Alex Niu of Roswell Park Comprehensive Cancer Center and Matthew Mei from City of Hope discuss changes and challenges in the treatment of Hodgkin lymphoma.
It's my distinguished, uh, honor and privilege to introduce one of my close friends and colleagues who go all the way back to University of Cincinnati for residency. uh, Doctor Alex News is assistant professor of oncology and sits on our NCCN guidelines for Hodgkin lymphoma at Roswell Park, and he's gonna talk about some of the massive clinical practice changes and the upfront or initial management of Hodgkin lymphoma and hopefully steal Doctor May's, uh, thunder for the second talk. Thanks, Matt. Oh, nice guys. Hi, uh, thanks guys. Um, so thanks guys. Thanks Matt, thanks, um, Paco, um, for hosting this, um, I thank you guys for sticking around. It's been a long day and so, um, I know I'm Doctor May and I are the last things that are standing between you and a fun Saturday night, so we'll try and make this worthwhile to you guys. Alright, so just a little bit of background first, um, for Hodgkin's lymphoma. So roughly about 900 to 10,000 new cases per year in the US, around 1200 deaths annually, so it makes about 10% of all lymphomas, which is not actually that much or as popular as Hodgkin's lymphoma is. I think everybody in this room is aware of the bimodal AC distribution with an early 20s followed by a little mid to mid late 70s peak, um, risk factors, Hodgkin lymphoma, EBV, uh, HIV gets immunosuppression, autoimmune disease, and then the diagnosis, um, I think as Doctor Napoli kind of mentioned, this is one of those that you really want a lot of tissue for because, um, it's really hard to make this diagnosis if you don't have the whole lymph node, and the reason why is because you need these Reed Sternberg cells here. And so for the fellows and residents here in the room, this is a question and picture you're gonna get on your board exams at every single exam because they love to show this picture. Um, it's necessary for the diagnosis of Hoskin lymphoma, and they only make up about anywhere from 1 to 10% of those cells. So it's really hard to find which is why you need it. So remember these words Reternberg cells. They always say it looks like those allies, so bright eyed, very excited, just like our eyes. Alright, so, um, for Hodgkin lymphoma, um, it's, there's a really big distinction between early stage and advanced stage, early stage being stage 1 to 2 and advanced stage being stage 3 to 4. Within the early stage, it's also deviates further into favorable risk and unfavorable risk and similar to a lot of different things we do in, um, lymphoma or cancer in general, there's a lot of different ways to kind of group with something's favorable versus unfavorable and lot and of course more than one way or one. Um, group that kind of defines what this is. So here I listed kind of, uh, from the NCCN guidelines just the three ways that we look at if something is favorable versus unfavorable. You can see they have little differences here or there, more or less they are the same thing looking at kind of a combination of VSR number of nodal sites, bulky disease, and so forth. So this is taken from the NCCN guidelines and this is looking at first stage early stage favorable disease and as you can see this is a really complicated and busy slide and it's for that for a reason. So, um, as Doctor Cortiz was nice enough to tell me, uh, to say, you know, I'm lucky enough to represent Roswell on our NCCN guidelines and you know when we meet each year. I, I can safely say this, this slide right here is the vast majority of the time that we spend, um, there's a lot of kind of back and forth and after various celebrations of learning we more or less come to the same thing and we don't really change that much and it's for good reason because there's a lot of data behind it that actually works well. So just to kind of walk through this a little bit, everybody for early stage as of right now for favorable gets A, BVD times 2, and then you get a resage with a PET scan. Now depending on what your response is, if you are a good response over Duva score 1 to 2, you have these three options. You can kind of choose from, um, the top one here is based off of a really, really good risk, uh, depending on if you're low ESR, no extra no lesions, less than two noocytes, and then the bottom two are kind of a combination of whether you want chemotherapy only or if you want a combined modality. If you move down to the Deva score of 3, it's more or less the same thing because if you look at these two, they're more or less the same except you can see there's a little bit more chemotherapy for the Duval score of 3 and that's from we know that if you have a Duvall score of 3, you tend to do a little bit worse than if your Duva score 2 therefore you need a little bit more chemotherapy now. I think across the board for all cancers, um, I think as you heard kind of throughout the day today, uh, the goal of everything is really to try and start limiting toxicity to try to pull things away and see if you can still get the same efficacy. So even though I don't show it here in the. Score 1 to 2 in the combined modality therapy where you look at the if you are if you have a good response and then you have ABBD times 1 followed by radiation. This comes from the rapid study at AS this past year they actually released the 16 year evaluation of this and what they found was that when they looked at patients who got ABVD times an extra 1. With or without radiation, so meaning that everyone got 3 A BVD, and then you they got radiation, no radiation. Patients actually did exactly the same. The overall survivals are about 94% versus 92%. So this starts to beg the question of can we start pulling things away, and I think this is something we're gonna discuss about here in our upcoming meeting. So another study I wanted to pull from the um from this past Ash was done by Doctor Yang, um, and this kind of falls in line with that see if we can pull more things away and have similar efficacy. So this study looked at early stage favorable disease and once again you follow the ABVD times 2. If you're PET positive, you got radiation therapy only, but if you're PET negative, you got randomized to either receiving. Additional ABD times 2 similar to what's on the on the um NC NCC in Ghana right now or you got ABD times 2. So therefore you're taking with the bleomycin, almost doing a a shortened version of the RAFA, which is ABD times 4. And what they see and what they saw as you can see here from the 5 year progression free survival is that 91% versus 95% and a 5 year overall survival of 90. Versus 100%, none of these were really statistically were statistically significant. So therefore showing that these are actually fairly similar across the board. So just another example that we may be able to start pulling things away, and we know that we want to because as we're getting more and more further out from the initial studies from RAPID and RATA, we know that we can limit doxorubicin, limit bleomycin toxicity, patients are overall going to do better. Now another study I wanted to highlight comes from Doctor Anne Lacase. Um, this is kind of looking at early stage again, but rather than just doing A BVD, which has been kind of the tradition for a while, what about incorporating our novel agents, which I'll talk more about here in a little bit, but the novel Hs being Nebolaab and Brent Tuximab, which we've heard a lot about throughout today already. So what this study did was once again looking at standard of care ABD times 2, and as you can see we'll start at the bottom here that if you're PET 2 positive afterwards you got sent to the BBBD arm for 4 cycles followed by novolliab maintenance. If you'reET 2 negative, depending on if you're bulky or non bulky, you either got an ABBD times 2. By Neboabab maintenance or you got rituximab Novolabab only for 3 cycles, and then they followed these patients out. And as you can see here from the progressive free survival at 24 months between the A group, which is the BB Nivvo for 3 cycles, and the B1 group, which is the ABBD times 2 followed by the Nivvo maintenance, they had the exact same very good progressive pre survival. 