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So I'm here today with Doctor Edward Cliff and he's currently ask her and we're really excited to, to talk about the latest advances in lymphoma research and the hot topics that everyone's talking about. Uh lymphoma. Ask you this year to kick off. Could I ask uh Doctor Cliff, would you, would you mind just giving a quick, quick introduction to who you are, what you're passionate about and um maybe a little bit about your career journey. So, my name is Eddie. I'm an Australian trained hematology registered with a focus on malignant hematology, particularly myeloma and lymphoma. And I'm a postdoctoral fellow at Brigham Women's Hospital and Harvard Medical School. Uh looking at particularly health policy and the intersection of pharmaceutical policy, clinical trial design and hematology and oncology. Uh huh. Super. It's, it's really exciting to talk to you today and uh really interested in diving into, to ask you, I'm going to kick off by asking what are the hot topics that everyone's talking about uh Osco in lymphoma this year. So, yeah, we're fresh out of the lymphoma session about half an hour ago. So it's very much uh hot off the press and it has been a very exciting asco for the lymphoma maniacs around the most exciting and most practice changing I think is was featured in the plenary session, which is the swab s 18 26 randomized trial of nivolumab plus AIVD versus brentuximab vedotin versus A B D in upfront treatment of Hodgkin lymphoma. Hodgkin lymphoma, as many of you will know is particularly common in younger patient's and although outcomes are very good, we always want to make outcomes better. And so this was a cooperative group study in the US that looked at combining checkpoint inhibitor immunotherapy in the form of Nepal a mob with the chemotherapy backbone. Uh They gave six cycles of either Nevo aivd or brentuximab vedotin aivd. And the headline result is that the progression free survival was, was uh even better than I think I expected. There was very early difference in that trial. And so was read out and presented earlier than expected uh in favor of the NovoLIN a farm in favor of the immunotherapy arm. And in addition to an efficacy benefit, there was clear toxicity benefit as well. So it was less toxic um particularly in terms of peripheral neuropathy for patient's with nivolumab, we receive the Nivolumab. Uh And so, you know, it's, it's kind of early days, there's obviously no overall survival difference just yet. But I think despite that given the kind of robustness of the study is cooperative groups that it's a big study given the lower toxicity and given the improvement in progression for survival for patient's and for countries that can access that drug nivolumab in the front line setting. To me, that's a practice changing study and particularly for younger patient's the likelihood of reducing kind of long term toxicity is really exciting. The second study that really uh I guess would say is practice affirming, but it's particularly important outside the US where many funding agencies are very interested in overall survival. A lot of in the US kind of progression free survival is usually enough to get your drug approved and funded. But a lot of funding agencies such as in the UK or in Australia are very keen to have overall survival data. And this was presented yesterday in a special late breaking abstract session. And this was the overall survival data in the Zuma seven trial, which was around a phase three trial of uh car T cell therapy that is access L in the second line setting in diffuse large B cell lymphoma, the most common aggressive lymphoma. And so these patient's um compared access l party against standard of care, which was uh salvage chemotherapy combination chemotherapy followed by an autologous transplant. Again, very well run. Uh this time, industry sponsored but that very well run large phase three study and ash. In 2021 we heard that there was a progression free survival benefit. But in an aggressive lymphoma like diffuse large B cell lymphoma, you really want to know, is it going to change overall survival? Something that really matters to patient's. And indeed, that's what we heard yesterday that there was a substantial uh difference in overall survival. That is if you've got cart is o and the second line therapy, you lived longer, you have a higher chance of being alive at two years than if you received the chemotherapy arm of the trial. Now, one very small caveat is that there was not crossover built into the design of that trial, which is kind of a bit of an equity issue. But fortunately, the majority of patient's uh still were able to cross over in the control arm to receive Carty therapy. Think despite that kind of small ethical oversight or big ethical but small big ethical oversight, there was a kind of small impact on the trial interpret ability. And so I think that's a very, still a very robust result that is um practice affirming in the US and, and and should be practice changing for funders around the world. Although of course, cutie cells are still very expensive. So that's another challenge to tackle but, but another very exciting result. Um The next trial that I thought was really kind of impressive and, and practice changing was just presented just now, the I S L G um I L S G 37 trial, which is the Italian Cooperative Group in primary Mediastinal base of lymphoma which is a relatively rare uh lymphoma isolated to the mediastinum and area you're familiar with, which is commonly occurs in younger women. And so that, that becomes important because historically, that's been treated with radiotherapy. And so in addition to cardiac and lung toxicity, you also have breast cancer risk with radiation to the chest in young women, of course. And so this was