Join Roswell Park experts Alex Niu and Kara Kelly, along with Matthew Mei of City of Hope National Medical Center for a discussion on new approaches for adult and pediatric Hodgkin Lymphoma.
All right, I'm gonna go ahead and get it started. I see some people trickling in. Come on in. It's my distinguished pleasure to introduce, uh, my, my one of my best friends in the world and close, uh, lymphoma colleague here at Roswell Park, Doctor Alex Nu. Uh, Doctor Nu, um, is a recent, uh, father of a young boy, so he's here on, uh, paternity leave to join us today. So, um, without further ado, uh, he's also on our NCCN guidelines for Hodgkin lymphoma as well. Um, he's gonna talk about some of the massive clinical, you know, frontline changes for classical Hodgkin lymphoma and, uh, kick us off, Doctor Nu. Thank you, buddy. Awesome. Thank you for that kind introduction, Matt. Um, yeah, I've known you for 10 years, and every time he introduces me that like, oh, pulls out the heartstrings for what he says. So, um, so thank you guys. Um, so once again, my name's Alex, and thank you guys for having me for this talk. Let's see, do I just press the forward button? Yes. There we go. OK. So yeah, I'm gonna talk to you guys about the clinical practice changes, um, from the ASH um meeting this past year. So, first and foremost, just a little bit of background, um, you know, for Hodgkin's lymphoma, roughly about 90 to 10,000 new cases per year here in the US. We get about 1200 deaths annually in the US. It makes about 10% of all lymphoma, so it's on the rarer side for lymphomas, um, but it's actually very popular. Everyone seems to know about Hodgkin's lymphoma. Um, we have a bimodal age distribution, meaning that it's in. Initially in your early twenties that we see a peak and then it kind of goes away and then it comes back again in your mid-seventiess. Risk factors for Hodgkin's lymphoma, you have EBV, um, uh, virus infection, HIV, immunosuppression due to organ and stem cell transplant, autoimmune disease, these all increase your risk of Hodgkin's lymphoma. Um, for diagnosis, we always want an excisional biopsy when possible, and the reason for that. is because you have to have these Reed-Sternberg cells to um to make your uh diagnosis, and these are the infamous Reed-Sternberg cells for the trainees in the room. You guys will always get at least one board question where you guys see this and they ask you to kind of identify what this is. This is your bilobe nuclei here. Everyone says it always looks like the, the out eyes, which makes it really, really cute looking, right? And so, Now, um, in terms of, in terms of staging, yeah, right, yeah, in terms of staging, um, like other lymphomas, you, uh, you go through stage 123, and 4. Unlike other lymphomas, though, um, Hodgkin's lymphoma is broken down into early stage and advanced stage. Early stage is stage 1 and stage 2, advanced stage is stage 3 and stage 4. This is important because your treatments actually differ between them. So it's an important distinction you have to make. Now, in terms Of, um, early stage uh Hodgkin's lymphoma, it further breaks down to favorable versus unfavorable, and it's based off of these risk factors here, um, as you can see at the top of the table. Depending on which group you look at, uh, you, you can have any one of these, and if you are positive for any one such as more than 3 nodal sites, you have high ESR, mediastinal mass, it automatically puts you in the unfavorable range. Once again, this is important because this can dictate your treatment and what type of treatments you get. For advanced stage, um, our kind of prognostic scoring system is something called the IPS, which stands for International Prognostic Scoring. It is kind, it doesn't dictate your treatment, but it does kind of tell you how well somebody, uh, how well you think somebody will respond to treatment and kind of overall survival. This may change you a little bit and I'm gonna show you a reason why in later. So, um, without further ado, let's get to the abstracts. Um, this year, there wasn't a whole bunch, um, in terms of groundbreaking abstracts for Hodgkin's lymphoma this year, and I think that's a testament to how far along we've come with Hatching, which is great, you know, we're not seeing these big, big studies and big trials anymore. We're kind of focusing on how can we improve the patients that we already know do well or also look at the ones who don't do well. How Can, what can we do to kind of improve their survival, to pick them out that these are the ones are not gonna do well. Now, I will say this year's Hodgkin, uh, this year's Hodgkin attacks were seemed to be dominated by the SWAG 1826, which I know, um, it's to the delight of my colleague Doctor Matthew May here, um, as well as some other colleagues in the room. Um, so without further ado, I have to start with that one. this is the 3 year follow-up of the SWAG 1826 study. Uh, so, I think I've shown this at every single, um, Hodgkin talk I've given, but just to kind of refresh everybody, the SWAG 1826 study design looked at newly diagnosed stage 3, stage 4 Hodgkin lymphoma, um, and it kind of broke down patients for a randomized patients. In a 1 to 1 fashion between Nvo AVD versus BV or rituximab AVD. Each, each group got 6 cycles of chemotherapy and then you evaluate them at the end of treatment. If you had some residual disease, you could get radiation therapy, although very little patients did get that. Age-wise, you had a wide, wide range of patients. You can see here that this trial was kind of a little innovative in the sense that included both adolescent all the way down to age 12 and then past age 61, past age 61, which is really great to see because normally adolescents are, um, excluded from these big trials. Some other key notes from this is that they had some, a decent amount of patients who are African-American. Um, you can see also they had some patients who are HIV positive, a decent amount of stage 4, and then the majority of patients had a lower IPS score of 0 to 3. So in terms of the, the results that they saw, so what we saw at the 3-year mark was a 3-year progression-free survival of 91% for an Evo ABD and 82% of BVAVD. This is more or less exactly what they saw at the 2-year mark, which was 92% Evo ABD and 83% BVAVD. So more or less exactly the same, showing that our, our rates are still continuing on. To hold. In terms of subgroup analysis, this is kind of what really drove this study at the beginning where they compared all of these different subgroups, and you could see that all of them are still really favoring Nevo ABD versus BVABD, particularly in the age over 60 and the lower IPS score. When they looked at um adolescents, they saw still the 33 year PFS 93% versus 82%. And then when they looked at the 18 to 60 year olds, same thing, and Ibo ABD still winning of 91% over 85%. In terms of looking at the actual IPS score, like I said, this is a kind of a risk, um, prognostic scoring system. You can see Eva ABD um being better in both the lower IPS score as well as the higher IPS score of 4 to 7. And then when you look at separated between stage 3 and stage 4, once again, Nuvo ABD being better, um, both by about 7% points um for both of these. And then finally to the overall survival. So you can see here, overall survival, 97% for BVABD 98% for NO ABD. Um, the amount of deaths that you got that seem to be double for BVABD over Nvo ABD, um. I do want to make a point here because, you know, the overall survival here is almost more or less exactly the same and you know, I think one of the driving points people had at the beginning was, is this enough to kind of say, we should abandon BVAVD or not. So I'll make a point here that BVAVD is still a good regimen, right? It's, it's not Not a bad one because I get some patients who say, is it bad that I, I got BVABD? I said, no, it's not. Um, it's, people are still living quite long with it. The differences that we're seeing that I, I didn't show here are really from the side effect profile and the discontinuation rate really driven by that older patient population. Um, that's been really well documented in previous AS, um, responses as well. So, you know, it makes sense that if you're not able to tolerate the treatment, you're gonna discontinue and then therefore you're gonna have, um, lower overall results. But if you're able to finish out your course of treatment, as I'm showing here, then patients seem to do well. So I wanna reiterate that BVABD is still not a bad regimen, um, compared to Nuvo ABD. So kind of the takeaways from it, PFS benefit with Nvo AVD over BVAVD advanced stage sustained at 3 years, PFS benefit across all the subgroup types, um, including high risk as well as lower uh PFS, lower rate of secondary malignancies, and the FDA did just finally approve this uh Nvo AVD on March 20th, 2026. I'll say probably about a year later than it should have happened, but it did happen, which is great. So The next big study I want to talk about is really the other arm of this battle for advanced stage Hodgkin lymphoma, and this is looking at the HD21 study. And so this looked at BRCA versus escalated BACO in the similar patient population of advanced stage um Hodgkin lymphoma. So, what they did in this study was they took escalated be a cop, which is a regimen that we've been using for a very long time, mainly previously in kind of an escalation phase where somebody needs um an increase in the amount of treatments they got, and then Bree had um said, all right, can we, what happens if we just remove a few of these drugs to make it a little bit more tolerable, and let's see if it's at first initially non-inferior, that was the initial design of the study. So you can see I listed out the drugs for Escalade Bacop and then the drugs that they did for Breacca, and really the main difference is that they got rid of bleomycin, vincristine, switched out procarbazine for dcarbazine, and then added rituximab. How the study design went was, it was a randomized 1 to 1 study again, people either went into the BRCA arm or they went into the escalated Bacop arm. They got 2 cycles of each one and then they got an interim PET scan, and this is the really cool part about the study is that based off of your responses, you either got an additional only 2 cycles of BRCAd or you got 4 cycles of Breaccad. Um, same thing with the escalated BACop, you either got 2 additional ones or 4 additional ones based off of your PET scan. And it's similar to the, um, the SWAG 1826, if you had some residual disease, then you could get um some end of treatment radiation. This study had higher rates of end of treatment radiation. I did want to make that point of about 15%. So what do they find? Well, progression-free survival in the um in the tent to treat population. At the initial 3-year mark, it was 95% for breedcat and 92% for Escalade Beacop. At the 5-year mark, which is the final analysis of this one, pretty much exactly the same, 94% and 91%. In terms of overall survival, pretty much exactly the same, 98%, and um I'm not a stats guy, but that's about as good of a line as you can get in terms of overall survival. So showing that, you know, this is a very good regimen. Now, a big concern with this regimen is gonadal function and fertility because a lot of our patients who, uh, like I mentioned, a lot of our patients in Hodgkin are younger patients. So try to preserve gonadal function and fertility is a big, big deal. And the concern is that if you're giving all those big drugs I was just showing that you're gonna impact their fertility. So what the, what the researchers did was they looked at gonadal function via evaluations of SFH. FSH levels. And what they saw was that for women up to 40, for the BRCA arm, they actually had 95.3% um gonado function fertility compared to 73% in the, in the Escalate BACO. Men up to 50, this difference is even more pronounced with 86% versus 39.7%. And then when you look at the 4-year motherhood and 4-year fatherhood, meaning that patients who are fathers and mothers, um uh within their end of treatment in 4 years, you can see. Um, for motherhood, 14% versus 12%. It's not statistically significant, but it is seeming to correlate more with um the Breaca and for fatherhood, this was statistically significant favoring breaca. And then when you look at kind of childbirth at 5 years, once again, more children born in the breed of cat arm. And then finally, for in terms of um health-related quality of life, in terms of BRCAD versus escalated BCOP, you could see that people who got BRCAD reported higher levels of quality of life both during treatment as well as the 3 years after treatment. So another important point here of saying that these toxicities are ones that we have to not only focus on during treatment but well after treatment as well. So kind of the takeaway. So, um, hazard ratio for PFS was 0.64 favoring BRCAT over BACO, five-year progression-free survival of 93.6 versus 90% favoring BRACAT as well. Um, five-year PFS and PET 2 negative was 96.2 versus 92.4%. This is an important point