uh, anti-CD20 alone in upfront therapy, but there's a few other options there. I have a colleague who really just loves our squared upfront for low-grade lymphoma, and so that is on there as well. Second line, basically, again, and if you didn't use it before, you can now start using covalent BTKIs in the relapse refractory setting and you consider R squared as well. And then the third line, we do have some CAR T data and I will go into some of that today. So, I think it's important to remember, I think we lump marginal zone and follicular together in our heads a lot, and that's because the studies lump them together a lot, right? So, I think it's important to remember that while there were marginal zone patients included in the in-m study that was talked about earlier, the TFA R2 versus R2, um, there actually were a fair number of patients with marginal zone, but we actually haven't seen that data yet. They have not presented the marginal zone patients. I went through the publication and there's just a little line that says marginal zone to be presented at a later date, um, and it's not on guidelines for marginal zone. EPOR2d was also talked about previously. This study actually only had follicular lymphoma, and I think it's important to note we actually have no bi-specifics approved for marginal zone lymphoma to date. So it's kind of funny. This is a disease where we have CART approved, but no bi-specifics so far. So let's talk about the CAR T. So we do have data for Lisa cell. This was patients with two prior lines of therapy, and they must have had an alkalator and an anti-CD20. So they couldn't have just had, for example, two lines of anti-CD20 therapy. Bridging was allowed. I think it's important to kind of note that the intention to treat population was 77 patients and only 66 ultimately made it to the therapy, which is important to keep in mind. In terms of the subtypes of marginal zone, you can see this here, um, in terms of the age breakdown, there were patients older than 75, not a ton, but a few. And I think it's important to note that, um, about a third of these patients were considered POD 24. So that's a progression of disease within 24 months. Um, and you can see some of the other elements here. In terms of efficacy, um, overall response rate was quite high. More, most important always when you're looking at CAR T data sets is the complete response rates because these are the patients who get the sustained responses and the CR rate was 62%. In terms of sort of the duration of therapy, you can kind of see that most patients actually did quite well, but of course, the CRs always do better than the PRs, but I think that that PR curve actually is not bad. Um, even with a PR at 36 months, a lot of those patients were still in remission. Um, and then on the right, there is overall survival, which generally speaking was quite high. In terms of, uh, side effects, so CRS, any grade was very common, however, high grade CRS was relatively uncommon. Uh, very few grade 3 events. The time of onset was what we're very used to with, um, the cell therapy. In terms of neurologic toxicities, they did happen, but only in about a third of patients, exceedingly rare that it was grade 3, no grade 4, grade 5 events. And again, happens kind of exactly when we generally expect those. Toxicities to occur. I think maybe important to talk about are the cytopenia, right, because typically we don't have to worry so much about these in our marginal zone lymphoma patients. But if you do the CAR T, obviously it's something we need to worry about. Um, grade 3 cytopenias at the 90 day visits though, once it's been a few months, was relatively uncommon, but not zero and worth, um, keeping, keeping in mind when you're talking about the pros and cons of sending a patient to a car. We're not supposed to do cross-tri comparisons, but we all kind of naturally think about it anyway. If you go back to the Zuma 5 data, which is a little bit older now, um, it was a very similar population. If you look at the inclusion criteria. Medium number of prior lines was also about the same. In this data set though, way more of the patients were considered POD 24, although the overall N was much, much smaller. And here's. PFS curves. They did have, um, higher rates of grade 3 cytokine release syndrome, um, as well as, um, a pretty high rate of grade 3 or higher neuro neurologic toxicity, um, which I think that in particular has sort of, um, skewed many of us away from really being all that excited about sending marginal zone lymphoma patients to CAR T, um, up until recently. In terms of the long term follow up, um, you can see that the cause of death, um, was, uh, typically some other, um, non-relapse mortality event. In terms of what we saw at Ash this year, so there was a lot of res what I thought was cool was there were a lot of response adapted studies. So two of them use mocinatuzumab. So this, uh, first abstract came from the group at Brown, and basically what they did is after 4 cycles of mocinatuzumab, if the patients were not in CR, they added low dose lealidomide, and it was relatively low, it was only 10 mg. Um, this study did include both marginal zone. And follicular. They did the response assessment after 8 cycles. Um, only a third of patients had the lens added, which I think is interesting, showing pretty