the largest ever trial in primary mediastinal b cell lymphoma. Uh And it's sought to see if they could uh see if we still need to give radiotherapy and patient's who have pet negative disease after six cycles of induction chemotherapy. Now, there's still some controversy and primary mediastinal B cell lymphoma around the best chemotherapy regimen. Um many people believe and, and in many cases believe strongly that the standard R chop which we use in other aggressive lymphoma like D O BCL isn't enough in PM BCL. But there aren't, although there aren't randomized data to support that. Um the actual data from this particular trial kind of affirm that in um in the among the physicians in the study, there was quite a diverse range of different chemotherapies used indicating that the field kind of hasn't agreed on on one universal chemotherapy backbone. But again, data from this trial kind of do suggest if not definitively that that something more aggressive than R chop is probably warranted but not definitive. But the kind of headline from that study was that although uh they came to realize that of halfway through the study that, that if they wanted to prove the non impurity margin that they had set out to prove, which just for listeners who may or may not be aware and none. And if you're non inferiority trial, but seeks to show that one strategy is not inferior to the other trial often requires a bigger sample size in a superiority trial. But that does depend on the noninferiority margin. And so as best I could appreciate from the presentation, which we just had, they did some uh kind of very reasonable, seemed to me, very reasonable statistics. And that again, seemed pretty convincing to me based on what I saw that indeed, um we can omit radiotherapy in the patient's who achieve pet negativity at at cycle six. Now, there is an additional COVID of people who have kind of a false positive pet scan at the end of cycle six. That is the pet lights up, but really, there's not disease there. When you, when you biopsy them, you don't find residual disease and they have a very good outcome. And this study didn't really uh certainly what was presented today, didn't really address that cohort of patient's. And so I think ideally, it would be great to be able to omit radiotherapy in that group of patient's too, but still very impressive to run such a large again cooperative group robust study uh in radiation oncology, which is harder to get funded. Then when you've got the novel drug and a company to pay for it. And that looks at deescalating care in a kind of young group of patient's where long term toxicity is really important. If we can avoid. The, the next one that I that I thought was really, uh well, I'm sure generate some controversy from the session just now was from the French Cooperative Group uh Lima trial, which was the seven year follow up of this trial. There's a trial in mantle cell lymphoma, which is a again a rarer type of uh typically aggressive, but it kind of vary in it's aggressiveness. Lymphoma represents about 5 to 7% of lymphomas. And this trial looked at whether there was a benefit in adding maintenance Rituxan that so after you have your induction chemotherapy, should you um should you then receive maintenance Rituxan ever for every three months, for three years? And interestingly, it had previously shown both a kind of substantial benefit in both progression free survival and overall survival. But today's presentation with updated seven year follow up actually show that that overall survival benefit has faded and there's no longer an overall survival benefit. And although it's very difficult to tell why, that is one hypothesis is that some of the novel therapies such as Britain Tyrosine kinase inhibitors and car T cell therapy are making an impact for the patient's that do relax. It does seem that the patient's who relapse in the maintenance riTUXimab arm relax with more aggressive disease. And so I think while it didn't quite sway me away from what, what I think still does seem to benefit patient's in maintenance riTUXimab. It did make me think that now if you're in a setting where there's some issue, whether that be access or, or patient concerns or toxicity, that it is actually now a reasonable thing. Not, it's not now not compulsory, I guess to, to pursue maintenance tax. Although it still does seem, you know, the progression free survival benefit is still robust. It's becoming they're biosimilars available for attacks in many parts of the world. And so it does still seem like a very reasonable thing to continue doing even if this overall survival benefit has faded. The last study I picked out, I'm sure we'll also generate plenty of controversy. And that was uh I should mention that the swab study Zuma seven were both at in the New England Journal yesterday. And this study I'm about to mention now the transcend C L 04 was out in the lancet today. Um And that was really the biggest and kind of most complete or most detailed data we have for the use of carticel therapy in chronic lymphocytic leukemia or CLL and very much a mixed bag in that there were some a small group of patients who did very well and you know, I guess with more time we'll see just how well. But there were some, some people whose disease really melted away with car T cell therapy. And in CLL, that's tricky because you often get T cell dysfunction inherent in the disease itself. And so actually manufacturing car T cells has been particularly challenging in CLL, which is why even though uh people were treated in trials of car T cells with CLL more than 10 years ago, there's still no uh cart is a product on the market for CLL. So because of this challenge around T cells, so yeah, so the reason I say that it's mixed is that while there was a small group of patient's that