because the PET 2 negative. Remember is your um escalation for exhalation point. So whether or not you go less treatment or more treatment. Among some other variables I didn't show, but I'm mentioning here, male sex and hemoglobin less than 10.5 seem to have higher risks of events. Um, mean tumor volume was at baseline was not actually associated, which is a little interesting. Secondary malignancy is roughly about the same for both, and then lower rate of long-term side effects with Breaccad, um, better in quality of life as well. So I, I think, I just want to pause here really quickly because I think the million dollars or a billion dollar question is which regimen, right? I'm, I just showed you two amazing studies with Nvo ABD versus and Briaca, both for advanced stage Hodgkin lymphoma, so which one's the better one, right? The answer is no, we don't know. Um, I think without a direct head to head comparison, there's no way to definitively tell. And for the trainees out there, this is another big rule of you never cross compare trials because your patient populations are different, the rules of the, the rules of your, um, of your actual trial are a little bit different. And here, like I mentioned, the ages between the two, groups are a little bit different. The breedcat armor was only 18 to age 60. It didn't include African-American patients, it didn't include HIV positive patients either. So you have to be careful when you're trying to compare these different trials. Now, I will say here in the US we are mainly a Nvo AVD um user, whereas in Europe, they're mainly Bricad users. Um, we were, I was at a conference at Mayo Clinic actually, and, um, Doctor Peter Borschmann, the main investigator of this, was there, and we're all sitting around lunch, uh, at lunch at a table and somebody asked him like, hey, how many times have you used Nvo OVD? He's like, none. Like, oh, OK. Um, so, you know, I, I think where you are also impacts what you're likely going to use. Now, I will say there are some cer certain circumstances where you'll probably favor Nvo ABD a little bit more, more so in your older patients, your frail patients. That's where I think Nvo ABD is really going to be the more bang for your buck in this situation. If you don't, if you can't take a PD1 inhibitor, you know, is BRCAD the way to go? I don't know because there's no comparison between BRACAd and BVABD, right? So the question is, are you going to make that big jump there? We don't have the data for that, so it's kind of more extrapolation. I think the big question of where this is gonna take us is if you have a younger patient who can tolerate all the toxicities and they have a high IPS score, meaning they're at more high risk, is that the patient you pull the trigger for Breaca on? Because one, you get hit with more drugs and, you know, you potentially, it could be a little bit better, but two, you have the ability to escalate or de-escalate based off of your results. Nvo ABD you treat all the way through. Time will tell what we see here. All right, so the next two trials, um, abstracts I'm gonna talk about really focus on SWG 1826 and they're kind of offshoots of that, um, of that study, and I think it's another testament to how well run that study was that we're able to say, all these patients who did really well, let's see what we can learn from them. Let's see what we can glean from them, um, and looking at certain aspects. So this first one here, um, looked at circulating tumor DNA of the molecular tumor burden, and they compared it to PET scans to see which one offer a better prognostic value during treatment. So what they did was they took 388 trial patients and they collected um baseline circulating tumor DNA both at baseline, cycle 3 day one, which is pretty much right in the middle of your treatment and at the end of treatment. Um, the sequence that they used, uh, was a, a DNA fragment, and then they're able to kind of match this, and then that's how they're able to distinguish how much tumor burden that they had. Of note, of the 388 patients, 375 had detectable circulating tumor DNA at baseline, indicating that this is actually a good marker for this to kind of compare throughout your whole treatment. So, what did they find? Well, when you first look at PET scan, they actually found that interim PET scan was not associated with progression-free survival in all the patients or even in the individualized patients. And you could see here that, you know, even though the lines seem to correlate, it wasn't statistically significant. And even here in the Nvo ABD arm, which is the top right here, you could see a 3-year progression free survival, 92% um for all, for the Nvo ABD arm, 82% for the patients who are PET2 positive, still pretty good. So I think this is Just reinforcing the fact that for the Nevo AVD study, that this is not a pet adapted response, meaning that if you get an interim pet, it's not the kind of end all. You have to con, you should be continuing on throughout your treatment, but that's also why the study is designed where you don't actually have to get an interim pet. Um, throughout your treatment if you don't want to. Now, all of us, I think in practice, usually get a PET scan at, at some point because it's a little scary to do 6 months without any type of PET scan, but this is just showing you that it's not that PET scan, if it's positive during your treatment, it doesn't mean that it's all it's all kind of um inclusive of it. What about the circulating tumor DNA? This tells a different story now. So if you look at the circulating tumor DNA. Um, at the first one here at the top left here, this is all patients. The top line here is if your circulating tumor DNA was negative at cycle 3D1, and the bottom one here was, if it was positive at cycle 3D1, you can see there is a big, big difference in terms of progression-free, um, survival here. And then when you break it down between treatment arms or Nvo ABD and BVABD, that, that difference still holds. So, this one did seem to have a big um indication of how patients were going to do. But this is not the whole story though, right? Obviously, if you're circling tumor DNA is positive, that's not as good as if it was negative, but that wasn't the end all um question here. So what they did was they then, all right, they said, let's continue our treatment on and let's continue to measure the circulating tumor DNA and see what happens at the end of treatment. And what they found was for patients who had a major drop in the mean uh tumor um burden in the circulating tumor and DNA and they defined this by anything above the median value of a one log drop, it was considered major. If you had a major drop in the tumor volume, you did almost just as well as if you were, if you were negative at the interim scan. If you did not and had what was considered a minor drop, those are the patients that did not do so well, and you can see this holds true for all patients, Nevo AVD and BVAVD as well. So now what happens if we compare these two? So, at the top left here, you can see circulating tumor DNA seemed to have more prognostic value as opposed to the uh PET scan. You can see a difference there of about um I think it's 20% there or so. And then when you look at the right-hand side, um, the circulating tumor DNA had a higher hazard ratio, meaning that it was able to more accurately predict how patients were going to do. But I think the real strong suit of this trial, what is likely going to point us in the future is when they combine these two. So you can see here for the bottom right here, when they looked at um the 3-year progression-free survival, the top, the top number here of the 92% is we're circulating tumor DNA negative. And PET scan negative. Those are the patients who did the best. The next 1, 78% is if your circular tumor DNA was negative and PET scan positive, the next one down is those get flipped. PET scan was positive, circular tumor DNA is negative, and then obviously, as you can probably guess, the ones who did the worst are the ones who had both positive. So I think the takeaways, um, so certainly tumor DNA guided analysis could enable early risk stratification. Um, the DNA at cycle 3D1 provided prognostic discrimination. Now, even with that said, if you're positive, like I said, it wasn't, it doesn't necessarily mean it was bad. It really looked at what was the, the discussion moving forward, what was the major drop, um, because that's what really dictated how well you did. And circulating tumor DNA could potentially outperform interim PET scans. And at the end of treatment, both the circulating tumor DNA and the PET scans are prognostic and the combo is likely where we're gonna move here in the future for this. All right. And so the last, uh, abstract that's, uh, that's kind of piggybacks off the SWAGE study is looking at something called the AIPP score, which stands for Advanced stage Hodgkin lymphoma International Prognostic Index. And they compared it to patients in the SWAG 1826 study. So, remember, at the very beginning of this talk, I mentioned the IPS score for Hodgkin's lymphoma. Um, this is a score where they say, all right, there's certain, there's 7 risk factors, and if you have one of these, you get a yes or a no. Um, and if you get a yes, you get a point. And what they did was they plotted these numbers out and then they All right, how do patients do based off if you have 1., 2., 3., 4 point, or, or 5. And you can see here, the five-year progression-free survival and the five-year overall survival. So this was developed by Doctor Hansen Cleaver in 1998, so over 30 years ago, and this has really been, or close to 30 years ago, and this has really been the kind of gold standard for how we evaluate advanced age Hosian. But over the past year, we've started to realize that as our agents have gotten better, the IPS score seems to have been, it's not as accurate as it used to be. So as you can see here in this analysis, they looked at 2012 numbers and they can see that for a risk factor of something like 1 back in In 1998, you had a 77% progression-free survival. In 2012, it's up to 85%, um, over overall survival, 90% versus 97%. And this is good. This is exactly what we want to see. We want to see the numbers getting better, but it's also indicating to us that this is not, that this scoring system is not quite what it used to be. And you can see this is the initial study where they looked at the actual um risk factors and looking at progression-free survival and overall survival based off of the numbers that you get and the scoring you get from the IPS and then in a more recent analysis, You can see that the lines are starting to become muddled. They're starting to kind of cross over and so forth. So it's just showing us that it is just not quite as good as it used to be. So that's what led to the development of this A hippie. So the A hippie is a more modernized version, calculator, more or less, to try and figure out a prognostic scoring system for Hodgkin's lymphoma. This came about from a large consortium called the Holistic Consortium where, you know, a lot of people came together and then we We pulled all of our samples and it created a biobank of over 30,000 patient samples uh to generate a huge bank um to kind of run these analysis and run different things to come about. Um, and so one of the things that came from that was this AIB score. So, what is the actual score? So this is pulled right from um uh QXMD and what it is, is it takes 7 risk factors, um, a lot of them cross over from the original A hippie score, but the difference here is that instead of just saying yes or no, you're actually inputting in a number and that by itself is already generating different outcomes because a hemoglobin of 16 is vastly different than a hemoglobin of 11, right? A lymphocyte count of 5 is going to be different than a hemoglobin score or than a lymphocyte count of 1. So it just allows for these extremes to kind of play into, to take a bigger role um in effect here and so you put in the numbers here and then it spits out a five-year progression free survival and a five-year overall survival. So, what did they do, um, in the, in the actual research, uh, in the actual abstract. So what they did was they compared the A hippie to the IPS score and the patients um with SWAG 1826. So they pulled roughly about 800 patients, um, and then ran a hippie versus IPS scores on them and then they want to see what the overall progression of your survival is. On the A hippie side to the left here, what they did was they calculated the media. In a hippie score for them, and then they said, all right, if you are above that number, you're kind of high risk. If you're below it, you're gonna be low risk. And the IPS score, if you were 0 to 3, you were considered low risk, and then if you were um 4 to 7, you're considered high risk. And then they saw, all right, what happened to the progression-free survivals. So you can see for the A hippie, the high-risk patients were considered 80% PF uh progression-free survival at 3 years versus 