24 months showing that we're likely able to start integrating these novel agents into into early stage favorable early stage favorable and potentially unfavorable disease. We look at the other two groups, 86%, 77%, still not too bad, um, granted that we know that patients bulky disease and PET 2 positive tend to do a little bit worse. So now we go to early stage unfavorable and last year this slide actually looked exactly the same pretty much as the early stage favorable you have as you can see, you had ABBD times 2. You get restaged and depending on what your score is, you get a combination of A, BBD or ABD only depending what you wanna do. But as you can see down here, there's this other little button here that says other regiments down and when you click on that, that kind of opens up Pandora's box a little bit with all these newer different regiments. And because these are approved now and uh you know, for NCCN guidelines and they are likely coming, I want to spend a little bit of time talking about a few of these studies. So the first one here I wanna talk about is the the ball study, and this is a randomized phase two study. I'm using air quotes here. You guys can't really see me, but I'm using air quotes, and I'll talk about that here in a second, and this is looking at early stage unfavorable disease. So what this did was it looked at RMA, which was Ebolaab ABD times 4, followed by radiation versus R&B, which is sequent. the volumab AVD looking at 4 where you get 4 volumab only followed by 2 in Navolabab and ABD and then 2 more ABD followed by radiation. So the reason why I'm saying randomizing air quotes is because it's not really comparing against the traditional standard which is a BBD. It's kind of looking at each other just in sequential, um, just in sequential manners. So the result of this, as you can see at the top here is progressive for survival, the bottom here is overall survival, and even with me receiving a minus in stats in intro college, um, I can tell you that those are pretty good numbers there and pretty good lines. That's about as good as you can get. And when you look at the side effect profile, because the two drugs are because the two regimens are so similar, except for in terms of sequentialness of what they did, you have pretty similar um side effect profile. The main kind of side effect being your hypothyroidism and your autoimmune phenomenon that you get with Nebolimab. So the other study that I that came up was the breech study, and this is a randomized phase two, kind of really similar to the Deal study once again an early stage unfavorable. And for this one they looked at brintuximab, um, and then ABD times 4 followed by radiation, or they did the standard which is ABBD times 4 followed by radiation. They actually got PET scans after cycle 24, and at the end of radiation. And the results that they saw were at the top left here. I know this is a little bit small, but the top left here, the progression free survival was favoring more towards Brtuximab, ABD versus the ABVD about 97% versus 92%. This the authors also decided to look at, let's look at tumor volume as well as what happens if you're PET positive after two cycles, and you can probably guess what those results would look like. If you had a larger tumor volume, you had a little bit worse progression free survival, and if you're a PET 2 positive, you tended to do a little worse than if you were PET 2 positive. But an interesting thing that I wanted to bring about from the study is that the patients who were PET 2 positive, the renttuximab arm tended to do significantly better than the ABBD arm of close to around 92% versus around 79%. So that's a pretty big difference and it kind of opens up the possibility of if you were PET 2 positive, should you switch treatments to something else, particularly in this case something like a novel agent? We'll touch on this a little bit more later. And then in terms of the side effect profile, roughly similar across both sides here. So let's switch gears now and talk about advanced stage. So for the last 3 or 4 years, the Echelon one study, which is rituximab ABD for 6 cycles, has been king of the hill. Um, this came from one of my mentors at Mayo Clinic, Dr. Steven Ansel, and pretty much it took patients with advanced stage Hoskin lymphoma and it looked at ABBD times 6, which was, which was how they designed the original RATL study, or they looked at branttuximab ABD times 6, and then they ran across and then they ran the study. And they actually just released a seven year um update of this back in uh the last ASCO and what they saw was that for all patients, the rituximab ABD arm doing significantly better than the ABBD arm with overall survival here about 93 versus 88%. And there's just a few groups that I'm highlighting here for age less than 40%, the tuximab arm doing better, and then for uh more advanced stage for stage 4, even doing even even better than 94% versus 88%. Now this was a great study and it really opened the door and it kind of shot up the survival for advanced stage hospitals lymphoma and at the time everyone's kind of saying and there's nothing really that's gonna beat this moving forward and then lo and behold the new kid on the block was Navolumab ABD, um, done by Doctor Alex Herrera at a City of Hope. So in this study, this was a randomized phase 3 looking at nivolumab AVD versus rituximab AVD times 6 cycles, and this is the design of this landmark study where once again advanced stage Hodgkin patients you get randomized to either arm. The very cool thing about this study is they also included patients who were aged 1212 and higher because we know young patients tend to get Hodgkin's lymphoma and so it was really cool to kind of include these patients, uh, within it. And these are the results from the study. So progression free survival and progression free survival favoring Novolumab, um, the nevolumab arm over the tuximab arm of 92 versus 83%, and then the overall survival being roughly about the same. Now the big, big part of this. Study that everyone really highlights and that I want to highlight here is really when they did the subgroup analysis looking at it you can see every single one of these sub subgroup analysis favors evolumab um ABD. This is why this has become the gold standard now and this is why we use this for all of our for all of our advanced stage Hodgkin's disease. A specific group I want to highlight is the is the age older than 60. Um, at last year's actually I didn't include the data in this one, but last year's Ashtribute here that we did, I showed some data that they ran of patients who are older than age 60 within the SWA 1826 study, and what they found was that patients were older age 60 did significantly better with the Nebo AVD versus the rituximab AB. The are the event for survivals were somewhere between 90 versus 70%, so a huge, huge gap. So even higher than what I was showing here for the for the um overall population. And a big part of that is because rituximab ABD is pretty hard on older patients and so therefore they are higher risks of infections that require them to stop treatment and therefore out of all those treatments when you stop treatment you tend to do worse. So just something to really kind of highlight here and you know, showing that Nivvo AVD works really well for all patients, but especially for this for the elder patients. And talking about advanced stage, you kind of have to also talk about the HD21 study. So this was done by Dr. Peter Borschmann. This was a European study, um, done run mostly in Germany, and this was a randomized phase three for advanced stage Hoskin looking at BRCAT versus escalated BAO, escalated BAOP being the standard, another standard approach that you can use for advanced stage Hoskin. So in this study what they did was everyone with advanced stage, they did, they randomized to either the BRCAT or the escalate be a cop route. You got two cycles up front and then depending on if you're PET 2 positive or PET 2 negative, you got an additional 2 or 4. As you can see, these are the differences between each of these different regiments. Mainly the differences are for the BRCAT arm you get the addition of rituximab. You change out the steroid or you switch out the steroid, you switch out your alkylator from procarbazine to dearbazine, and then you get rid of bencristine and bleomycin. And so these were the studies. So this study was initially done as a non-inferior study. They want to see if BRCAD would be non-inferior to escalated BAO. What they actually found was that BreCAD was not only not, not inferior, it's actually superior. So you can see here by the left side by progression free survival at both 36% and 40%, they were both better than the escalated BA cop arm by a good, um, you know, 4 or 5% points in each one. Overall survival roughly about the same in each of these. And once again when you look at the right hand side, um, this is once again looking at pet 2 positive showing that pet 2 positivity has um uh a more of a detrimental effect than if you're petT2 negative. You can't really make a difference between these two whether or not Escalate to be a cop or breed cat is better if you're pet too positive, but just showing that if you were, you tend to do a little bit worse. And I think a big part of this also is really just looking at the doses because when I showed what the regimen for escalated BAO versus BRCAT is, you could see escalated BOP is a very intense regimen. There's a lot of things that go into it, not to say BRCAT is not. BREA also has a lot of different things that go into it that can make it rough, but when they compared the full dose of what the. Percentage of each uh of with each cycle, the full dose that patients receive in the yellow lines here, this is BRCAT and the blue lines, this is escalated BOP. So you can see as you move further down, more patients on the escalated BAOP are receiving their full dose as opposed to the BRCAT who are still receiving that full dose and therefore that likely has some efficacy effect. So as I mentioned, similar to the um to the Nebolaab ABD arm where they looked at an elder population, they also looked at an elder population for the HD 21. This was this was presented by Dr. Fernandez at AS