did very well and look like they've had very good response is although it's very early to be sure of that, there were a lot of patient's who had these kind of mixed responses with some of the disease melted away, but some of it stayed there and there was a bit of debate between the audience questions and the presenter as to how meaningful that was whether the end points we were using, truly captured that whether we should be thinking about things differently or whether the kind of tried and true tested um endpoints that we know in CLL are still the right ones to use. And so uh without kind of taking sides, I guess, cautious optimism is the read out there. And it's very hard to know what will happen from a regulatory approval standpoint, I will carty be approved based on this data in in CLL in the US. Very hard to say. So they were the kind of five uh top of them from the pics, I guess from, from vascular that I picked out. And I think particularly the Hodgkin's lymphoma trial is very exciting and immediately practice changing. Um And you know, and, and Zuma seven is also very exciting, especially for, for places where they kind of depend on that overall survival to get um reimbursement. Super interesting. Thank you so much. Uh Ready for that really comprehensive summary of some really great papers that have been that have been published in this space. And you've been talking just today about Car T, right? And um uh would you mind giving us a little summary of what you were talking about today with, with regards to party as well? Yeah, so we um I'm presented in the education session uh called Cars of the Future. And um the two colleagues of mine who presented in that session presented about car NK cells and car T cells for brain tumour. Sort of looking at where to. And my talk was focused on kind of how much car T cells for cellular therapies cost to manufacture, how you can appraise therapies for their value when they get incredibly expensive as Carty is and looking at the different components of the costs of of card and how we might be able to bring each of those components down. And so to give a kind of just a very uh taste tester of what that was about. We looked at the manufacturing costs, how you might bring the manufacturing costs down such as through allergenic products. I looked at the price and how you might bring the price charged by the manufacturer down. So just through price negotiation and then the third bucket I looked at was the bundle payment's that particularly issue in the US where Carty is billed by the hospital to the insurer as a bundled payment. And so sometimes those bundle payment's can be upwards of a million dollars. So even where the car t cell therapy might be billed as four or $500,000 which is already extremely expensive. Sometimes the hospitals are billing the insurers more than a million dollars per patient. And obviously that as you get, hopefully more and more Carty products available becomes very unsustainable very quickly. Uh Super important topic, right? How do we, how do we make this accessible? And I should mention that that we've got, we'll have an education book article coming up as part of the ask you education book and that will be open access and available through the ask your website. Amazing. Um And then looking, looking forward to the next 12 months. What are the hot topics that we should be expecting to see everyone talking about with regards to uh lymphoma what, what do you think are the most important bits of research that are, are currently taking place and perhaps a glimpse of what we might see, uh, vasco 2024. Yeah, absolutely. I think the by specific antibodies definitely have to be top of that list because they kind of take this excited excitement we've had with car T cells and they make it much more readily available and hopefully one day much cheaper because it's, you know, you've just got to kind of off the shelf product that um as we've seen with riTUXimab, which is a monoclonal antibody that really has made it to many parts of the world. I would hope that the same thing will be true by specific antibodies. And these, I always talk about them a bit like tinder. So they bring the T cell to the malignant cell. They've got to binding sites and they bring, they make, they sort of match, make the T cell and the, well, most of them target T cells and match, make the T cell with the malignant cell and sort of bring them together and let let leave the T cell to kind of destroy the tumor cell. And they work well, lymphoma, they're, they're available in a range of diseases, particular lymphoma and also myeloma. And I think there's lots of evolving data there. And so what will be great will be to see the randomized trials start to happen of those therapies to really help us know when and how to use them. But I think that's kind of capitalist in terms of exciting things on the horizon. Um The other thing that comes to mind thinking a bit about primary media Salopek cell lymphoma today with that radiation therapy study is that there's a trial underway looking at the use of checkpoint inhibitors again in private primary mediastinal B cell lymphoma because that, that's a particularly sensitive type of lymphoma. And so I wonder if sometime in the near future will be also adding the PD one inhibitors to up front therapy and primary media sambisa lymphoma. As you've just heard, we will likely be doing with Hodgkin Lymphoma, Eddie. Thank you so much for a really comprehensive summary of five great papers in lymphoma. A glimpse into your own presentation on how do we make carta more accessible and then looking forward to 2024 the exciting work that's already happening. We really appreciate your time today and, and thanks for sharing what's happening at Oscar with colleagues who couldn't make it. Thanks for having me.