92% in the low risk. So a difference, a difference of 12% here. And the IPS this difference is only 6%. So the A hippie was able to more accurately deduce who was gonna do better or kind of worse as compared to the IPS. So I had what we call superior discrimination, meaning that it was able to discriminate how the high-risk patients were going to do compared to low-risk more so than the IPS. And then when they ran multivariate analysis, you saw, you see that the A hippie um had, was able to predict a higher hazard ratio as compared to the IPS of 1.5 versus 0.97. So, I think the takeaway from this um abstract is that the AIppie has superior prognostic capability at discriminating outcomes. Um, it's a refined prediction model using continuous data values as opposed to just yes or no, and it may integrate critical biological factors like circulating tumor DNA in the future as well. Um, and it may soon serve as a new standard for our risk certification. And I think this is really important because as our treatments have gotten better, we have to find ways to really see if we can. Find the patients who are not going to do well because those are the ones that we really have to focus on and say like, OK, do we need to do a harder treatment? Do we need to give them more escalation? And that's really where I think the future of Hodgkins is gonna go. All right, so really quickly in the last minute I have, um, the last two, abstracts I want to talk about, um, really not quite ready for prime time, but just kind of an indication where things are going likely. So this one, the first one is looking at a PET adapted de-escalation uh for classical Hodgkin lymphoma. This was presented by Doctor Lee. And so this is a, a, a novel study design here, um, and what they did was they said, all right, we have patients who get everybody with advanced stage Hodgkin or early-stage bulky get Pembro and rituxim. Plus, um, AD, they get 3 cycles and then they all get an interim PET scan. Pending, depending on how well they do, if you had a Deval score of +12 or 3 with more than 90% reduction, you got kind of the maintenance arm which is Pembroke and rituximab only, or if you had, you know, Duval score 3 with less than 90, Deval score 4 or 5, then you got kind of the continuation of the Pembro um rituximab followed by AD for 3 cycles. So they enrolled 25 patients, um, and everybody after the initial 3 cycles landed into that de-escalation zone where they just got Pembro and, um, yeah, I know the red light's blinking. Um, they got Pembro and rituximab, um, and you can see here by the CRA 88%. uh CR rate here. Three patients technically had uh devolved score of 4, so they're not in CR, but then when they followed those patients out, one patient had a biopsy that showed it was negative. Another patient actually went down to devolved score of 3, and the other last patient, they're still waiting on results for. Adverse events were fairly well tolerated, as you can probably guess. So, um, why am I kind of showing this? Do I think this is going to be the future for advanced age? No, I don't, but I think this is a map of where, as I kind of alluded to, where the field is really going. Just as a plug here for our, um, AH 2131 study, which is, which we have here at Roswell Park. Which is looking at early-stage Hodgkin. It involves a more kind of similar res um evaluation where everyone gets initial treatment upfront and then you get randomized to two different groups, but based off of your response, you get different treatments. In that case, it's either going to be rituximab, Nvo or you get standard of line. So, um, it's a great, it's a great study if you, for the providers here, if you guys have early Hodgkin lymphoma, I would highly recommend you refer them out because I think that's where the field is going to go, um, it's kind of this escalation personalization medicine. And then just a really last one here, um, just because they did a lot of work for this, it looked at BAO versus ABVD for advanced stage Hodgkin lymphoma. This was a, um, a big study that they kind of pulled a lot of data on for ABVD and escalated BACOP for advanced stage and early stage with, um, high-risk features. Um, you can see that escalated BACOP seemed to do a lot better than ABVD group. Um, and then like I said, it's associated with, they, they found that the ABB, the Escalade BA cop did better to improved PFS compared to the ABVD. I included this because they also use the AIPB and they saw that the AIppie also held through with maintaining prognostic impacts throughout the disease course. Do I think this is going to change therapy? No, because I showed the BRICAD data already which beats be a cop for this, um, uh, group patients, but I didn't want to throw that out there, so. And that's all I got. Thank you guys. That's great. Thank you so much Doctor New. That was fantastic. So, uh, Doctor May is our colleague and, uh, former collaborator on a, a clinical trial we had together called, uh, from a company called Syntheine. So I got to meet him over a free dinner out in, uh, San Diego a couple of years ago and become friends ever since. So, uh, Doctor May, thank you for flying all the way across the country, um, being severely jet lagged with the young family as well. Um, here to talk about relapse refractory Hodgkin lymphoma, which fortunately is a smaller piece of the pie but still not zero, so. With that, Doctor May, thank you so much for coming. I That's right. I should have mentioned he's at City of Hope. He's associate professor of uh of medicine and their uh fellowship program director as well. All right, thank you, uh, Doctor Cortizi and, uh, Doctor uh Ibisiurri for the invitation here today. So, uh, anyways, you know, there, there, uh, I would say this talk is, um, has, hasn't really changed that much over the last couple of years. Uh, it's an interesting topic, right? It's an important one, and I think there will be a slide I'll get to later, you know, uh, outlining kind of the, the graveyard of, uh, novel therapeutics in, in Hodgkin lymphoma and. I'll talk a little bit about why this is such a difficult field to, to, um, push forward in and, you know, in some ways we may be a little bit of a victim of our own success, um, but nonetheless, I, I think, you know, some things have sort of coalesced, um, over the last couple of years, some themes have emerged as far as sort of management of, of relapse re fracture Hodgkin lymphoma, so I, I, I think those are still, still worth talking about. So, um. So brief outline, so, uh I think, you know, main big questions I think that are out there, um, you know, can we skip autologous transplant and, and, and relapse Hodgkin lymphoma, um, I mean, increasingly, it's clear that, you know, that the, the answer is, is yes, but we don't know in who, right? So it kind of depends on how you want to answer this, right? Um, but certainly some patients are almost, you know, are cured, uh, we don't really know how to prospectively identify the, these, however, at this time, um. You know, then, uh I want to also talk a little bit about the importance of checkpoint inhibition prior to auto transplant. So when, you know, when I talked about this last year, it, it was, uh, we had presented an Ash abstract, but the, uh, but the blood paper finally came out a few months ago, um. And then tru truly novel therapeutics beyond BV and PD1, so this is a very, uh, this is an incredibly challenging space, uh, and there's a reason why after so many years that these are still the only, you know, we still, we always call these, you know, drugs novel therapeutics, right, in every paper for the last 10 years and, and, you know, we still kind of attach this moniker to them, uh, despite them not being very new, but, you know, there, there really isn't that much new. Um, and despite some drugs that are really quite efficacious and really not that toxic, um, you know, they're, they even those are still falling by the wayside, um, and then finally we'll talk a little bit about alloe transplant in, in Hodgkin's lymphoma. I'm a very firm believer in aloe in, in Hodgkin, by the way, so. Um, all right, so, relapse Hodgkin lymphoma, so, uh, auto-transplant is the standard. Um, it's been the standard for a long time. Um, at one of these years, probably the slide will change and it will, when we figure out who we can sort of safely not transplant. Um, but for now, as far as I'm concerned, if you're a transplant candidate in the relapse setting, you should get transplanted with, with, with an auto. Um, the randomized data are very old, right? There are no current available randomized data in the sort of in the novel, um, era, you know, we were hopeful to as far to generate, um, some, but it looks like that, that may not end up being a randomized trial after all. I'll, I'll get to that, um. And so for the longest time that, and even now today, right, that the paradigm has always been, well, you do your frontline treatment, you cure most of the patients and, and this is actually precisely one of the issues of relapse refractor Hodgkin, right? Because, you know, back when I was a, back when I was a fellow, um, You know, when we're like geeking out over like raffle and stuff actually that that came out even after I, I wasn't attending, um, you know, we kind of knew what to expect, right, with ABVD and advanced stage disease, you know, you cure probably 70, 75%, um, which is, which is good, but certainly, you know, leaves, um, you know, a lot of patients not cured, right, with ABVD, uh, therapy, uh, but now then with BVABD, you know, we got that to the low 80s and now with Nvo ABD pushing to around 90, um, you know, this is a smaller and smaller piece of the pie. Right, so, but the paradigm has always been that, you know, if you relapsed after ABVD or, you know, any frontline therapy, right, um, then you would, you know, find some way to get the patient to respond, whether that's chemo, whether that's some combination novel therapies and, and as I'll go to the next, go through in the next few slides, pretty much every combination you can imagine has been tried, um, and then followed by autotransplant if you've responded, um. And so that kind of left open the questions like what is the optimal salvage therapy, which um I think we have probably answered this uh at least in broad strokes uh for, well, in patients who have not had frontline PD1 I think, I think we know the answer. Um, and then the other question is, is auto transplant really needed again, um, undoubtedly some of these patients are being cured, especially with PD one chemo in the salvage setting, we just again cannot prospectively identify them yet. Um, so yeah, so chemotherapy-based salvage, so, you know, for, you know, those of us who have been practicing for a while, uh, you know, for the, for the fellows here, it's probably just an interesting historical footnote, right? So, um, chemo works reasonably well, right, you do ice, you, you know, ice, I give, you know, we, I, I think we used to think that maybe one of these regimens was better than the other, that they're all, they're all the same, right? You know, the CR rate's about. 