this past year. And so this was a phase two that was built to the HD 21. It was advanced stage, media age anywhere from 61 to 75, medium age of 66.5. You can see the out you can see the, um, kind of what the, the, uh, schema here is just is just pretty much the recat arm. In terms of side effects, neutropeic fever was documented to be 54%, and then they saw treatment related morbidity at 77%. Treatment related morbidity is defined as any non-acute hematologic, um, event that's higher that's grade 3 or higher, or you have a grade 4, a grade 4 toxicity. So 54 and 77, those are high numbers. I just wanted to kind of point out that these are really high, um, but if you look at the progression free survival of 1 in 2 years, 95% and 91%, and the overall survival survival of 1 or 2 years, 96% and 96% and 90% patients responded very, very well. So it's kind of one of those situations where if you kind of survived through the fire you did really, really well. Alright, so that's kind of the standard current, um, current treatments and what we, what we do right now for Hodgin lymphoma. In the last 6 minutes here I wanna kind of talk about what's coming down the pipeline, things that I wanted to bring attention, not, not so much as practice change right now, but things of just how we could potentially what's potentially coming down the pipeline, and that's really exciting. So this first, um, thing I want to talk about is a study done by Dr. Lee, and this was looking at renttuxabab, volumab, and then combining with doxorubicin and darbazine. So you know, you're just kind of slowly switching out ABVD for kind of these novel agents. This was a phase two study and it looked at stage 2 bulky or advanced stage, once again, including young patients aged greater than 12. And so what they did was they ran 6 cycles of this branttuximab Nvo AD ADR. And as you can see from the objective response rate, you had an objective response rate about 93% with the majority of those being in CR and when you look at the two year overall progression for survival, it, it shows about 88%. Now I didn't show, um, another study that came from Doctor Abramson who showed the early stage kind of sister study of this one, but overall it kind of showed even better numbers. So why am I bringing this up. Why am I talking about this right now? Well, do I think this will replace the current standards right now? No, probably not. If anything, as we, as we're running the phase 3 data right now, we'll see what that shows. If anything, it'll kind of be another potential option. But where I think this will really sit is that as I was showing in my slides earlier from the NCCN guidelines, when you have early stage disease and you have ABVD times 2 and you're kind of trucking along it. But then randomly you, uh, but then after your PET scan, if you do, if you are PET 2 positive, which we know has shown continuously do worse. The current treatment is for for us to go to Escalate to be a cop or in this case BREAT because those are allowed, but that's a big jump, especially for patients who are older. So this may actually serve as a nice alternative to that, whereas opposed to having to jump all the way to BREAT or escalate to be a cop, we can just kind of use BV Nivvo AD, and then that may be enough to push them over so therefore they can get into a complete remission. So I think that's where this may have a very good um spot for, uh, into the algorithm. Now just to kind of talk about molecular subtypes, so, um, as kind of Doctor Napoli mentioned for Hodgkin lymphoma, we have the four, kind of known classical Hodgkin lymphomas which are the nodu sclerosing maxillarity, lymphocyte deplete, and lymphocyte rich, um, these kind of make up your classic Hodgkin lymphoma that we usually talk about. You have nodule lymphocyte predominant Hodgkin lymphoma, which is kind of like that's. Thing you never talk about really so we're not gonna talk about them as much, but in all essence, the four of these really get treated the same even though they have distinct differences they still get treated the same and so there's this big movement in Hodgkin lymphoma right now to see how can we better characterize these, these different Hodgkin patients and is there a better way to do it than the traditional way. So a big part of where this kind of different characterization is going is looking at the tumor micro environment. We know the micro environment plays a huge role in Hodgkin's lymphoma, and so there's a lot of different research right now going into seeing that can we analyze these different areas losing single cell. RNA sequences to see like all right what is working with what can we find new targets and therefore develop new drugs because it's been a while since we kind of had one I'm hoping we have one soon a little plug for my own clinical trial, but hopefully we have one soon um but you know it it's this is the process that we have to do that we have to dive into deeper. Now another way to kind of group these subsets of Hodgkin's lymphoma is really looking at mutations as we know with a lot of different lymphomas, we use certain mutation statuses to see to group these patients because we know they act similarly. So Doctor Aoki at last year's Hochkin lymphoma, um, symposium showed this abstract where he said that there was he kind of grouped 4 different subsets of Hochin lymphoma patients based off of certain mutations that kind of fall, that kind of grouped together, and he's able to show that these. Different subsets were linked with more, you know, older age with the EBV status, and I think it's only a matter of time before we're able to then to say, OK, we know you fall into this mutational status, can we use a different regimen? Can we use this regimen instead and maybe that'll have better effect. And kind of the last big part here to look at in terms of ways to kind of group people are circulating tumor DNA or you know looking at MRD status. So and a study done by Dr. Hager at also at the Hodgkin lymphoma symposium, he looked at circulating tumor DNA and kind of the differences between them, and what he found was three kind of distinct subtypes of these, um, I won't go into each. Of these, but you can see that they're different, that they have differences based on the T. rex differences based off the cytotoxic CDH cells, and when they mapped out progression free survival, you can see there's a difference between each of these lines. So this could be another way to really start grouping these Hodgkin's lymphoma patients into saying like, yeah, this patient has inflammatory, they're going to do better or worse based off of this. And so it's something that I think is really cool that's coming up and um the last thing I'll kind of end on here is saying that circulating tumor DNA similar to all everything that kind of Doctor Dunleavy and Doctor Rose were mentioning today for being able to track um Hodgkin lymphoma disease status, this is likely going to start coming to play here soon as well. There was another study done at the Hodgkin's lymphoma symposium last year. That kind of looked at um that looked at circulating tumor DNA and MRD status as well as PET um correlation and what they saw was that some patients who are PET 2 negative if they were circulating tumor DNA or MRD positive, they actually had a higher risk of relapse as opposed to if they didn't. So once again, nothing that we're doing right now, but things that will potentially come up as we move forward. So conclusion, um, for early stage we're trending toward limiting more toxicity if we're able to, um, it seems like we're able to do that and still have similar efficacy, which is great novel agents are getting incorporated into the front line. Um, I think this is where the future is going. Like I said, we're I, I showed you the. Data I show you the breach study 8 those are both phase 2s. The phase 3s are undergoing right now, but I think it's just a matter of time before those kind of come into our front lines the stuff that we reach for right now. For Advanced Stage, Nivva AVD and BRECAT are technically gonna be your front line settings. Older patients with advanced stage, you technically have the ability to use either one just choose. Based off of the data I showed you and so like you can take either one and then there's a lot of new evaluation modalities coming up on the horizon and with that I finished with 8 seconds, so thank you. Thank you, Doctor N for crushing that talk just like uh frontline Hodgkin lymphoma, but for the unlucky few patients um who we still need of course to treat and manage and help hopefully get them to a cure or at least to make it a chronic disease, uh, it's my pleasure to introduce Doctor Matthew May from the City of Hope in Los Angeles. Uh, Doctor May is an associate professor of, um, hematology oncology at City of Hope and he's also their fellowship director as well. Doctor May, thank you and please take it away. Which one is What, huh? Oh, the oh, the big green one, it makes. OK, all right, uh, so last and, uh, probably at least you get to hear me talk about relapse ofracy Hodgkin lymphoma. Um, so thank you, um, to, to Doctor Cortiz, to Doctor Hernandez Ilia de Turri for the, the very kind invitation to come here today. Um, so I'll be