high efficacy as a single agent for the Mohsin. Um, you can see the overall NCR rates there. They used, uh, the Roche CT DNA assay that I'm not super familiar with, but you can see that actually, um, undetectable MRD by that assay was quite high, especially for the patients who were in CR by P PET. Another study, which was led by Ryan Lynch in Seattle, um, was adding Pola and Oin, if not in CRR after 8 cycles. So in this case, there was more motion before the evaluation was done to kind of add the second therapy. Um, And so The CRA actually again was quite high to the Mosin alone, so not that many patients ended up getting the, um, add-on therapy and the, um, MRD rate in this case, they use the Phaiq, which was talked about earlier this morning, um, was relatively high just with Mosin alone. There's also ongoing studies with ecariumab, both as a single agent and in a combination. This was just me kind of poking around on, you know, various clinical trial sites to see what else people were up to. So in summary, for marginal zone lymphoma, anti-CD20 plus or minus bendamustine, or I didn't talk about it, but there's still a role for local radiation for very limited stage disease. It's still the first choice for most patients. There's a lot of room for personalization and subsequent lines. Um, we have no approvals for bi-specifics. There's probably some coming at some point. We just don't have it yet. I'm actually pretty intrigued to see if TFA R2 performs any different. Certainly in marginal zone versus follicular lymphoma. I have no idea when we're getting that data. Maybe somebody in this room does. Um, CARTs are approved, but generally, I think the use is going to be relatively limited. I think it's going to be our younger patients. It's going to be third line plus. It's gonna probably be POD 24. Um, there is longer follow-up with Axi cell, but I think the safety is generally going to favor using Lisa cell as the cell of choice in this space. And, uh, with that, I'll get us to the Q&A and go Sabres. F 3. Fantastic talks all. Uh, Doctor Brem, thank you for catching us up to speed here. We're gonna do a brief Q&A. Um, we have an extensive panel of, of esteemed experts, so please don't be shy or bashful. I'll be monitoring online as well for any questions, uh, from our virtual audience. Please feel free to type them in the chat. Hey, uh, it's Sammy. I'm Sean again. Um, we have 6 experts up on stage, so again I'm gonna use the opportunity to kind of pick your guys' brains. So every single one of your talks, uh, I, I talked a lot about kind of balancing efficacy and toxicity and kind of a recurrent theme throughout was infections and for. Both, uh, especially for I guess the immunotherapy, the T cell-based immunotherapy approaches, the bio-specifics, the CAR Ts, we do see a lot of post-car infections. There's actually some data that actually the infections might even be worse in bi-specifics than cars, um, but there's no unified approach for when do we give IVIG, what prophylaxis do we do? So I'd actually love to hear all six of your approaches too because I'm still, I'm still teasing out. What what I do in my clinic and I'm not consistent because there's no rules and so um I'd love to hear actually all of all of your approaches to uh monitoring prophylaxing, etc. uh, in especially in immunotherapies but in general in the relapse refractory indolent lymphoma setting. It's a fantastic question. I'm gonna propose we start with Doctor Hernandez and then work our way on down this train this way our senior most speak first. Well, well, I think first I don't think there's consensus and I think we should invite our illustrious IT department to maybe help us out here. I think in general I think at least in our practice, um, for by specifics we normally do the herpes prophylaxis and the PCP prophylaxis from the get-go, you know. Um, in terms of IVIG, we just don't unless they're having infections, uh, for the car therapy patients, we normally, in general we are favoring now doing routine IVIG, especially if they have hypoglobulinemia coming out of the car therapy, and then they do get the sacro for like 2 years and. And the PCP professor for one year. But again, and even despite all of this, you know, patients, they managed to get infections for things that they have nothing to do with this because we have a couple of patients they have no card infections and, and, and those are quite challenging because they are pretty much if you can resect them, that's good, but if you can't, then it is hardsome but. So I actually uh put a comment and I actually think our myeloma colleagues are doing better with this than we are. Um, I still treat some myeloma and there's definitely a push in that field to make it more standardized and in particular, very big push for more liberal and earlier use of IVIG, um, and I think that part of the reason we see it more in the bi-specifics and the CART is just because of the duration of therapy with the, with the bi-specifics, right? Um, which is why it's a particular issue, myeloma. Um, so I actually don't put everybody on PJP prophylaxis because I've yet to see a case of PJP with, um, bi-specifics either in lymphoma or myeloma. I'm very liberal user of VZV prophylaxis. I used to not give IVIG until they got an infection, and now I'm just so sick of dealing with