60%, most patients respond and if you transplanted someone in in a PET CR you would cure most of them, you know, 60%, 70% if they're in a PR you cure about 30%, right? So that and, and those are those, those data, you know, even though slightly dirty have been kind of around and kind of been, you know, confirmed over and over and at least in single center studies, right? And so, uh, so BV was the first, you know, novel therapeutic to come on the scene, right, and it's not like, you know, 15 years plus old now, right? So BV based salvage, uh, well, originally it was approved, right, in the multiply relapse setting where patients post auto or two lines without, you know, not eligible for auto, right, that was the first approval. Um, and so obviously the next step was to try to incorporate in the salvage setting, so. Um, as you may imagine, every, all manner of BV, um, you know, based, uh, uh, regimens were, were tested. So we did, we did the BV monotherapy, um, as a bridge to auto, um, memorial had a, had a BV, you know, followed by ICE and patients who didn't get a CRBV alone. And then also it's a BV plus chemo combinations and again, you know, if, if you got a good response to BV meaning that, you know, if you got a CR if you got close to it, you did an auto, um you did probably about as well as a, as an auto transplant realized with with uh you know. After a CR to to chemo, right? So it was, it was a reasonable bridge, um, and then with BB plus chemo again, if you squint really hard, maybe the CRA was a smidge higher kind of is eyeballed kind of in the, in the, in the low to mid 70s, you know, and all these aggregate studies, um, so, you know, maybe a small incremental step forward. Um, and then, then Nevo obviously came on the scene in 2015, um. And so, given how Nvo, given that Nevo and BV had by and large non-overlapping toxicities, you know, the next step was obviously just put, put the two together and, and see what you get, um, and so that worked really well, right? Um. And so, uh, as a, as a chemotherapy-free regimen, um, it, it resulted in, in most patients going to remission and a very large number of patients being able to get bridge directly to, to auto transplant and so the preliminary data were published in, in blood in 2018 and then the, the, the three year uh follow-up was published in 2021, um. And on top of that, if you look at the post-transplant er pot survival, um, that was also excellent. Um, the one thing that kind of emerged and and Milly this is a subset analysis, uh, so whether this is, you know, a real biological effect, uh or not, um, but that, um, that's that results, uh, in, in patients with primary refractor disease did eyeball a little bit worse. So, you know, there's kind of a 30% difference between patients with, you know, later relapse versus primary refractory. Uh, I will confess again, even though it's not probably not the right reading of statistics, but you know, in my own practice, I'm a, you know, and for patients who've had a maybe a very late relapse after ABVD I'm pretty comfortable with BB Nvo. I'm a little bit nervous about it for primary fracture disease. Um, So, OK, so we did, so there's BV, BV plus minus chemo, BV plus Nvo. So the next step would be the Nvo without BV, right? So Nvo by itself, NO plus chemo, right? I mean, this is, this is kind of how we innovate in medicine, right? Just kind of, kind of play with all the different combinations. So we, you know, we tried Nvo with or without ice, um, and so I there's a little bit of a, this, the slide's way, way, way too busy. Uh, I cribbed him from the Ash talk from years ago. So, um. We, uh, so we tried Nivo by itself and then the idea was if you, if you got a CR with Nvo, you would just go to Otto. Uh, and if you didn't, then you would go to Nvo plus IC followed by Otto. Um, and, you know, it worked, um, a lot better than we thought it would. So, um, like 70% of patients basically went to transplant with, uh, just off of Nivvo, uh, and so, um, And actually that this, you know, and, and as a result, uh, this kind of, uh, this led to us actually opening a second cohort of the study where everyone got Nvo Ice because part of that intent of the study was this kind of studied PD1 plus chemo, Nvo plus ice I, um, and you know, I would say that this, this concept I think was out before Pember EVD, but you know, um, but you know, the Neo plus I, uh, you know, ended up only being given in a very small percentage of patients because they all got bridged by Nvo, uh, so we had to open a second cohort just to look at the combination in, in all comers, um. And so, so this kind of was a first sort of proof of concept that really um PD1 bridging, you know, had, had some legs behind it. And, um, and so, you know, again, outcomes are very good and especially patients that proceeded to auto so in all, and then the, on the left side PFS and all treated participants, that does include a number of patients who, who for one reason or another, um opted not to, not to um undergo auto um so there are I think 4 or 5 patients who were eligible and, and just declined auto, uh, all of them did relapse. Um, but overall, again, the results are very compelling. And so, um, and so we opened a second cohort, so which gave Nvo plus ICE to, to all patients, uh, and then we restricted this to a high risk population, relapse population, so you had primary fracture disease, you know, be symptoms of relapse, you know, kind of like Ethera, um, plus like, you know, front or if you got frontline BV as well, which we, we figured it is probably a high risk feature as well. And so those patients, um, you know, again, uh, obviously this, so this did come out a little bit after Pembridge EVD, um, but kind of in line with what you expect, right? So the, you know, CR rates now, you know, with these PD1 plus chemo combinations in the high 80s, low 90%, you know, percentages and, and really outstanding, uh, post-transplant PFS and, and one curious thing was right, that the post-transplant PFS also looks a little bit better than you would have what you would probably expect with, with chemo alone. So there's also kind of raised the question of, you know, is there some, some other effect going on there as well. And I'll get to that. Um, and so Pembroke GVD, uh, you know, an, an amazing regimen, I, which I, I honestly, I, I do use this quite a lot as well since it's, uh, it's, it's a little bit easier to give in the outpatient setting. Um, so Pembroke GVD as a bridge to, um, as, as a bridge to auto, uh, so this was, you know, it was pretty dynamite, right? So 95% CR, everyone responded, patients who went to transplant did, did incredibly well, um. The one thing that was noted was that there was a high risk of engraftment syndrome, so, um, so they found over, you know, over 2/3 of patients with engraftment syndrome and the Pember GBD data in our Nvo ICE, and we were pretty, and we actually went back and since this data came out first, we went back to Nevo ICE, we combed, combed through it pretty carefully. And it was still around 25-30% again, whether there's a true difference in the regimens, whether it's just chance, uh, who knows, um, you know, we are like there is a multi-center study looking retrospective study looking at engraftment syndrome with specifically with PD1 based combinations pre pre-auto and so hopefully that will, you know, help to answer the question a little bit more as to, you know, what is the, the real uh incidence, but certainly, you know, anyone who gets PD1 prior to auto, they're starting to get like fevers and it's like. Day 8 or 9 and you know, it's a little late for like the, you know, the, you know, the fever from like, you know, your standard neutropenic fever from infection or whatever or colitis, um, and then they, and then their ANC is like going up the next day like, you know, think, think about this, um, not everyone has to give steroids, but if they're if they're febrile for a couple of days in a row, just, just throw on some steroids, you know, you know, at at this time, at this point they're grafting, they're still febrile, that's, that's the clue. Um, and then also, so, you know, there, there's Nevoce, there's Pembro GVD, now there's Pembro ice, and, and it's, it's a nice proof of concept, right? So it kind of almost doesn't matter which PD1 you use, which chemo you use, like, you know, everything works, right? Um, just this general concept of PD1 plus chemo. Uh, so again, outstanding results, uh, you know, pretty much mirroring, you know, pretty much mirroring the, the results that we saw with Nevo Ice. All right. Um, and so, so one thing that all, all these have in common is the use of PD1 blockade prior to, um, prior to transplant. And so this is an interesting topic and, um, And this is one of I think the more important, uh, so these next couple of slides, I think one of, one of the more, you know, important points I have to make. So, um, so when PD1 blockade first came out on the scene, right, you know, we had all these patients that had refractory disease that blown through ABVD and ICE and, and so basically they all have gotten ABVD, ICE, BV kind of in that order. A lot of those patients had never even made it to auto because they never had a good enough response to, to go to auto and then they're getting Nvo and then they're all responding, right? And you know, you know, 20, 30% of them with a CR and then, you know, a lot, but a lot of them when, you know, get a really good PR maybe they're close to CR and then it would be sustained and then we were wondering, well, now, now what do we do, right? I mean, do we just kind of just leave them on it and for forever, uh, you know, should we try to transplant them, um, you know, which kind of runs counter to all the dogma that we ever learned, right, of, of, of transplant, you know, being, you know, high dose chemo. To be only employed in cases where the disease is chemo sensitive, right, a little chemo works, a lot of chemo works better, so, um, but should we actually attempt high dose chemo in patients that are really ostensibly chemo refractory but are responding to PD1 blockade, um, and so, you know, so not to answer the question of whether we should or not, but, you know. We sometimes did or some people did and so there were these scattered cases, um, both at City of Hope and you know, from other centers as well and so we were kind of collecting these cases in 2017, 2018, 2019 of patients had good response to the PD1 and who just got auto. Um, that, you know, just, just to see like, you know, what, what are we finding like, you know, are we actually curing anyone, anyone this way, right? You would think that for chemo refractory patients that this would be kind of a losing endeavor. Uh, but surprise, patients who got auto-transplant after PD1 blockade, even the chemo refractory ones that had not been responding to previous lines of therapy, they did great. Their 18-month PFS was 81%. It's better than you, that's better than you would expect after second-line ICE, right? Um, and in this study, uh, pre-transplant PR versus CR didn't even matter. Now, I, no, I'm not sure that's like real, but, uh, but still, it, it kind of goes to show that, that, um, that, and that, and sort of the irony of ironies, right, was that, that, uh, instead of chemo sensitivity, act actually your response to. PD1 blockade uh was more, was the most important predictor of success, right? So for high dose chemotherapy, um, it works in chemo refractory patients, Hodgkin patients, and what matters is what your PD1 sensitivity, right? Go figure, um, but that was that was sort of the, the, the weird messaging that came out of this study, um. And so, um. So we decided to test this in the real-world cohort. Um, and so, uh, this was a pretty Herculean effort. Um, so we looked at, um, almost 1300 patients across 6 centers, uh, with Hodgkin lymphoma, um. And so, um, and, and kind of focusing on the impact of salvage therapy on, on post-transplant outcomes. Um, and so what emerged and so the kind of the, you know, the, the top slide or the top graph rather is the, is the really key one here, um, that PD1 blockade pre-auto was associated like independently with a higher post-transplant PFS, um. And it's not just, and so, you know, the immediate gut react, you know, knee jerk reaction as well, is this because we know with PD1 plus chemo, you have a, you know, 90% chance of CR as opposed to maybe 65-70% with chemo alone, maybe 70, 75% with BV plus chemo. Um, is that difference in post-transplant survival just due to the fact that you're taking more patients to transplant in CR, um, but not really, right? So we found that even if you control for, for the disease status of transplant, so let's say if you restrict it only to the universe of patients who are in CR pre-transplant, that still, if you got a PD1 blockade. You know, as a way to, as you know, in part in your salvage, you had better post-transplant survival and, and it wasn't close, um, like the hazard ratio is like less, you know, it was, it, it cut the relapse risk by, by, by more than, by more than 50%, um, and the thought is that this is we think, right, it's hard to prove, but we, we think that this is likely, um, a, a chemo sensitization effect of the PD1 blockade which, which has, has been suggested in multiple other, other, um, you know, pre-clinical studies and. And so, so that's, so I think for patients who, so even though I would say I don't know that we know like the single, you know, superior salvage regimen, but I think for sure for patients who did not get PD1 blockade in the frontline setting, granted that's gonna be a shrinking. Population of the patients like going forward, at least in the United States uh for advanced stage disease, but if you didn't get frontline N or Pembro, um, and you're relapsing you, and you need to go to auto like there, I think it's a no-brainer that P1 blockade needs to be part of the salvage and I would argue that that should be part of, that should be standard. Um, the other thing, so it's actually the paper wasn't just accepted, that it's actually already published in blood, it was published, um, I think earlier, earlier this month in Blood Advances, um, so our, you know, our the same group, we also looked at the question of, well, if you got a novel therapeutic, or, or if you got PD1 blockade pre-transplant, um, does that, you know, what about BV maintenance, right? So we've been doing BB maintenance or, you know, consolidation, uh, for years based on the theory criteria, but remember when, you know, when we did it with the theory study. You know, the 5 year PFS for the control arm was less than 50%, right? Isn't the 40, is it is 40%, 44 or something, and then it went up to like close to 60% with BB consolidation, so, um. And so, uh, but what about if your starting point is a lot higher, right? So if you, so now that we think that if you get PD1 blockade pre-auto, you have a better depth of response, you get chemo sensitized, you know, your, your beam or CBV or whatever like works