talking about relapse fracture Hodgkin lymphoma now. Honestly, uh, the stuff at AS 2024 was not really all that inspiring in, in this space, um, probably because, as Doctor Ne has pointed out that, uh, we, you know, we are, we are rapidly conquering uh Hodgkin lymphoma from the get-go. But having said that, I, I will discuss two abstracts from 2024, um, but then I'm gonna just, you know, talk a little bit more about, you know, one of my sort of favorite topics in Hodgkin lymphoma, which is, you know, the, the what I think is the optimal salvage. Therapy and the salvage approach, um, and then kind of dovetailing with that the importance of, uh, checkpoint inhibition prior to auto transplant. I, I, so again spoiler alert, I, I think, um, that the impact of checkpoint inhibition prior to auto transplant it's, it's, I think the magnitude of effect is too big to ignore, uh, and then also, uh, I guess we'll talk about novel therapy so you know I'm gonna put novel and air quotes, right, we still talk about, uh, BV and, uh, PD1 blockade being being novel, right, even though these have been out for, for a while. Uh, now, but yeah, have you noticed, right, every single Hodgkin lymphoma paper starts out saying, oh, you know, since the advent of the novel therapies, you know, Bertuximab and, you know, checkpoint inhibition, these have been transformed, right, this same, same thing, right? I mean, all my papers are like that too, so, um. So right, without further ado, so, um, so kind of blitzing through the, uh, the second line Hodgkin lymphoma, uh, space. So, um, so auto transplant has uh been the standard, um, it's not really a de facto standard it is a standard. I don't know why I put that in the slides. So, um, not a lot of randomized data though. So these data are very old, right? Um, so, uh, you know, the original, for instance, BEAM versus DeXABeam, I mean 1993, I mean that was just a little bit before when I was a fellow, um. And but in the interim, right, there's, there's no not really any good randomized data in the, you know, quote unquote right novel era, um, you know, basically, you know, circa early 2010s, right, with BV and PD1, um, and so we're kind of stuck with, so we've been kind of stuck with this paradigm for a while, right, for relapse disease which is, you know, someone with Hodgkin lymphoma, they're not cured with front line. Therapy and then you know you do some sort of salvage um you get some sort of response um and then you go to transplant and I, I probably should have had a box under there uh with you know, question mark, you know, maintenance consolidation, um, but really kind of around each step, right, there's some prominent questions, right? I mean what is the optimal salvage therapy, um, you know, right, we got chemo, we got BB we got PD1, and we have every possible permutation of those three. Um, and then, you know, with transplant, OK, I mean, the transplant conditioning has been, and I think the field has generally coalesced around, around beam for the last decade or so, um. And then, but you know, the kind of a more provocative question, do we even need to do auto transplant, um, and so we'll talk a little bit about how we're kind of chipping away at this question and kind of where we are today with this, um, and then also a little bit about, you know, one slide about, you know, do we actually need consolidation is uh at all, um, hopefully see how genetics isn't here so. Um, alright, so again blitzing through the chemotherapy part, right, this is, this is old, um, but basically irrespective of which regimen you pick, you know, um, pick basically any three side of toxic chemotherapy drugs that weren't given the front line, and you get a CR rate around 60%, right? I mean 65, 60, you know, I, I get the have, they're all the same, um. And then we know also very well from this era that you know the type of response or the depth of response you get with chemo uh kind of writes your ticket as far as your post auto outcomes, right? I mean if you get a CR now pro probably be cured if you don't, um, auto doesn't work nearly as well, right? So, so, um. So obviously the next, you know, to the scene was Brintuximab, uh, Voton, um, not gonna belabors, you know what what this is, um, but you know this was, you know, for, for the fellows here, right, it was initially approved as, you know, in the relapse refectory setting after a couple lines of therapy and then came the maintenance and then came the frontline approvals, um. But kind of in the early days, right, in the early like free for all days, and we're trying to figure out how to use this drug, right? So we had this approved in the in in kind of relapse refractory settings and then, you know, we wanted to bring it in earlier settings, right? So, um, so this was tested in all sorts of ways, right? So, uh, City of Hope, so we ran the trial of BB monotherapy to try to bridge people to auto, um, and so we're actually in our small in the in our series, and then that was published I think in Annals of Hematology in 2018 we were able to get about half of the people straight to auto just off of BB alone. Um, you know, you know, CR rate again, the 3 was about 40%, and then, you know, some patients with a very BGPR, you know, went, went straight to auto without any other chemo. Um, certainly, you know, then there was a sequential BV followed by augmented ICE from Doctor Moskowitz's group in Memorial, then, you know, BB plus ice and then BB plus all the other, you know, chemo, you know, you know, Dhab Bop, whatever, um, bendomusine, and then, you know, broadly speaking again. Maybe if you squint really hard, the response rates might be a little bit better than than chemo but really not, not that different, right? um but still like this is sort of the first incorporation of, you know, one of the novel right therapeutics into the space, um. And then I, I would say that the next sort of big step was, was when when Nevo kind of burst on the scene, right? um. And so BB and Nivvo being um, you know, drugs with non-overlapping toxicities right it's natural you kind of put it together, right? You take the two best drugs for Hodgkin, put it together and and see what happens, right? So, so we tested this in the in the uh in the second line. Uh, uh, setting, um, and the, the results were great, right? So for uh an ostensibly chemo free regimen, depending on how you define BV and the MMA moiety, right, gonna essentially chemo free, um, we were bridging the large majority of patients straight to transplant. Um, and so one, you know, and kind of two things from that, from that study that kind of made you go a little kind of hmm, right? That number one was that you know the of the patients who went to transplant and so most of the patients who didn't go to transplant. Did not want to go to transplant. It wasn't for lack of response. Most of them had refused, but of the patients who went to transplant, the post-transplant PFS was really, really good. So that was one thing. It's like, yeah, again, limited numbers phase two, who knows, right? You know, but it seems it kind of eyeballs better than what you would have expected after uh auto transplant. Done after, you know, chemo salvage um and then the the other thing that again and kind of a small subset but it was also kind of it was like hm interesting that there was a pretty wide separation of results between patients who are primary refractory and for patients with relapse disease um. And so this, you know, and so the PFS was obviously quite a bit different in those two groups and, and the CR rate was also and it was mostly driven by like a pretty sharp difference in CR that kind of, kind of mirrored that as well again, you know, subset analysis, you know, for the fellows you're not supposed to look at subset analysis to, to care, you know, you're not supposed to dissect it out too much, but again, you know, kind of, you know, food for thought, right, so the, so then the, the next, um. There we go. Then the next, um, thing that we did was, well, you know, so now there's been, you know, BB, BV plus chemo, um, BV and Nivvo, so, so let's look at PD1 plus chemo or PD1 + minus chemo, right, kind of the next, uh, iteration of, of, uh, studies for this. So, um, so we, uh, put together a trial of, um, so this of pet adapted Nivvo plus, uh, plus or minus ice so. This actually kind of went in two phases, so the initial cohort, uh, was, uh, wasivvo monotherapy. We gave it for 6 cycles, um, and then for patients who had a PET CR, um, they went straight to transplant and then for patients who were not in a CR, then they got 2 cycles of Nivvo plus ice together, um, and again the idea was kind of explore. Kind of this, you know, the, the space, you know, we thought, hey, maybe we could bridge, you know, a third of patients to transplant directly off of Nivvo and then the rest would get Nivvoice and whatever, um, and so we were kind of, um, kind of surprised when, uh, almost all the patients just went straight to transplant off of Nivvo. It was kind of unexpected, uh, to this day I don't really know how to explain that the fact that, you know, our CR rate was 70% and I don't really think it was spurious because the post transplant, you know, results were, were awesome, right? So the large