URIs and pneumonias that I'm basically just gonna do it. I think the moment that they go below 400, I think I'm gonna start using it more prophylactically. Yeah, kinda, kinda same thing. I, I do, I do PJP and VCV prophylaxis for everyone, especially when they go on the combinations like for sure, um, yeah, I, I still figuring it out right for the IVIG, um, I, I think, um, I'm, I'm gonna probably do what she does right now because I think it's a good idea, uh, but, uh, but I've been having like I, I haven't, I've been having to do it very much recently, um. Uh, especially when, when we put them on clinical trial with the combinations and so yeah, I, as soon as they, they have some sort of infection and we don't know what it is, etc. it just started. Um Share the same opinion. Uh, I do PGP, uh, prophylaxis, but not too long, especially when probably the first few cycles like 3 or maybe no more than 6 months, and the reason is that the first cycle, especially with, you know, choriumab, when you do the steroid prophylaxis, a lot of steroids, um, patients do get infections, not necessarily PGP actually I saw one only, but. Yeah, I do that. I, I haven't implemented, uh, you know, IVIG prophylactic, but I think it's a good idea for, not for all, I would say, I would say for the high risk patients, you know, kind of older patients, patients who had recurrent infections, some patients had like a low CD4 count, so, so, but no, not for all. Yeah. It work. Um, so, so, um, so in Rochester, we have guidelines for CAR T prophylaxis. So those are well established in our guidelines. So, there will be antibacterial, antifungal infections starting day 0, day -5, until neutrophil recovery. And we monitor IgG level, keep the IgG above 400 monthly with checks. And then, We monitor CMV monthly, we monitor CD4 count monthly and give viral and the PJP prolexis until CD4 count is above 200 and then at least 6 months, 6 to 12 months minimum though. And so I mean viral PJP is 6 to 12 months minimum, but at least with CD4 count, you know, above 200. Um, for by specifics, we don't have written guidelines yet, um, but, uh, we'll start to think about, you know, CD4 count checks and IGG checks. But we, my sense is that we're probably gonna give more IGG than we do now. Um. The other thing is we're, I think we're starting to see some unusual fungal infections, um, with the biospecifics. Uh, some interesting thing is, you know, the patient may be doing just fine, no symptoms, with, for example, a pulmonary nodule you see on your staging scan. As soon as you stop the fixed duration therapy, all of a sudden they start to have fevers. In, in the case we biopsied the patient actually had a coccylial infection. The nodule has been there for like 6 months. We just thought it was just post-pneumonia, but, but on, on the patient was not able to mount a fever even. So I think we're going to monitor things more closely. Yeah. I think these are all fantastic comments. I just have, uh, one call to action, I guess is that we should be collecting data, collecting practices, standardizing, harmonizing practice throughout the country. Um, I'm always a fan of, of monitoring periodically CMV, uh, you know, PCR, you know, know that if you have colitis and lung inflammation that, you know, blood test is not, isn't always uh sufficient for that rare viral infection. I've not seen one yet, but just know that it's something to watch out for. Uh, PJP, it happens, you know, to one for one patient. Uh, it really does affect you. It's a nasty, nasty infection. So I, I tend to offer prophylaxis and talk to my ID colleagues, good detailed clinical history. We're really bad at, at quantifying and, um, T cell function, frankly, and, and T cell, um, and I think that goes on both sides of the coin here as far as the efficacy and the toxicity for all of our immunotherapies. Um, I had a wonderful conference with Doctor Emmons. I see you're, you're queued up for a question, so I'll, I'll call you next, sir. Um, in Kentucky, uh, talking about immunotherapies and our poor understanding of T cells. So with that, I'll, yeah, just two quick comments about that. First of all, first of all, you know, in, uh, bike therapy we're driving all T cells all the time. In car therapy you're driving a subset of T cells over a limited space of time. So the infectious cycle is gonna. Be quite a bit different between those two, and we're trying to figure this out too in terms of how we look at these differently. There was also an AS this year you may have seen the myeloma groups have shown that even below 400 you have a legal clonal production of, uh, you know, the IgG and so they're giving it to everybody regardless of what the levels are. So levels may be an imperfect thing. So my big question to the panel is now we know that many of these lymphomas are high risk, so blastoid and high P53 and the transformed folliculars that aren't responding to chemotherapy. We also know that when you get patients to allo transplant, they do the best with lymphoma when you're in a very deep remission. So when we put them on these secondary therapies and we get them into the deep remission, what are the biologic cues that that's enough as opposed to getting them into the deep remission and sending, sending them to allo transplant when they're in very good remission at that