better and you get less, less relapses, do you, are you, are we still moving the needle with BB consolidation and. Um, probab probably not. I mean, there, there may be a small group of patients that, you know, are not cured with PD1 block PD1 plus auto and who might be cured subsequently BB consolidation, but that's gonna be a vanishingly small group, um, and so, you know, our, our practice, I mean, to be honest, even before this, our practice has kind of shifted away, uh, from doing BB consolidation for the, for this group, but now, but, but, you know, with this paper, you know, certainly I think there's, um, there's definitely more, more ammunition for, for, for that approach. So again, in patients who get PD1 blockade pre-auto. Um, I generally don't do BB consolidation. The one potential caveat is if you've got PD1 blockade in the front line. Um, and again, that's, um, that's probably gonna be a question later that someone has, um, you know, these data, uh, so this study or this, the, you know, these two sort of groups, uh, really pointedly, um, uh, omitted, uh, that group of patients because we're not really sure how that works. So that's the one group that I will still consider BB maintenance in, uh, is that if you got PD1 frontline and then you relapsed, uh, because for those patients, honestly, we don't really know what the optimal approach is and that, and we try to incorporate everything we have. OK. Now, can we go, can we do it with auto transplant altogether, um, and so, uh, this, um, this is a surprisingly difficult question to answer. So, I mean, there are a few approaches out there, uh, right, you know, CTDNA, you know, driven, um, you know, there's that randomized trial which uh it's, I'm gonna present in a couple of slides, although now the, the study design's actually gonna get modified and it's not gonna be randomized anymore. Um. But the, you know, given the really high responses, um, and deep responses that we see with PD1 plus chemo, this really begs the question of whether, whether this could just be our destination therapy, right? Can we just do this and not do and not do, um, and not do auto. Um, and so there's been a few sort of studies kind of looking at this. So, um, so there's, so one of the first ones was actually a Chinese study, um, looking at tis tislilizumab. And Gemox, um, followed by Tesla is a maintenance, um, you know, a little bit of a different patient population that we have in the United States, right, these are patients that like none of them had had like, none of them had prior, like, you know, BV, um, like, and these are patients that probably we would have just normally taken to auto, so it's a little bit of a brave study, but, uh, but nonetheless, they, they, patients did really well in this group, um. So they, um, what was it, um. Granted, um, they got up to 2 years of maintenance tisillizumab, and we've now seen with Pembroke and with, and we've seen now with Pembridge, uh, or rather with Pembro GBD with, with, uh, maintenance Pembroke and no transplant, um, that there is still kind of a pattern of ongoing relapses, at least for the first, at least, at least for the 1st 2-3 years, um, and, and then some patients relapse after maintenance, but, but still, at least it was kind of, um, you know, it's an interesting initial signal, I guess, in, in, in this direction. See. And then so then, so this kind of led to um. This kind of uh led to um uh uh the, the, um, the team at Memorial looking at uh Pembro GVD right? So Pembro GVD as we already mentioned, everyone knows that it's, it's really an incredible regimen to get patients to A, but what about, uh, well, given how good it is at uh, as, as a bridge to auto, what about just using it as a therapy without auto, right? So just do Pembro GBD and, and then stick patients on Pember maintenances for a while, um, and so the next, you know, cohort of their study was Pember GBD times 4, Uh, followed by Pembroke Maintenance and um. And so they, you know, so it's, again, the results a little bit in, a little bit in the eye of the beholder, right? Uh, so the 24 month PFS was 60% overall, um. And uh some patients relapsed during Pembroke, some patients relapsed sort of, you know, soon after and a few later relapses for the non for the non-transplanted patients. Uh, all of the patients who, um, well actually all but one patient who relapsed uh without transplant was then subsequently bridged to transplant again with, with, with the addition of, of chemo, you know, they basically all went into remission, went to transplant, and then so far like the PFS 3 for those patients has been, has been excellent, um. And so the one, and then the thing that kind of emerged was that um was that uh you know, when they were kind of looking at some pre-specified um uh uh groups that uh patients with extraneal disease at the time of transplant or rather at the time of salvage uh really did poorly with this with this approach. Um, and so this led to the design of a um of a randomized trial for basically patients with, with, um. Uh, uh, with basically relapse that was not external, so, you know, stage 1 to 3 at the time of relapse, uh, with Pembro GVD randomized to, to auto or not, um, but more recently the study has just been modified to, to make it, um, to make it non-randomized again, uh, given the, uh, the, the, you know, quite frankly, the, you know, difficulties in recruiting patients to a randomized study that includes transplant, right? And we've seen the same issue with PTL PTCL status as well that it's just hard to recruit patients to a randomized trial that includes transplant or, or, or not. Um, so yeah, so novel, so what about novel therapeutics? Well, you know, honestly, this is a kind of a been a pretty dry area for, for Hodgkin lymphoma. Um, and so, at the end of the day, right, we, you know, we have BV, we have PD1. Um, a lot of the more novel mechanisms that don't rely on those, right, so non-CD30 targeted or non-PD1 access targeting, um, agents, uh, really haven't had much traction, uh, despite some of them being clearly pretty effective, um, and so, you know, thinking about can we optimize PD1 blockade or can we optimize BV, um, so number one is we don't really know why people get resistant to PD1 blockade and, and, and Hodgkin lymphoma. Uh, we know, we all know. Very well this phenomenon of patients with very slow progression while on PD1 blockade where you can just kind of leave them on it for for years at a time sometimes, uh, and they can, they're just the disease gets a little bigger every time and and they're OK for 234 years, um, so what it, you know, what's that all about, right? It's, it's, you know, the, the whole sort of cadence, the natural history, history of the disease seems to change, uh, with the P1 blockade on board. So, you know, question is can we restore PD1 sensitivity, um. So I got it. OK, so, um, there's a few sort of, you know, smaller study that, that has suggested that maybe we can, so the addition to citabine decamelizumab, which is a PD1 blockade or PD1 um. Um, uh, antibody, uh, in China, uh, have found excellent results in PD1 treated diseases or rather PD1 treated disease. They were a little bit cagey about sort of which patients were truly PD1 refractory in the actual, in the actual paper, but, but nonetheless, uh, results that were certainly were much better than you would think they would be. So, um, so we had a, we had, um, a trial at at City of Hope, uh, looking at oral azoytidine, so CC 486 plus nivolumab, um. And so this was specifically in PD1 refractory patients defined as the progression within the 12 weeks of the last PD1 dose. Uh, patients, you know, most patients responded. Uh, so over 60% response. Um, and so this trial has, has finished enrolling or we're analyzing the final data now. Um, pembrolizumab plus variostat. Another another trial that we did at City of Hope, uh, kind of a similar concept, right? So HDAC, not the same as HMA but still an epigenetic therapy plus PD1 again really did work as well, um, same concept, p pembrolizumab and, and tinistat. Um, there is a Pembro, uh, azacytidine study right now, I think, at MD Anderson. They run the whole shebang and maybe it works even better. So there, so there was another Chinese study, PD1 plus HMA plus an HDAC, um, and that was interesting because they had some very long responders, uh, that have been in remission for like years and that. Now, here's sort of, here's sort of the sad part, right? In Hodgkin's lymphoma, the novel therapeutics, uh, so given the, you know, this, the overwhelming success of PD1 blockade, you know, we. Uh, it's natural to think, OK, what about all the other immune checkpoints, right? And you know, here's just, just a smattering them, right? CTLA 4, LAG 3, TIM 3, whatever, right? So, um, unfortunately these have all been looked at and they're basically all dead, right? I mean, you know, CD 47, you know, digit LAG 3, and, and that's in, that's despite, you know, some very long, you know, responses with Pembroke favilizumab, right, but, but Merck, you know, um, discontinued that one. Um, you know, Tim 3, TJ, I mean, the, these have been, these have been looked at, um, in, in every combination, and again, pretty much all of these have been dropped by the wayside at this point. Um, and then what about other novel therapeutics? So, um, yeah, so the CD30 car, uh, yes, there are a couple of CD30 car trials still floating around, um, but the kind of the, the large pivotal one, was, you know, was, you know, shut down, um, uh when the company went bankrupt, um. I was, I was, I mean, I was a PI City of Hope for, for the charity trial for CD 30 car. Um, and I think what, what really did it in was like the, that the preliminary, like, you know, 1st 15 pages, the one year PFS is only 20%. So the, in the phase one, it was like closer to 40%, but when it was only 20%, um, that really kind of, that, that really put the nail in the coffin for that one. another CD30 car was. Halted due to toxicity and then others, right, the CD30 by Pacific gone AFM 13, all this buzz at MD Anderson discontinued, um, so they tried the AFM 13 AB 101 trial. So I, I was a PI for that one also, also shut down SGN 35C, a very safe CD30 ADC like we, you know, we had a City of Hope, uh, I think we were the leading enroller. 70% overall response rate looks like BV this, you know, discontinued. Um, Cam and Danlab testimmarine, um, another ADC fantastic overall response rate, not as safe, uh, for those of you who know the story of that one, also also discontinued, right? And so this kind of highlights the fact that it's just very difficult to make progress given a very small group of patients patients, right? And so these sort of, you know, metrics that would look incredible in any, any other disease type, you know, you don't move forward in Hodgkin. And so finally, the last slide, so allo transplant Hodgkin's lymphoma, um, so I'm a huge believer in allo transplant, very big improvement over the last, over the, over the, over the last like many years, right? So, you know, and just to sort of highlight how different, how disparate the results are now compared to before. So not that long ago, right? So CIBMTR study published in 2020, like I'm, I'm some like middle author on that one too, right? So there was, it was a 4-year, so for reduced intensity transplant in, in Hodgkin, 4-year PFS of 30%, so basically, 50% chance of relapse, like 25, 30% chance of like really bad GVHD. So your, you know, your, your grips was like 20%. It was, it, it was not very good, right? It's really kind of staring down the barrel as your last, last resort, right? The new data, I mean, if you looked at the, you know, if you guys have seen the, the Hopkins data for, you know, that was published in Blood Advances last year, 3-year relapse of 7%, that's like better than auto, right? It's like it's incredible, right? So PD1 plus PTI, um, and those are the two big innovations with PD1, you know, with PD1. Blockade on board, pre-transplant, and then the PT side to attenuate like the GBHD after the fact. 5-year PFS of 84%, you get like very little relapse. Uh, the, the kicker in this one was, was that, you know, normally when we do PTI, right, we, for the transplanters here, we keep Tucker on board. You can stop it, right, day 60, day 70, you can stop it pretty early with PU1 plus PTI, the general recommendation to keep it a little bit longer in, in. Hodgkin to kind of around day 180, um, but you know, and with that approach, you get very little chronic GVHD as well. So it really works incredibly well, um, and clearly the PT1 and PD1 blockade and PTI, those are the, those are very clearly like the secret sauces. We thought at the beginning it might be the haploidentical donor thing because of of the hep, but it seems like as the dust settles, it's really more the PTI rather than the haplo donor, um. So again, so for patients relapsing after auto, I, I, I type them all. I don't necessarily go straight to transplant. You can kind of juggle them around on stuff, but when they're when they become PD1 and BB refractory, my approach, throw