majority of patients didn't need to do transplant. Um, but the kind of the upshot of it was that we, uh, you know, didn't really get to learn much about the Nevo ice combination because not that many patients actually needed to get chemo with this. And so, so these are the results that we, so these are the, the data, the charts from, uh, I think this is taken straight from the blood paper that we had. Um, so again, you know, excellent to your PFS overall survival, um, and then for the, and then PFS for all treated patients, a lot of those patients opted not to go to transplant, and the ones who, you know, for instance, got a CR, didn't go to transplant, every one of them relapsed, so that, that kind of a diluted the PFS out there and there there's, I think 5 or 6 patients that that decided to, to, um, you know, to skip transplant. Um, So as a result we then decided to look at Nivvo plus ice together, right? So you know we're like, hey, we wanna learn more about Nivvoice this combination and so then we opened a second cohort on this trial so all patients will get the whole shebang. So you know they would get one dose of Nivvo and then two cycles of Nivvo plus ice together, uh, and then we restricted it to high risk patients. Uh, we define it as meeting, you know, one of the old Ethere criteria or receipt of tuximabbidotin in the front line setting, um, and so. And um and yeah so these results are, you know, these are the results are strong, so, uh, kind of on par with what you would expect with PD1 plus chemo. So and I, I promise I'll be talking about Pember GVD in the next slide, um, but you know since uh N Ice from City of Hope and I'm talking I go first with Nero I. So, uh, so you know, you know, CR rates in the high 80s, uh, again very similar to, to, to Pembro GVD Pembro I, um, post transplant results have been really good. Uh, one thing that we, we don't really. Understand is, you know, the engraftment syndrome, um, and this was, was 14%. I think in cohort A is around 20%, uh, once the difference between this and the the engraftment syndrome risk is over 60% in in the memorial data, I'm not really sure what this where this discrepancy comes from. We are actually specifically looking at the question of engraftment syndrome, uh, post auto now in in a multicenter study, so hopefully we'll try to figure out what why why there's such a gulf between the regimens, um, and so this was accepted in the hemisphere, the. I sent in the proofs a while ago but I guess it's not online yet. So, um, and so Pembro GBD, so this was published in 2021, um, by Doctor Moskowitz. So, um, so Pembro GBD, um, given for four cycles prior to auto, as you can see that this curve looks better than like a lot of front line curves, right? This is a relapse curve, uh, so really, really spectacular results, um. Interesting, like the, the, the rate of engraftment syndrome was, was really high, uh, you know, which is, which is one thing I point to saying Evo ice is better just no just kidding. I, I, I really don't, I honestly do not know why there's this discrepancy, um, and I, and this, we are, we, we do, this is a very interesting sort of finding, um. But really like an incredibly um you know, effective, um, effective regimen and the nice thing about this one too is that um it's a little bit easier to give as an outpatient since you don't have to do, you know, 3 days of ice. A lot of community places can do ice as an outpatient, but Pembro GBD is, is very easy to do as an outpatient. The one big thing is you get a lot of mucositis with this. That's the only major issue, um, but otherwise it's, it's very well tolerated. Um, and then on the heels of this, well, there's, there's also Pembro ice, and you know, again results that are frankly pretty similar to Nevoice. Uh, one patient did die of actually engraftment syndrome post auto, uh, so you do have to, you know, be vigilant, right, you know, for, you know, the fellows if you see someone who, you know, gets PD1 plus chemo salvaged, then goes to auto, and then, like, you know, they're not really febrile when they're neutropenic, and now they're like ANC starting to peak up and then they get high spiking fevers, uh, that's time for the steroids, not the anti I mean you get them the antibiotics, but you gotta give them steroids too, right. Be just be vigilant for for this, um, but the nice thing also about all these is that kind of it's a proof of concept, right? you know whether you use Nivvo or Pembro, whether you use ice or ice or GBD, um, either way, right, that if you kind of, you know, in putting all three of these studies together, right, there's a decent number of patients that, um, that it seems like there's a kind of this class effect, right, this concept of BD PD1 plus chemo kind of irrespective of the backbone works incredibly well and obviously now we've also seen this with ABD in the front line as Doctor N talked about. So you know, the striking synergy between PD1 blockade and chemo to me is one of the most remarkable stories in Hodgkin lymphoma in the last 20 years. And OK, so a little bit more uh about this topic of PD1 prior prior to uh auto. So, um, you know, so in the early days, um. The, uh, you know, I, I remember a lot of patients, you know, when I was when I was a, you know, younger attending. Um, you know, they would have a BVD, they had ice, and then, you know, then they weren't responding that well. Then they would get some BV, to get a transient response and they progressed before you could get the auto, right? We saw that a lot and then, you know, as Nivvo and Pembro kind of, you know, coming on the scene, you know, they get, they'd get one of these, they'd respond and then they'd say in response for a while and then we're just like, well, now what do we do, right? I mean they're, you know, and it was kind of very tempting to, to be like, huh, maybe we should consolidate this in some way. Allo seems a little overkill. What about auto, right? Um, and so. And on the face of it, it sounds, uh, seems like it doesn't make much sense right again to the, to the fellows, uh, here, right? You know when we do auto transplant, you think of this as, you know, the one of the central dogmas right in lymphoma is you do auto transplant for patients who are who are chemo sensitive, right? The auto is just a really big dose of chemo and so if they're not responsive to a little bit of chemo, they're not gonna be responsive to like a big dose of chemo, uh, at least not, not in a durable fashion, right? Um, but having said that, right, you know, these patients were responding well to people. One blockade we're kind of getting some itchy fingers and some people just, yeah, we just ended up transplanting some of them, right? I mean we did a few at City of Hope, you know, throughout the country there were a few patients that just they just got an auto, right? And then so we were interested in kind of just seeing like, you know, collecting these like, you know, individual anecdotes from different centers and, and seeing how these patients did, and it turned out they did really, really well, like shockingly well, right? So, so in a group of 77 patients, all of which were ineligible for auto because they didn't respond. To second line therapy and then who got transplanted after PD1? The 18 month PFS is 81%. I mean that's like, you know, maybe even better than what you would expect after second line ice, right? Um, and so this was a really remarkable finding, right? So ostensibly chemo refractory patients were getting cured by auto, right but after PD1 blockade. Now we think it's probably due to this chemo sensitization effect from, from uh checkpoint inhibition, but it was a really remarkable thing when you actually looked at. Data and I mean ironically like the pre-transplant, you know, PET PET scan which is like you know the most important thing ever, right, but it seemed like maybe not even that important whether they're in PR or CR, you know that I don't know if I really buy but uh but nonetheless it the kind of the, the big irony of it all is that you know perhaps in Hodgkin lymphoma, you know, this PD1 exposure and and PD1 sensitivity might be more important for auto success than chemo sensitivity in in a certain kind of weird backwards way, right, um. And then to that end, so we are, um, so we also decided to look at this question in in bigger detail. So, uh, we have a, um, so, uh, we did, uh, a retrospective study of a lot of patients from many centers, uh, a lot of charts were were reviewed, um, I think we reviewed like 500 charts of city vote, um, of, of patients who had got transplanted in in in Hodgkin lymphoma. So this is, um, so, so, um. So, uh, so this was presented, um, you know, recently at, um, at, at Ash, uh, so this is one of the ASH presentations right from 2024, um, we are working on the manuscript right now, um, but you know, in this study, so 3/300 patients had been exposed to PD1 pre-transplant as, as you can see, uh, that green curve is the, uh, PD1 group, right? So it seems as though PD1 exposure. Really makes a big difference and again the study is definitely power to look at this, um, and then the interesting thing is I, you know, the first, you know, gut reaction may be, well, you know, maybe just because, you know, you