point. Yeah. Well, I, I think that's, that's challenging because one, an allergy enabled marrow transplant, you can open a Pandora box very quickly. And again it's also because while certainly post-transplant Cytoxan has decreased rapers host disease, one, you still have significant morbidity from the transplant. And then when you have patients who you can maybe retreat with Rituxan alone every 5 years because we have some of those ones like at what point do we activate the toxi like at what time do we move from OK it's time to activate the higher gears because maybe you we're gonna need to take higher risk and I don't think the problem is is that. There's like a like a clear cut for every for all the patients every patient is different, you know, um. To me, certainly when I look at younger patients like, and when I mean younger, like people in their forties or 50s because we see them even in their sixties and they'll be POD 24, definitely those are the patients that we kind of worry the most if I have someone who's like 75 and you know it's like. You have 10 more years of life, you know, I think we can control the disease with some kind of less aggressive treatments, even if you are repeating treatments every 3 years, you know, um, I think that's what I tend to kind of divide patients, but it's really that's again it's just my own practice, so. Got you. But given the falling mortality rates for allo transplant and the flat curve that we see in some of these patients, especially for the blastoid and P53 mantle cells, uh, you know, Per Burton, it works, but it only works for a certain amount of time. We put them on the car. It only works for a certain amount of time. The curve doesn't plateau like it does in large cell as well. So how do you make those decisions in your world for mantle cell? Yeah, exactly as you mentioned, like the bad players after CAR T, that's probably, you know, when we consider alloy for a young patient. Uh, I think with different lymphomas, we have different views when to or if to use allo transplant. In some of these diseases where we have more options than others, we try to reserve aloe for the, you know, last resort if they're still young and fit at that point. It's just calculate the risk, you know, whether it's worth it or not. In some diseases, we tend to use aloe a little earlier like a T-cell because there's no good options after front line, right? Uh, another thing, another disease where we still use quite a bit is, or at least considered a little, uh, a bit, a bit more than others, the Richter transformation in CIO patients after, uh, you know, even, even as a consolidation after CAR T. So it's based on whether the disease is curable, uh, whether we have options, you know, at this point, uh, for, for this patient's disease and whether they are still fit or young, you know. I wanted a quick question, how do you sequence therapies? Bendamustine paralyzes T cells for 6+ months, and sometimes these patients have high risk disease and they're still getting bendamustine, and you know they're maybe going to bite her car or something like that. So how do you, uh, tailor those to avoid that kind of toxicity from not just bendamustine but other therapies that might paralyze T cells? Yeah, uh, I guess that's for me, um. That I, I haven't really used bendamustine in a very long time, at least for follicular lymphoma, because of all these problems and, and partially because the data looks so good, um, with our CHOP, it looks so good with other combinations, other single agents, uh, that I really can't recall. A patient I recently did Benamas our Bea in frontline um. Maybe Paco can also comment on, I know he sees, I think it's, I think it's long. They like to do more art job than PR a little bit so, but, um, but also in Italy in because there are pros and cons. I think one of the problems is that you don't know if you have a bad player until you go through your first line therapy because in reality again, uh, you don't know who's gonna be POD 24 until you become POD 24, you know, um, certainly. Your SUV and your PET scan, you are grade 3A. You're a bit more worried again right now, for example, at the institute, we have this habit of doing gene sequencing in every biopsy, so which is great because we're checking for ES2 mutation, but we are getting back these biopsy results without all of a sudden you have a P53 mutant clone from the get-go. We don't know what to think about that. We do not know if that's gonna end the POD 24, but I think the problem is that we don't know who's gonna be POD 24 until they become POD 24. I think in general I favor our job in a follicular lymphoma that is diagnosed and needs treatment when they're in their fifties because again the chances that they will maybe require car therapy down the road will be higher and you don't want to beat the T cells too much with bendamustin. You're in your 70s, normally if you are a grade 1, grade 2, we tend to do be the mosten, um, once you declare yourself, then personally is based in is like I tell patients follicular lymphoma is like a marathon you sprint too much, you die too fast. So I like to alternate a chemo-based regimen versus an immunotherapy-based regimen back and forth, so the interval in which a patient is getting something that is too toxic is stretched out. I think it's good now to have other