in a little bit of chemo, get them a response, and then go to aloe, and then, and then we cure almost all of them. Um, and then, yeah, so that's, that's it. So I went a little over time. So, um, I think in summary, so I think PD1 based therapy should be, you know, standard in the relapse refractory setting, especially going to auto and all, in all honesty, especially if you're going to Aloe as well, um, we still have not defined who can skip auto transplant, relapse refractory Hodgkin. Hopefully that will be the next, um, hopefully we'll be able to, uh, you know, solve this in the next few years at least, um, but, you know, and then unfortunately, further progress in the relapse refractory space is challenging. Uh, we are quite good at treating Hodgins. In both newly diagnosed and relapse refra in both and and in the relapse refractory setting and I'm, you know, this is not meant to, to imply that this is not an unmet need right for the, for the patient who's like, you know, who doesn't have any other therapies left and who can't get the aloe or relapsed after his second aloe like as is the case for one of my patients recently, you know, that, you know, that person clearly has an unmet need, right, but it's just to say that, uh, from a, from a real world, um, drug development perspective that is a very challenging landscape. So thanks a lot. Thank you so much, Doctor May. I'll be a little more conservative with the next introduction. Um, so sorry for botching yours, Doctor May. Appreciate your patience on that. Uh, it's my pleasure to introduce Doctor Kara Kelly, who's our, uh, division chief for pediatric hematology oncology at Roswell Park. Uh, she's also the, the last or second to last author on most of those studies you just saw for, uh, nivolumab AVD and an ongoing, uh, clinical trial investigator for Hodgkin's lymphoma and many other. Pediatric malignancies at Roswell and she's also our um Kaminsky Endowed Chair of Pediatrics as well uh and Doctor Kelly please uh join me on stage we'll talk about uh special needs for for young adults and adolescents with uh hematological malignancies thank you Doctor Kelly. Right, uh, thanks so much for the kind introduction and for the opportunity to participate in today's, uh, program. Um, I'm gonna talk about adolescents and young adults that are defined by the NCI as, uh, patients that occur that are diagnosed between ages 15 and 39 years. So, um, a big bulk of the patients with Hodgkin's lymphoma that we all see. And the reason that we pull this group out separately is because, um. There are gaps between the pediatric and adult approaches to care, uh, that do lead to some challenges for this population, especially related to survival, toxicity, and quality of life. And so I'm gonna focus my, uh, my talk on, on Hodgkin lymphoma. So my disclosures are here. OK. So, um, for those of you that practice in Western New York or Central, uh, New York like we do, um, you know, unfortunately, um, adolescent and young adult cancer is, is, uh, particularly a, a challenge for our catchment area. We, um, unfortunately have the highest incidence of cancers in the AYA population. Of any of the NCI designated cancer centers, so, uh, we're not quite sure why, but it is, you know, a significant burden, uh, for our areas. Now, um, cancers in adolescent and young adults, um, it, it, it's about a little over 4% of all cancers that are diagnosed each year. Uh, that translates to about 86,000, uh, new cases of cancer. And leukemias and lymphomas are the predominant type of cancer that occur in this age group, especially in the kind of the younger end of the spectrum. Um, in, uh, patients 15 to 19 years, it's, you know, most common, uh, it's, um, as you can see, it's about, uh, 35% of all cancer types, uh, 20% of those ages 20 to 29 years, and then it starts to trail off, um, as a percentage in the 30 to 39 year old group as you start to see more breast cancer and other solid tumors emerging. Now, as I said before, I think the, the challenge for this group of patients is that they do fall into this gray zone, uh, between pediatric and adult care. And as a pediatric oncologist that treats Hodgkin's lymphoma, I think one of my, um, observations is it's been kind of crazy that I see an 18 year old, uh, who gets one recommendation, and if they go down the hall and see Doctor, uh, new, they may, in the past would have gotten a completely different, uh, recommendation. There's a variety of reasons why our practices have diverged historically. Um, I think in part, uh, in, on the pediatric side, we tend to care for a younger population that doesn't have comorbidities, so we tend to really push the envelope and use more dose-intensive therapies. Um, additionally, on the pediatric side, vast majority of care delivery is in an academic center. So, um, enrollment on clinical trials is more the norm, whereas adult patients are often treated in the community. But yet on the flip side, on the pediatric side, we've been limited in access to novel therapies like rituximab, for example. It took 6 years before it was approved in, in pediatric patients, um, from when it was first approved in adults, and that's because historically clinical trials have started at 18 and have not, uh, included those adolescents, although fortunately, um, that's changing. So, um, here, you know, this slide kind of summarizes the historical conventional treatment regimens that we've used, um, for Hodgkin lymphoma. Uh, on the pediatric side, we've used more, um, multi-agent regimens, um, as a. Means of trying to limit the cumulative exposure of any particular drug as a, a way of limiting long term toxicity, whereas on the adult side, as you heard from the, uh, from the other presentations, you know, ABVD had, you know, had been the norm for, for many decades. Um, radiation approaches have, have also differed. While we, both in the pediatric and adult side have evolved our practices. So when radiation is used, it's now being used more as involved site or response adapted radiotherapy. Overall, um, much fewer percentage. of patients are, are receiving radiation therapy as part of their practice. But even, you know, historically, we've differed. So on the pediatric side, we've tended to use less radiation for early stage, more radiation for advanced stage, whereas, you know, all of you adult practitioners know that the opposite, um, has been true. And, and so, um, you know, a lot of our efforts in Hodgkin's lymphoma have been focused not only on improving the survival outcomes, but also in. Really being mindful of the, of the long term complications of therapies. Um, a lot of our understanding of this has emerged from the pediatric side, uh, through the development of very large cohort studies such as the childhood cancer survivor study, uh, which was, has been continuously funded by the National Cancer Institute. Which really helped us to understand and recognize that many of our Hodgkin's lymphoma survivors were developing pretty significant complications, cardiovascular disease, uh, subsequent cancers, particularly breast cancer related to the use of chest radiotherapy, but as listed here, a lot of other long term, uh, complications. As we use these novel therapies, which I agree probably we should get away from the word novel because they have been around for quite a while, but They, um, we really don't know what the long term toxicities are, especially in this younger population, you know, the checkpoint inhibitors, while they've been used in, in melanoma, lung cancer, um, you know, those are diseases where you don't have the same decades long, um, of survivorship. So there still is a great need for us to be able to understand, uh, those, those impacts. So, I wanted to, you know, a lot of the information we have about long-term toxicities of therapy is either based from the pediatric side, you know, mentioned the childhood cancer survivor study, or in studies of adults, but the adult studies have typically included adults 18 and up. So a very large age range, and, and there clearly are, are risks that are associated with, um, kind of how old you are at the time of exposure. More recently, there have been efforts to, um, to really describe the, the late effects in AYA patients and this is one very, uh, recently published paper, which was, um, uh, it was uh conducted as a, a linkage of statewide cancer registries in California and Utah. Um, and they had a pretty large cohort. It was over 4000 Hodgkin lymphoma survivors, you know, AYA patients. These were more contemporarily treated. Their, um, ages, uh, these were patients diagnosed since 2006, and they were all, um, at least 10 years out. And they looked at the, the cumulative incidence of, uh, various organ toxicities at, uh, 5 years and 10 years, um, out from treatment. And. As you can see from these curves, you know, the risks are pretty significant. Uh, cardiovascular disease, at 5 years, um, about 4% of this early as 5 years, which to me seems incredibly early, that 4%, um, had some type of cardiovascular toxicity. By 10 years, it had doubled to 8%. Uh, thyroid disorders were about 3.5% at 5 years, about 8%, um, at, uh, 10 years, um, and, uh, and, um, I think the second, um, malignancies were also, um, pretty, pretty common. They then looked at it though. It's not all a bad story. So of the overall cohort, uh, 3 quarters of them had very low morbidity and were not showing any late toxicities, but they could identify some other groups that were particularly at risk. So there was a thyroid group, which like 12% of them had, um, thyroid disease at, at 10 years, uh, cardiovascular group, about 9%. And then they're about 2% of the overall cohort had a mix of multiple different, um, conditions. And, you know, again, these are young patients, so these, um, these effects are going to lead to significant morbidity and impaired quality of life. Now, in the study, which I thought was interesting, is then they tried to figure out, well, who's really at risk. So they looked at quite a number of clinical factors and social determinants of health to see if they could really tease out and then put together this heat map. So, the red, um, areas are the groups that the risk factors that were associated with, um, more likelihood of developing all the various toxicities, which is, uh, each of the columns, uh, in the table. And some, so the, uh, survivors that seem to be at particular risk included those older AYAs, so those diagnosed between 30 and 39. Um, females were more at risk, uh, certain underrepresented, um, uh, groups such as Hispanics, um, or patients with public insurance, and also those that, um, underwent, um, bone marrow transplant. So I do hope that, you know, we'll continue to see less use of auto transplant in these Hodgkin's survivors because, you know, it is probably the most intense, um, across all of the different domains in terms of risk of long term toxicities. So, the other interesting observation in Hodgkin's survivors is that they seem to be um really at risk for accelerated aging, and I think there's still a lot that we're trying to tease out. Is it just something about patients that develop Hodgkin's lymphoma to begin with, or is this really a complication of their therapy? Uh, in another, um, kind of interesting study recently published, uh, from the, um, Saint Jude Group, uh, they looked at, um, a large cohort of very long-term survivors of childhood cancer. These were on the median of 25 years out from their, uh, treatment, and this Hodgkin was a sizable percentage of the cohort. It was about, you see, 12%. What they did was they looked at, um, epigenetic aging using a, a genome-wide DNA methylation assay, and then they compared it to, um, more of a clinical score, which they called a deficit accumulation index. So it looked at a number of different, uh, patient self-report measures of chronic health conditions, functional, psychosocial and mental well-being. And as I've highlighted here, you can see that among all different types of childhood cancers, the Hodgkin lymphoma scores were really kind of off the roof. They, they had considerable evidence of epigenetic aging even across the three different groups that had the deficit accumulation. So, um, the other interesting study recently published was from, uh, another study from Saint Jude, and, you know, Saint Jude with all their resources are able to bring in their, uh, long term survivors for very comprehensive assessments, uh, including, uh, brain, uh, MRI's and. So, in this cohort, of which a third were Hodgkin's lymphoma survivors, again, long term, 21 years out, um, from the MRI, they applied an AI model and were able to estimate, um, the gap between the chronologic age and what their brains look like. And on average, in this cohort, their brains looked like they were 6.5 years older than they were. And then, uh, patients that like females diagnosed at a younger age who had gotten radiation, 16.5. And then there was this other group that had, um, had a 37 year acceleration, um, in their, what their brains look like. Uh, they also looked at a number of