get Pembro GBD you go into remission and then you know it's because everyone's going to transplant CR. Well, if you actually just restricted to patients in CR, right? So just of all the patients that were transplanted, you know, pre-transplant CR. Regardless of how you got there, the effect is basically the same, right? So it does seem like perhaps not, you know, this kind of, you know, points to the notion that perhaps not not all CRs are made equal, right, that a CR that you realize with PE1 plus chemo may be better than a CR with just chemo, and especially as far as subsequent auto goes and again, you know, we theorize that this is probably because of a chemo sensitization effect from the checkpoint inhibitor. Alright, um, and another slide, so the, so this is from, uh, the Ash the previous year, so this is from the same, you know, there's a this, this large data set, right, it's not just this gonna be just this one project that there's a lot of side projects with this. So one of them also is that we didn't really see any benefit from BB consolidation, uh, for patients who had pre-transplant. Uh, PD1, we actually didn't really see much benefit for people at pre-transplant BB, uh, either, and then, you know, and also Doctor Shah has shown that maybe the, you know, the dose sensity of BB or cum, you know, maybe it doesn't really matter either, right? It seems like you got 8 cycles of BB did fine, right? He, I think that was a couple years ago as well, um, so that was another sort of side thing that that came out, um. All right, and so, um, so, so again I think. You know, as an, as an opinion, right? I think there's enough information to, to suggest that really PE1 blockade is critical prior to auto transplant. Um, I'm not sure really that there's actually echo poise left, you know, as far as, you know, PD1 plus chemo versus chemo, you know, I know there was a randomized trial being being planned for this, but, you know, I think that would quite frankly be challenging with these data. Um, now next question is can we do away with auto transplant, right? So with Pembro EVD for instance, right, you're seeing a CR rate of like 95%. So surely some patients must be cured with this, right? Well, I, I don't know, do we know the problem is we don't know, right, because the paradigm for so long has been you do salvage, you do auto. So what is the impact of this, you know, independent of auto, right? So Doctor Moskowitz then did a, you know, extension of the trial where they did 4 of hemorrhage GBD and then they just follow up for patients in CR you just follow up with Pembro maintenance for, for 13 more cycles. So, so the total is about a year of treatment and then. And then so the 2 year PFS was 60% so you know it's a little bit of a glass full, you know, half full, half empty, right? And it's kind of in the eye of the beholder, um, you know, it did seem like, you know, again this is 2 year PFS, medium follow up was 30 months and then the treatments was for 1 year, right? So there at least is some staying power, uh, for this, um, and. And if you look at the, the patients who relapsed, um. The, uh, if you looked at the patients who relapsed, you know, about a third relapsed during maintenance and some after early, some a little bit later after, but the ones who relapsed, uh, all of them except for one who was not eligible for transplant due to comorbidities, every single one of them otherwise was salvaged by by some salvage therapy, most, mostly chemo plus minus PD1 went to transplant and then none of those transplanted patients relapsed actually. So it seems like sort of at least failure from second relapse was fantastic, uh, in in in this data. And so, um, and so as far as sort of thinking through that like what um. Sure OK, as, as, as far as thinking through sort of what you know what might be predictive of, you know, who might be who might do better or worse with a with an approach like this, you know, skipping, um, skipping transplant, um, the one variable that really popped was the, the stage of the disease at the time of relapse. So patients with external who relapse with extranodal disease. You know they didn't seem to do so well with, you know, PD1 plus chemo with, with, um, you know, PD1 maintenance and skipping transplant and so this actually has now, um, so these data actually have been formed a randomized trial so there's uh gonna be a randomized trial of of Pembro GBD, uh, for 4, you know, at Pembro GBD times 2 for patients in CR they'll either basically go to. Go to auto or you know 2 more Pembro GBD and followed by Pembro maintenance um and then you know we'll we'll, we'll see, you know, the main, um, with the main uh end point being a 55 year failure from the disease or not failure from progression but failure uh free of disease, um, and so we're, uh, so we've definitely signed on, on board at at City Hope so see we believe in Pembro GBD as well, um. OK, and then another again this is, this is, uh, so this is a Chinese study that's published in hematologic a couple of years ago, uh, kind of another, you know, small provocative study, um, this was with tisslizumab, so it's a Chinese PD1, um, uh, monoclonal antibody with gem ox as the as the backbone, uh, and there was up to 2 years of maintenance, uh, tissellizumab, um, so, uh, a lot of gem ox was given like 6 to 8 cycles, um. And then, um, let's see here. And then the results looked, uh, really, really, really good. So you know, median PFS was not reached, uh, everybody, everybody responded, you know, and obviously, yes, you know, getting ongoing, you know, maintenance PD1, you know, means you're less likely to relapse in that period. But we saw with Pembro GBD, right, that, you know, about a, you know, 4 of the 10 relapses happened during Pembro maintenance, right? And so, you know, it was, you know, remarkable findings, right, that, you know, they, you know, there's, there's this kind of ongoing claim that Gem mocks a little bit more immunogenic, right? So you know, who knows if the backbone really matters, but again. Um, you know, yet another sort of, you know, kind of yet another data point to sort of nudge us in the direction of maybe skipping auto. OK, alright, so what about, what about like truly novel therapies, right? So, so now we can finally lose, lose the uh air quotes and you know, something actually new right beyond Nivvo, Pembro and BB. OK, so, um, you know, so this has been frankly a little a little bit, uh, a little bit disappointing, um, you know, the the the last few years, right? And so one area of research and one area that's, you know, that that I've also been involved in is is kind of optimizing PD1 blockade and and. With the thought that you know, uh, so first of all, PD1 blockade probably works different in Hodgkin than it does in solid tumors, um, and the other thing is that we for those of us who've who've, you know, given it more than a couple of times there's a phenomenon that we all know really well, right? You, you know, you give it as monotherapy patients get a nice, like let's say they get a nice partial response it lasts for like. You know, 8 months and then they're progressing, but they're progressing slowly and you scan them in 4 months and they're progressing a little bit and you scan them again it's progressing a little bit and then it's been like 2 years and they're fine and you're still giving it right so um and that's very weird, right? I mean that's not like any sort of progression that you would see if the tumor truly is like mutating like a new pathway or whatever, right? So and it kind of smacks more of maybe maybe the immune system is just is just getting kind of tired of like you know getting getting hammered like over and over and over with P1 blockade. And so this, so there's been this, um, so there's been efforts to, to so called, you know, restore PD one sensitivity and, and a lot of things have been tried in this space and so I just kind of run through this really quickly, right? So hypomethylating therapy, so, so the Chinese study cameraliab and decided being, um, you know, in the PD one experienced cohort, they didn't specifically they didn't specify who was refractory or not, but you know. P1 or in the PD1, uh, experience subset, you know, most patients responded, right? And so we also, we, we had an, so I had a trial of Novolliab plus, uh, oral azocyanine AKA CC 486. Uh, it was convenient because, you know, you know, this is the oral version of Aoyinine plus they're the same company, so it's easier to do IT that way. Um, and you know, in the, in an exclusively PD1 refractory cohort, most patients respond to it and so this is the preliminary data from Ash. uh, we've, we've enrolled all the patients we're, we're analyzing the final data to, to presenter publisher or something, um. And then also, so, um, so OK, so there's one, you know, epigenetic therapy. What, what about, what about a different one, right? What about HDAC inhibition? Well, uh, we looked at Pembro Vernastat and, um, you know that all that also worked, right? So, um, you know, initially it was for PD1 naive and then we kind of allowed PD1 treated and then we restricted the PD1 refractory right as the results were, were, you know, we were coming out, um, and then most patients. PD1 