alternative di BTK inhibitors or bites, etc. but. But I also think outside of, I think for the high risk mantle cell this is an important discussion. I think for the most of your low grade lymphoma patients, most of them you're not even gonna ever think about a CAR T cell, right? Most of them, you're gonna give whatever you're gonna give and they're gonna go into remission for 5 or 6 years and you're gonna do this again. So I think that that. Tailoring your therapy, worrying about the worst case scenario when probably that patient's gonna be in the best case scenario for most patients is, you know, it's important to keep that in mind. I also was trained. I do very limited courses of bendamustine. I don't do all 6 cycles. I will do 2 to 4, and I will do it kind of based on response. That's not data-driven. I want that very clear, but sometimes. You can get somebody in a CR with two doses of bendamustine and you're not trying to cure them, right? You're just trying to put them in remission and I just sort of cut bait and then limit the amount of the exposure that their bone marrow and their T cells have seen to bendamustine. So I think it's just important to keep in mind that yes, there is the occasional follicular lymphoma that you have this like little worry in the back of your head that maybe there's some large cell that you didn't diagnose or the high risk. Mantle cell lymphoma patient, but I think that that's important to notice that that's keep in mind that that's not, that's the rarity, that's the exception, that's not most of the patients popping into clinic because like when you got POD 24, it's only really like 15 to 20% of the patients and when you got mantle cell lymphoma, the ones where they have P53 such a genetic abnormalities are like 15% so. Luckily, you know, it's really like it's 85% of the times you will be doing great, you know, so but you know. Yeah, I, I actually agree with you. I don't do a lot of, I mean, I give vendamastin for not for too long. And also the effect of vendamasting is not permanent. So, you know, usually about 18 months kind of wear off, and then CD cell efficacy is kind of the same, you know, whether it's mental cell or low grade lymphomas, but I think limiting bendammassing is what I would, I would do to, uh, yeah. Except, except the secondary malignancies, but on, on that note, that was my question actually. So as far as the bendamustine associated later, you know, 10 year plus, uh, now kind of emerging data for secondary myeloid neoplasms, um, I think Paco, you touched on this with young patients, you try to steer clear of the beammastine. I'm guessing for one of those reasons, right? Uh, and for one plus T cell, uh, suppression for subsequent immunotherapies. Um, bendamustine, I think the, the T cell depletion actually, it lasts almost indefinitely. It's, it's right, I think it's 1 year or 2 years even. There's still this kind of shadow on those T cells. They never really truly fully recover. I think a year is close to good enough to normal T cell function, but they're, in my brain, they're 90 or 90% what they were before bendamustine exposure, right? They're, I don't think they're ever quite back to fully normal. Correct me if I'm wrong on that, y'all, but um. With 6 cycles, correct, um, I guess I was gonna ask briefly as far as like still, still in bright, you know, trials still ingrained in my my mind from fellowship training, right, um, how do you see, you know, the BR versus RHO question I guess, um, in those in those terms for efficacy I think it was my main question for Doctor Gion on that one, how do you kind of. Yeah, I mean, it's, it's tough because the data of the maintenance looks so good after our chop, um, and the, the infection rate with vanamastin is higher. I think if you were talking about an older patient deciding with mantle cell lymphoma, for example, deciding. In uh to give bendamastin makes a little more sense because the data looks so much better um for follicular lymphoma again I if I really have to give chemotherapy, I, I try to I try to start with with RH or RCDP even compared to giving bendamastin, um. But and, and then it depends which line of therapy you are, etc. but even if I were, you know, in between deciding whether doing bendamastin uh in third line uh versus maybe CT, uh, I may, I may decide CART first, you know. Thank you. Any other questions? One more thing, so I think just we cannot forget that you can still do R square in the first line setting, uh, because it's equivalent to B R. So again, so there's certainly like different ways to, to, to try to stay away from you can select a less toxic regimen and again, and in some elderly. Patients Rituxan could be good enough. So sometimes I was gonna say I, I'm a, I'm a fan of abbreviated maintenance Rituxan, right, especially with all these new toys coming in the near future, um, try not to bank on, on approvals, right? Um, they're, they're coming. So I think a lot of hope for a lot of patients. Um, just don't, don't kill your patient with your first treatment. I think that's the, the moral of the story. Thank you. All right, with that, please a hearty round of applause for our panel. And uh with that, we're gonna take uh, I think uh about an hour or so break, 1 hour-ish break, let's say maybe 45 minutes just check back in here. Uh we'll.
BROADCASTMED