biomarkers, um, and looked at neurocognitive outcomes and saw that there were, um, clear associations with this kind of advanced, um, uh, imaging on their, on their MRI's. So I, I wanted to highlight, um, a couple of, uh, studies that were, uh, that were, uh, presented at this year's ASH meeting. Uh, the first one was a study that was done, uh, led by the University of Rochester Group just down the road from here. Um, they looked much earlier on, so it was patients that they looked at patients at time of diagnosis and at end of chemotherapy. Uh, this was an adolescent young adult cohort, um. And they, um, measured a variety of different biomarkers and had the, uh, the patients, uh, complete a neuropsych test battery. I think what they observed, not surprisingly, is that the inflammatory markers were more elevated in the Hodgkin patients compared to controls. They found that the oxidative stress markers did get better over time, but they were still elevated over normal. And importantly, um, several of the markers did correlate with impaired measures of, of neurocognitive function, particularly executive function impairment and attention and processing speed. So I think this at least is showing that there is some biologic marker of some of this dysfunction. Many of our patients describe this chemo brain that they feel, um, during treatment and immediately after. And so there, there may be some, you know, biologic, uh, rationale for that. Um, and then there was another study, uh, from the Saint Jude Group, again, looking at those very long-term survivors. Uh, these are among these, uh, 39, uh, Hodgkin lymphoma survivors. They were 25 years out. Um, they did extensive measures of cardiopulmonary function and cerebral blood flow and found that the, the patients that had, um, the really the most impaired pulmonary dysfunction. Um, had, um, had much lower anterior and posterior cerebral blood flow in response to exercise, and, uh, they found that this may give some, you know, explanation. So our therapies, you know, typically are radiation or doxorubicin, bleomycin are affecting. Cardiopulmonary function and in the long term, that can impair cerebral blood flow and put these, uh, patients at risk for, you know, early, um, neurocognitive dysfunction, potentially dementia. So I think that these are really important things for us to all be aware of. So I think the other take-home message is that all Hodgkin's lymphoma survivors need lifelong care, either through a survivorship program or working with an experienced primary care provider. Uh, these patients should all have a treatment summary and survivorship care plan, which includes guideline directed organ toxicity monitoring, as well as, uh, psychosocial support. But I think the challenge is, and I'm sure many of you, you know, experienced this, is what guidelines do you follow? Um, uh, just, you know, last year we, we did a, a, an analysis where, um, we looked at the various, um, you know, guidelines, survivorship guidelines that are put out by all, you know, number of different national organizations and, and compared them, and, you know, as you can see from the check marks, there's a lot of, you know, variability in terms of what's covered. If you look individually at the guidelines, there's differences and recommendations, so. In practice, I think it's really challenging in terms of, you know, knowing which one to follow. So it is recommended though that you find a guideline that you're comfortable with and at least use that, you know, to, uh, direct, um, subsequent care. Um, I did, you know, want to highlight the children's oncology, uh, group survivorship guidelines and the, the website for those are available here. These are free and readily available. And they're, they're somewhat more comprehensive in that the guidelines are based on the therapeutic exposure and then gives recommended for testing. The caveat is that these were developed primarily for patients 21 and under, but I think for Hodgkin's survivors, many of which are in their 20s, the recommendations are, are still relevant. So, I'm going to now switch, you know, that's our patients that have been treated. Let's talk about ways that we can hopefully, uh, decrease the risk of many of these long, uh, long term side effects. So, really, in all of our clinical trial development, our focus has, has been on trying to make. Maintain those really excellent, uh, progression free and overall survival rates, but try to cut back on the therapies that have been associated with these long term toxicities and, and hopefully our more novel or targeted agents will help us to do that. So, um, I'm not gonna go into Doctor Nu gave, you know, a great, um, overview of, uh, the SWAG 1826 study. Um, I was, you know, really just very fortunate to be part of the team that helped to include the adolescents for the first time. Uh, in, uh, conducting a big study like this, and I'm just gonna highlight a few of the correlative findings. Um, I am gonna with more of the lens of looking at it from the AYA population just to, you know, to make sure that that's kind of, uh, pulled out. So, um, so you saw this forest plot from, uh, Doctor N just a short while ago, and I just wanna again bring your attention to that adolescent group that, you know, really did quite well with the Evo ABD, um. So, uh, I think that's important, uh, to highlight and I think what, um, and the other, but what's interesting about it and you saw the, the a hippie analysis, um. Uh, what Doctor N didn't mention is that the AIIPI only included patients 18 and up. It didn't include the analysis because the original score was validated only in clinical trial data that was, um, included adult patients. It didn't include any of the, the pediatric trials. And what was observed in the initial validation studies, and again seen with the S1826 cohort is you've got this really interesting U-shaped, you know, curve there. So, The, the patients that actually do the best on that trial are really patients in like their 30s and 40s. Um, and so it's not clear why those younger patients, those 18 to, you know, um, 20s patients, um. Didn't do, you know, quite as well. Um, it may be related to things like treatment adherence. I, you know, I think, um, you know, patients in their early twenties can sometimes be more challenging as they're trying to get their lives or they may not have a health insurance or other things, or maybe there's some differences in biology, but I think that still is a, a very open, um, area for additional research. Um, the other thing I wanted to kind of pull out from our observations in the adolescent cohort is that unlike the older adults, um, we actually had more discontinuations of nivolumab in the, in the in the adolescent, uh, patient. We had 12 discontinue Novo versus only 4 with rituximab. Um, many of you have probably seen the elderly cohort where many didn't tolerate. There was a very high discontinuation rate of, of the rituximab, which contributed in part to the poor outcomes. But in the pediatric, despite the fact that Nevo was, uh, discontinued more frequently, um, and it wasn't for immune-related, um, AEs for the most part, um, and fortunately, most of the AEs did, uh, did resolve. But despite in those 12 patients, there were no progression events. So, even though they got a much more truncated, um, course of therapy, which raises questions about how much nivolumab is actually needed. And some of our, our colleagues, uh, on the pediatric side that are working in lower, uh, lower resource settings are beginning to look at lower doses, um, as a means of being able to kind of share, you know, the drug with more, more patients. Um, so you, um, Doctor N had referenced, uh, the PET data, and, um, I wanted to highlight this one abstract that was, uh, presented at, um, at the AS meeting that, uh, he didn't go over. This was the data he presented was just from the cohort of patients that had the concomitant CTDNA analysis. Uh, what I'm showing here is the, is the curves for the, um, were for the PET results from the over the whole entire cohort and. Again, you can see that the end of therapy, um, PET is much more predictive than interim PET. So I think we can say if you're using Nuvo AVD, you don't need to look at your, you know, interim PET anymore. Really, um, really the outcomes are based on, on where patients are, you know, at the end of, uh, of treatment. And that was also observed in the adolescent cohort. Uh, we saw really a marked difference in outcome, um, in both the Nevo and the BV arms, you know, based on their end of, uh, treatment, uh, PET, which is, is highlighted here. So I won't, um, go through this because Doctor N did cover the CTDNA and concomitant PEET data, um, you know, showing that it seems like CTDNA does a little bit better and when you add in the end of treatment pad it, you know, even is more discriminatory. Just more to say that there's going to be a lot more coming out about CTDNA. Um, besides looking at, at changes in the quantitative amount, we have really a rich amount of information on the specific genomic alterations that are detected with the CTDNA. And there's some hint that there are differences across the age spectrum with certain genomic, um, alterations being a little more common in younger versus older patients. Um, I think the other thing to point out, this essay was done at the Dana-Farber. Um, there are a couple of different CTDNA assays out there, uh, in some of the upcoming, uh, trials that are going to be conducted by the, through the NCTN, probably the Nera assay is the one that's going to move forward, and that one is available clinically. But I think that the take-home is CTDNA is exciting, but we're still really figuring out how best to use it, um, in these patients. The other, um, uh, abstract that was presented, I also wanted to highlight was, um, the patient reported outcomes because, um, S1826 was the, really the largest study conducted in North America to incorporate, um, serial measures of patient reported outcomes, um, serially across the study. And, you know, this was a huge study, like over 350 centers participated. And yet we had really great participation rates, 98% at baseline and 70% at one year. Um, kind of the, the key take-homes is that there are age-related differences in outcome. Uh, Nevo was better tolerated, uh, with less fatigue and neuropathy. However, um, the fatigue was more notable in adolescents and the older adults, and we're not quite sure why the older adults make sense, but why the adolescents, there probably is some. Fatigue is a multifactorial domain and you know, some of the depression and adjustment issues that you have in adolescent may be part of it, but I think that was uh an interesting finding. And, um, the other, um, interesting part of this trial was that for the first time it included measures of, uh, what are the, the pro-CTAE that's the patient reported outcome CTAE measure. So rather than just looking at clinician graded AEs, this trial captured information from the patient perspective. And so we recently published in the adolescent cohort, um, the findings with this, and it showed that the NO ABD had a much improved tolerability profile. The way that this, um, this figure is, is anything above one means that BV is worse than NEO, and you can see really across the board, um, the patients reported, you know, better tolerability, uh, with the NO. So I know that, uh, Doctor Nu put in a plug for the early stage trial. Uh, this is a trial that I'm co-chairing, uh, nationally along with Doctor Boy Yu Hu from University of Utah. Uh, this trial is open to patients ages 5 to 60 years of age with stage 1 or 2 classic Hodgkin lymphoma. And everybody starts out with two ABVDs, but then the subsequent therapy is, um, assigned based on, on interim PET response, as well as, um, uh, favorable versus, uh, unfavorable disease. And we're hoping if successful, um, that will really, really cut down on the amount of conventional chemotherapy and radiation use in this patient population. So. Uh, trial's going really well. We're almost at the halfway mark. You know, it's a big study. It's enrolling over 1800 patients, but, um, we do have it open at Roswell Park, so please contact us if, uh, you're interested. Um, and so I'm just gonna end with, um, a, a, a last abstract that was presented at the ASH meeting from the Mayo Group Group where they, um, looked at data from the National Cancer Database, uh, patients with a median follow-up of almost 7 years, um, and they looked at 5 year survival among patients less than 40 years, and you can see that with those novel agents that we're making progress in that there's, um, significantly improved, um, survival with the use of, of these drugs. And so, uh, just lastly, here's some AYA patient resources to consider referrals for your patients. Many cancer centers, including Roswell Park, have, uh, AYA programs that are a great resource to help them through their, their therapy. So, and with that, I'll, I'm, I'll finish up. Thank you. Fantastic job, Doctor Kelly and, and for all of our