refractory disease responded, which is remarkable. I mean they didn't respond as well or as long as PD1 naive, but nonetheless it was working, right? I mean, there is some mild measure of overcoming PD1 resistance for this, um, and this is actually in the, uh, this actually has the NCC and Compendium listing now, right? And then, um, and then, you know, another ASH abstract, right, uh, so Pembro and tennistat, another HDA inhibitor, these results are basically identical to ours. Right, so you know it wasn't just a flukey thing, right? You know, a different HDAC inhibitor works, um, so you know what, what, what about the whole shebang? What about just putting it all together, um, results were even better and there was actually very interesting some, some, a number of durable CRs even when the therapy was all stopped. So very, very, very provocative paper from, from Blood that was published last year. My time is about to come out, come, uh, finished. So, uh, in terms of other novel therapy, so, uh, so obviously there's a lot of alternatives. Checkpoint and, you know, check, uh, immune checkpoints, uh, short answer is they've been looked at and they've all been found wanting and we're not really pursuing them anymore in Hodgkin lymphoma and, and the, the basically the development for all these has stopped and I this is a very partial list on the bottom. These are just trials that we've opened a city of hope for, you know, that enrolled Hodgkin lymphoma patients. Every single one of these programs have like stopped enrollment unfortunately they, they, they've been terminated in Hodgkin. Um, and what about other stuff? So the CD 30AT, it is an incredibly sad story. I'm not gonna, I, I, I'm not gonna regale you with the whole, like, you know, whole, like tragedy, except to say that the that the company went like bankrupt literally during the second line trial we found out during for like a press release, um, and so, you know, the CD 30AT, long story short, you know, kind of miss the trial was mismanaged, but also quite frankly, it just wasn't working that well. The the one year PFS was like 20% and that's not gonna get you anywhere, right? um. For the phase two, right, the phase one looked good. Phase two kind of like, kind of, uh, you know, didn't go so well. Um, what about other stuff? So there's another CD 30 car that was, you know, published recently in Blood Advances too toxic. It was stopped, um, and then the enmb had a CD 30 by specific program stopped, right? A lot of DLTs, a lot of rashes, and then they, they stopped development, right? So just to say again, highlight that this has been a very difficult space for innovation and then finally, you know, the one thing that may, you know, may have a small chance, although. I'm, I'm the PI of this one city hope to and you know some, some questions about about where this is really gonna go from, from the company standpoint, um, you know, although there it has been accepted a couple of ROI abstracts this year, um, AFM 13, you know, a CD 30 by specific, uh, with CD 16, which is not NK cells, so pairing with like sort of NK cells, you know, at first they did it with, um, pre-complex and you know they precomplex complexed it with NK cells at MD Anderson had a great response rate, although, although the response is kind of cratered after 6 months if you actually looked at the. You know, in detail, and then so this is a and then kind of a riff on this where they kind of at they instead of doing it with pre-complex NK cells they infused it simultaneously with an off the shelf NK product, you know, early results have been, you know, OK, right, but each cycle requires more flu size so I mean it's not, it is toxic, it is very cumbersome, um, and so we'll, we'll see jury's out as far as where this is gonna go, um, and the other thing I did mention is there's also, there's also another novel CD 30, um, anti-drug con conjugate from CGen. Uh, with a Catohesin backbone that you know, SGN 35C, uh, which is also in trials right now, um, but ultimately, um, so in summary, um, I think PD1 therapy should be standard in the relapse refractory setting, especially if we're like contemplating transplant. I, I think the data to me are too strong to ignore. Um, we're not quite there as far as omitting auto transplant. Um, I think hopefully we'll figure out who we can do this for safely. Um, although again it does seem like if you skip it and you and you guess wrong and they relapse, it seems like you could still cure them, um, you know, with more salvage, um, and then ultimately the further progress in the relapse refractory space is, is very challenging, um, I think this is, um, you know, in some ways a, a byproduct of just uh how good we are at treating Hodgkin in the 1st and 2nd lines, um, but at the end of the day, you know, there's still, you know, a small but real group of patients who, who do need newer therapies and, and we're not. Really offering it to them right now, uh, but you know, but innovation in the space is very challenging so uh with that thank you very much. I'd like to invite Doctor N. Thank you for coming up. If there are any questions, either online, please put them in the chat for Hodgkin lymphoma experts. Love to hear them. Yeah Thank you. Uh, two questions for Doctor Mai. Uh, one is that in one of your studies you, um, give, I think 1 or 2 cycles of nevolloab followed by NOIs. So, we, what is the pre pre-clinical rationale? That's one question. OK, um, so the pre-clinical rationale was that. Originally there was this debate as to should we be doing sequential PD1 chemo versus combined, right? And the, the thought was that. If you do it sequentially, maybe you, I guess, well, uh, so first the concern was that if you do it combined, you know, are you in some ways, you know, could you be canceling out the PD1 effect by, by your cytotoxic chemos or maybe you're, you know, you know, maybe you're you're trying to activate T cells and you kill them at the same time. So maybe you're kind of attenuating the effect. So then the thought was if you did sequential therapy, maybe you, you know, you let you kind of unleash the full power of PD1 blockade and then you hit it with the chemo after. I think with all the subsequent stuff, you know, I mean, yeah, you know, to, to write the original Pembro ABD data right from, from, um, uh, from, from, uh, Doctor, uh, from I can't remember the name so but the original Pembro ABD it was sequential, right, um, but then, you know, you know, that then there was another one that was kind of, kind of concurrent then Neval had a concurrent versus sequential, you know, Nero AD didn't seem to matter. And then, you know, ultimately 1826, we just, you know, gave it all at once. So I, I. I feel like, I think the rationale initially when we designed this cohort B was to kind of just give one priming dose, you know, let the PD1 work its magic before you hit it with chemo, but I think in retrospect, it probably doesn't matter and full disclosure, when we actually give it like outside of a trial, we just give it all together, so. And the second thing is that in the on the last slide when you uh put your conclusions, you said that, um, almost all salvage regimens should have PDL1 or BV or some kind of combination. So what you're saying is that the ice and all those things are totally extinct. They should not be used for salvage. No, no, no ice is great. I mean, just, but I think you should give it with PD1. I mean, I, I, I should have, I, I mean what I meant to say was, especially the intents go to go to if the intent is to go to auto transplant, it should have one of those in there. Um, you know, if you're just giving, you know, single agent palliative therapy in the like the 8th line or whatever, you don't, you don't necessarily have to, but, uh, you know, if you're trying, if the intent is to get a good response to get someone to auto, I think adding PD1 blockade is really important because I think you, um, not just you, not you don't you not just turbocharge the chemo, but I think you, I, but I think the actual transplant conditioning then becomes a lot more effective. Excellent thank you. I have a question for my um, do you think that, um, the duration of the remission, uh, in patients with relapse Hodgkins lymphoma maybe play a role in whether you need to have a checkpoint inhibitor or not. So, um, so what was, so does it as far as does it affect the, well, yeah, so like if you have patients that this primary refractory maybe the checkpoint inhibitor plus chemo may be a good idea. But if you have someone who was in remission for 2 years, maybe they don't need the extra. So this is a, this is a great question. I, and I, I wrestle with this too, right? So I mean one thing that was so obviously right in BB Nivvo we saw that there's a big difference between primary factory and not again whether that's real, who, who knows, but the, the magnitude effect was large, whereas in every single one, right, every single PD1 plus chemo study there's no difference between primary factory like that, that, that risk factor completely drops out in every one of these studies. Does that mean PD1 plus chemo overcomes the primary refractory thing and BBevo does not, I, I don't know if we could really say that definitively, but