panelists just a quick uh round of applause for uh concluding and then we'll take some questions. With to finish strong. Yes, sir. Go ahead, doc. What are you currently doing for the CTDNA positive and PET positive patients? Are you going for salvage? Are you biopsying? What are you doing for those patients? Go for it. I mean, we're not really, um, I mean right now we're not checking CTNA like standard of care, so, um, but so don't know the answer yet, but prob those patients probably need early salvage realistically. I think that just the point with the, with the PET is you have to be a little careful in interpreting, um, the results with the, especially with an EVO-based or checkpoint inhibitor-based therapy because there can be some false positives. So depending on what it looks like, especially if there's no increase on the CT component of it, we generally recommend repeating a short interval scan. Yeah, I totally agree with that, especially with the Nebo AVD or BVAVD like I mentioned, they're designed to go all 6 trials, all 6 cycles. So if I get one, I see it, you know, obviously anything besides like a new lesion that I usually kind of continue to treat just like Dr. Kelly said, closer follow up for it. I, I think along with uh, with some, you know, skeptics in large cell lymphoma and other lymphomas we're still waiting for commercialization and validation, you know, more real real world outcomes, but by the next 5 years will be part of standard practice I would imagine. Dr. Emmons. So a couple of comments. The AOD 2131. We have increasing numbers of patients who say we want nothing to do with bleomycin. We've heard bad things about it and maybe we smoked or smoked in the past. Uh, what do you tell your patients who say, I will not be included in that trial because I don't want any bleomycin, let alone two cycles. Yeah, I, I guess we have fortunately we haven't been hearing that a lot. Uh, it's only two cycles of ABVD, um, so that the cumulative exposure to it is really quite low and should not translate into, uh, pulmonary toxicity, and you know it is a younger pop you know we're capping the age of 60, so it is a, a more of a younger population. You know, I, we had to do it this way because the standard of care for early-stage Hodgkin was a response adapted design. And so this is kind of the only way we'll be able to to demonstrate compared to what the standard is. I just wanted to hear if you yeah, but yeah, not, not too many for that. The one I thought you would ask is that um in the very small percentage of patients randomized that with the slow early response randomized to the. Uh, control arm, um, we have, you know, the augmented therapy we have, uh, it is be a cup, but we did adapt, we did modify the study to have the E, um, the BDcap, uh, I'm probably saying it wrong, but it substitutes darbazine for the procarbazine. And since we made that substitution we've seen much more acceptance of it and most patients have opted for that that regimen. Then with regard to checkpoint inhibitors, how much autoimmunity is too much? Uh, so will you guys accept somebody who has a distant history of something that isn't active now and how much do you worry about it? Does it depend on where it is? If any MS at one time 10 years ago, they can't get it, how much is too much? Yeah, I mean, in our trial, we actually, as long as somebody doesn't have active symptoms and isn't on active treatment, they're eligible for the study. So only active, no history of correct, correct. Got it. Yeah. Any others? I'm curious, do you. It's only active autoimmunity that you worry about. I mean, personally, I mean, I've had a couple of cases where patients had, you know, either like a history of something it wasn't that active or maybe like a squirrelly history or something wasn't, wasn't formally diagnosed, and I, I'm always a little nervous given that. The cure rate with ABVD, you know, is already pretty high, and so I'm, I'm a little nervous about, you know, fifty-fifty randomization of BBD. I, I, I do have a lot of patients on this trial, but that I guess I tend to, you know, opt for, for ABVD and, you know, and say the discussion of checkpoint inhibitors if they relapse later. So yeah, I think for me it's if anybody has a history of something like like MS or something a little bit more extreme, even if it's not active, I tend to shy away from it a little bit. I'm, I'm the same. If it's a young healthy patient, I might go to recad honestly for, for, so especially things like, you know, lupus, um, some kind of immunosuppressant, you know, actively, I think certainly for me I would avoid it. Um, I've got a patient with Crohn's disease, you know, I'm not doing well on Skyrizzy, for example, you know, I've been talked to lots and lots of docs around the country trying to kind of pull the audience on that one as well. It could be a little letter to blood, probably not at this point, but, um, I haven't asked Doctor May actually yet or Doctor Kelly, but I should, but, uh, um, but, um. In general, I, I try to steer away if I have um other options that look like a similar cure rate, but it's, it's a shared decision with the patient and with the, the docs who are managing those autoimmune conditions as well, of course, as well. And given the patients who get chest radiation and the emerging information about thymic health in adults and microbiome issues and the association with response to checkpoint inhibitors and other immune therapy, are you aware of any of these corollary studies being done in these patients to see how immune outcomes. Yeah, I, in the trial we're collecting, um, serial measures of immune function and so in real time they're being processed so I'm excited that we'll have that at the end of the trial. Uh, additionally, we're collecting stool samples for microbiome analysis and, um, actually have a fair number of samples already which you would think with this population they wouldn't submit, but we are, we're doing pretty well with that. Do you encounter a CD20 classical Hodgkin CD20 positive? Do you change treatment or you add something to it? Because I've seen a couple of patients with CD20 positive. And if you're adding Rituxan to the regimen. I, I know I was part of a paper many, many years ago where we looked in about 20% of patients had concomitant CD20 expression, but, um, I don't treat those patients differently. I know there have been some studies adding in rituximab, but that has not been my approach. Right. Yeah, I, I don't do that either. I feel like the only time I will sometimes add Rituxan is if they're like EBV is driving their Hodgkin and um we can't control their EBV then I'll add Rituxan into whatever else I'm throwing on but not in the front line, at least. Although now with nivolumab, that seems to work particularly well for the for the EBV so that may may not be necessary. We'll save lupus. Sam's for real est refractory. I was gonna say I do. I will if I need it in a pinch. Real est refractory. It's only been one patient for me so far. I've, I've done it and it augment responses and it's worked, but not common. Sam's. Ye Yiman, yes sir, I, I was gonna stay out of this one. So, so thank you. So, um, I, I think all, all three of you kind of hammered the point, uh, hammered home the point that checkpoint inhibitors are, uh, just incredibly effective in this disease, um. And now that Nvo AVD is in the front line, uh, you know, the, the, the vast majority of those patients do don't relapse, but there's still a minority that do. And so, you know, Doctor May, you, you kind of brought home the point that these patients, you know, do much better with their salvage treatment, getting a checkpoint inhibitor. I, I'm curious. I, I thankfully we don't get many of these relapses, but still about 10%. So what are you guys doing for the patients who are relapsing after an EOAVD and now you're getting to the salvage and we've all, we've all said checkpoint inhibitors are the, are the most sensitive, the, the, you know, probably the best treatment here, but we've already used them. So are you retreating with checkpoint inhibitor combinations? Are you, are you doing just a BV based regimen? I'm curious actually, all three of you guys, what you're doing in your patients who relapse after an evo ABD. I mean, obviously the caveat is, you know, data free zone, right, so I can always hide behind that, but I mean, you know, for the, a, you know, number one, we, we do need to collect more data, right? So we do have, we have put together a, a reasonable size multi-center, um, series on, on, on these patients, right, who've progressed after PD1 plus chemo frontline, um, and so, you know, we'll see what we can tease out from, from, from that data set, and then, but beyond that in terms of from a practical standpoint. I, I don't think there's a one size fits all. I mean, I think there's a setting where we do try to in some ways incorporate everything we, we have, right? So meaning, you know, some combination of realistically probably ongoing PD1 blockade, you know, given the thought that it probably does, you know, exert a chemo sensitization effect, you know, above and beyond just, you know, the effect on the, you know, a direct, you know, tumor sidal effect, um. You know, some combination of that transplant and and BB, right, this is the one group that we probably will do BB maintenance on, um, so let's, so for instance, you know, we have often still gone to like second line like Pembroke GBD and at least give it a shot. A lot of those patients do anecdotally, some, a lot of those patients do turn out to be refractory and it is, it is what it is, but you know, they get at least like a good PR, you know, try to take the auto, maybe radiate quickly post auto and then maintenance BB. So basically throwing, throwing on like every tool we have at our disposal, so. Yeah, I think for me it also looks at the timing, right? If somebody relapses the AVD like less than 3 months, I'm probably gonna go to more of a BV regimen in that case. Somebody more than 3 months, I'm OK trialing like the like Pembro in that sense, Pembrose GVD because I think there's some data that shows you can use the other one and it still has some effect, um, so that's kind of how I approach it in that sense. Yeah, and I, I think you brought up the radiation, which I, I think we often get away from but also is effective and, you know, should also be considered in some of these patients. I, I agree with all that's been said that we, that's my shameless plug. I'm part of a little multi-center study with Tim Voorhees in 2025. It was published. The retreatment is effective. Um, you might just change your partner with your PD1 or your CD30, and generally it's at least 6 months, um, since the last exposure to those drugs, you, you'll recapture those patients, but PFS is short, and I would look for consolidation, things like aloe, uh, if there are multiple relapse. Just, just going back to the central question we talked about first time. The main question here is, is the disease or the patient's immune system that is the problem with this, and we need better measures of what the immune system of the patient really is coming into this to know how these checkpoint inhibitors are being modulated. Can we do a better job screening those patients and knowing what their response is going to be with checkpoint inhibitors? It may have nothing to do with their Hodgkin's, but rather their intrinsic immunity that's making them not a good response to this. Yeah, I can't agree more, and I think it also probably plays into their risk of long term toxicities too. Yeah, and I think that's what we're seeing with Hasin now, right, as opposed to just the four classical groups that we have. I think we're seeing a huge movement in trying to reclassify Haian based on the tumor markermime and viral load mutation that I think exactly to your point, I think that's where it's headed, which is cool. I think we, we should look at lymphomagenesis as well under that lens, right? It just from the get-go and can you even predict bad outcomes in advance, but not there yet. Any other questions? I'm seeing nothing from online. Uh, either everyone has had all their questions fully answered. We're good to go. I know it's dinner time, so you know, time to socialize, relax a little bit, um, so with that, if there are no last minute questions, I'm gonna conclude motion to adjourn. Can I get a second? OK. Great work, everyone. Thank you so much. So, um, with that, we're closing for today. Um, we're gonna start tomorrow morning with breakfast at 7 o'clock in the morning. Um, we do have a little, uh, dinner for speakers tonight, and then after that we, we probably are gonna go out and have a, a drink or two of, uh, you know, a cup of tea, right? Um, cup of tea, just contact one of us if you're interested, and otherwise I'll see you tomorrow. Um, don't forget your raffle tickets at the, uh, the exhibit booths upstairs, and, uh, that drawing will be tomorrow at the end of the last session. Thank you all for coming.
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