having said that, um, you know, and it's funny, I, I don't know exactly how many years I would say for late, but you know, certainly if someone had A BVD 5 years ago to come to me, you know, they have any comorbidity, I just, I probably just give him BBevo, to be honest and go to transplant, um. And so, uh, but I, and, and we also do see a lot of people in the, you know, and a lot of the community patients that get referred for transplant, you know, a lot of them have already gotten a cycle of something, and it's frequent, and I, I, I feel like in the community I see more BB Nevo than, than, um, you know, Nivvo I or Pember GBD, um, but yeah, for me personally, I'm definitely so you know if it's a kind of a lower risk relapse, you're not checking any of the the the boxes and it's a little bit and, and it's, you know, again it's after like a year or so I'm, I'm pretty comfortable just giving BB Nebo. Uh, quick question, um, you know, it's great that the PD1 antibodies are moving to the upfront, um, with the ABD. Um, what would you use when someone relapses after an upfront PD1 based regimen and what would you be a choice of regimen to treat in those patients? Yeah, I mean. You know, totally unanswered question right now, right? I mean, you know, we're, we're, you know, we are obviously starting to see a few relapses, um, you know, we have, you know, we've had a couple of 1826 patients who've who've relapsed, you know, on the Nivvo ABD arm, um, I'm still, I'm still a proponent of trying to get PD1 plus chemo in them, you know, at least to try to sensitize it for the for the subsequent auto. I mean they if they, you know, I mean there uh one of my colleagues had a patient who just like actually straight up blew through Nevo ABD, um, in a very refractory disease, um, I think had a BV based salvage and responded like transiently and but eventually went to Allo and didn't do well, but, um, I, I think I, I don't know. I mean my preference is still to do to still to incorporate PD1 but you know, certainly this is, this is an area where we have no idea, it does seem, but one thing we don't know is, you know, for instance, you know, PD one can salvage, you know, obviously, you know. Disease that's reflected to BB, uh, we certainly don't know if the reverse is true. I, I suspect it's probably not gonna be that effective as, as like, you know, or rather let's say BB bender, BB based salvage going to auto anecdotally it seems like it's not that great. So in this group that that this is a truly like very refractory group. Yeah, and I, and I think a big part of the question also is like timing I think for that, right? I think, um, people kind of throw out this number of about 3 months. So if you relapse within 3 months, should you switch over to something completely different? If you're over 3 months, can you rechalenge with BB or rechalenge with PD1? Obviously if you got a BV-based regimen up front, you should definitely like Dr. May said, definitely do a BD1 based regimen for sure, but I think within that little bit of time, I think that's kind of the question that we don't really know the answer to. Uh, question, how do you manage, uh, in the frontline setting an elderly patient with Hodgkin's lymphoma again, uh, doing an ABB regimen is gonna be tough to, to administer in those patients. So yeah, and I think that's a really interesting thing like we have all these newer things like the Naval and BB and the breach data um and they're approved right now for SCC guidelines but. It's kind of weird. Like if you ask me am I changing my practice right now, not, not just that I think I need to see more data, but also with that you're right, if I have somebody who's older, BB BB is kind of harsh on them, um, so would I reach for that? Probably not. What I do Nevo BD maybe, um, I think we need a little bit more time with that. Um, I think another component that I didn't really talk about, um, I'm kind of see what your options are, but, um, for the naval and breach, you actually had to give radiation at the end of it with the other regimens you actually don't, you know, some of the ABVDs, you don't have to do radiation but the the Naval ones you do. So that's something you have to consider if you have a patient who you don't really want to give radiation to, um, because they don't have the data for just taking away that the radiation. Uh, I mean, yeah, certainly older older patients, if I, if I can possibly get an Evo EBD, even, you know, we, even if you do like even if you dose reduced the ABD or something, um, I still think that, um, you know, to, you know, the right, the elderly subset, um, of 1826, they, they did as well as the younger subset the over 60 did as well as the under 60, um, granted that may not be the frailest of the frail, but still, I mean like there's no no study that's ever. Shown anything close to that, right? I mean, all the studies show like this sharp drop off at 60, right, whether it's ABBD, what you know, the echelon one, the over 60 group did not very well, right, with BB they had horrible toxicity. So I certainly think overall Nivvo AB, you know, you know, and again this is kind of also it, it can be difficult to say for sure, right, which older patients are fit for multi-agent chemo, you know, who can get anthraccycline, who can, who can, you know, but I think if there's any way, even like in abbreviated course or or if you lower the dose if if at all possible I, I try to do that. Quick question, have, have there been any updates? You mentioned Beam is kind of the, the tried and true workhorse, but like things like Nivvo or Pembro Beam or Checkpoint Maintenance post beam, like is it anything like that? I know. And then where do you see Ethera, you know, I mean, it's, it's funny because like Checkpoint maintenance, you know, I mean Checkpoint maintenance has been looked at. I mean, there, you know, I think Philippe Arman published the Pembro maintenance after and, and, and then we published BB Nivvo maintenance, right, rather than 16 of BB, which no one tolerates, we tried 6 of BB Nevo, but I mean even there. Um, you see quite a bit of toxicity, a lot more toxicity post transplant than before, and maybe it's because they're still reconstituting their immune system, but I mean, we, a lot of gnarly like immune related stuff. Uh, some people got very sick with BB Nevo maintenance post auto. So I, you know, and, and since, and, and so I mean I'm a proponent of just putting your PD1 before the transplant. I think that's just the way to go, um, and as far as other sort of, you know, riffs on sort of how to, how to transplant people differently, I mean, you know, we, we've looked at ATA beams, right, adding the CD 25, um, radio immuno conjugate. Um, and that that trial is actually still on still ongoing, uh, we, we still, we're still enrolling, um, but I'm not sure it's really gonna move, move the needle that that much, um, and again it's, but it's the reality also is like, you know, with these results being what they are now with PD1 based salvage followed by transplant, it's gonna be, it's gonna be very hard to move the needle with anything, right? Like a trial to actually demonstrate something that's gonna be superior is gonna be, you know, well not impossible to do study. Yeah, and I think the other thing you were kind of mentioning briefly you said Ethera and so I think you know for BB maintenance in the for for your board questions, the answer is if you relapse within, you know, uh, within one year so you're still gonna be the maintenance, but in the current setting if We don't know how BB Maintenance does with all of these novel, the novel agents that we're using in the frontline setting, you know, the data is kind of wishy-washy. I think it's pretty there's nothing strong for either giving it or don't giving it. I think we still give it if somebody still is a high risk, um, a relapse, uh, but there's no data for that so I think it just kind of. Shows again what's the point that you know all this maintenance is just very unknown. I mean, I, I don't usually give, you know, BB not but it's not never. I, I, I usually don't, um, you know, like talking about shared decision making right I go we we discussed, you know, where the data are, where theer comes from, you know, kind of limitations of that, right? I mean all the patients had only just had chemo right before transplant. Um, in the light of the novel data to say that you know there there's real toxicity, not sure there's any benefit, um, you know, if you wanna do something that, you know, may potentially reduce relapse, you know, in a population that's, you know, where you, you wouldn't really fit in. I mean we can, we can do it right, um, you know, we're allowed to do it, you'll get covered, but whether we should do it, I, I don't know and. You know, and when I put it that way, you know, very few patients wanna do it. But what I mean, once, sometimes they'll do that one, you'll get a couple of patients, right, who would be like, you know, it doesn't matter, right? If there's anything I could possibly do, I'm willing to do it. And then like, OK, fine, you know, but you know, at the first sight of any sort of, you know, trouble or neuropathy we stop, so.
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