Chapters Transcript Video Update in Mantle Cell Lymphoma So, so, on behalf of the T A si want to thank all of you for attending this uh dinner. So, man Farm is a disease that is very close to my heart. I've been working on this disease for more than 20 years. And so what I want to do today is give you a little bit of historical perspective and also to convey to you what there is a man selling form a consortium that brings together all the investigators working man from around the globe every two years here to the United States. Uh But I want to thank some old friends from Christine and a lot of good friends here that I have seen even friends from Washington. So I mean, so we, we know uh friends that we had in common, our chair of Dermatology at us f who just joined us today. And several of you were my fellows like a doctor a that was uh my fellow. So I started my career very young. So, so, so um but uh you know, and also, you know, thank you for being here. Uh So let me start just by giving you so the historical perspective of farm. And these are my disclosures. And so, so this is a professor uh Leonard from University of Kiel in Germany. And in the lymphoma field, we have have several classifications for several years. One of them is the classification, the real classification. But this classification came from Professor Carl. And the reason why I'm talking about him is because he identified the first case of centro lymphoma that become the first case reporter of cell lymphoma in the world in the in 1974. But you can see there. So these days we talk about B cell informa T cell informa and doctor was ahead of his time. So here was talking about informa T cell informa. And also clinically when we teach our fellows, we always tell them they are aggressive lymphomas, there are internal lymphomas and that's what Dr Leonard mentioned in 1974. And even more. So we have now molecular test, we talk about cell of origin. So he was already talking about cell of origin. It's a different perspective, centric centro plastic large cells. But I mean this is just to give credit to Professor Leonard that make this classification that killed classification in 1974. And here describe the central city lymphoma that as we are going to see later become man selling. So this is the first patient patient K you know, hi in 1974 right? I cannot disclose the full name of the patient So this is called OK. This is a patient central lymphoma new entity published in Lancet in 1974. And several years later, in 1980 he described with more cases uh this cents lymphoma. So, and what he he said is the source of this type of lymphoma defer morphologically and immunologically from the cells of all other known types of non hosting lymphoma and reserve centrocyte clear foliar center cells or reactive gein centers. Therefore, this type of lymphoma appears to be an entity that is closely related to or even derived from centralized. And he coined the name centro lymphomas. So, so what happened in the nineties? That was in the eighties, what happened in the nineties? So Michael Williams and he gave me these slides. So he, he found he found that in this central city lymphoma there, there was a specific chromosomal rearrangement in the in chromosome 11, the BC L one locus. And you remember lymphoma, we talk about, you know BC L one, you know, cycling the one as the hallmarks of the disease. And so what is interesting? He says, hey, this chromosome 11 BC L one locus is rearranging 28% of cases in this central lymphoma as compared with less than 5% in other lymphoma supporting a role for this BC L one translocation or rearrangement as perhaps being the molecular culprits of this entity name as a central. So, so, but then this BC L one abnormality was found in other type of lymphoma that someone says, well, these are called lymphoma of intermediate differentiation. So, same rearrangement, two different entities morphologically. But then in 1991 it was found that this rearrangement that occurs in central city as well as intermediate lymphocytic lymphoma is what now we know as mantle cell. So, so this is Professor Elaine Jaffe, one of the best or perhaps the best he hematologists in the United States. So she wrote an editorial and says, Id L and centric lymphoma are identical neo plants derive from follicular cells and should be unified under a common terminology. So then they proposed the term Montell lymphoma or diffuse variant and this was around in 1991. So in 1992 1992 this paper was published in the American Journal of Surgical pathology and they proposed a new entity named man. In 1992 I was an intern at Jackson Memorial Hospital in Miami. So in 1994 2 years later, there was this real classification. A man was incorporated as a new entity in the real classification. So now we have all the woo classification is what we want uh currently. So when we talk about lymphoma, we say yes, there is a term location. 11 14, the BC L one Oncogen is juxtapose under the influence of the heavy chain of immuno heavy change. But also we say one of the hallmarks of this disease is the over expression of cycline D one. So what is the connection between C and cycling D one? So in 1991 paper in nature, the first mammalian cycling one was named, it's called cycling. So these days, so this is the way that we diagnose lymphoma. The pathologist in the room, we say this is a monotonous proliferation of meat to middle size uh uh cells by immuno by 35 prosom, they are positive for CD five C 20 positive, negative for C 23. So this is the whole model. The disease. That location. 11 14 with the BC L one proton coin is, is placed under the control of the heavy immuno global change gene. So that leads to deregulation of BC L one. So you can see that by fish 100% diagnosis of informal, you find this location 11 14. This is by immuno histochemistry over expression of cycling, dyc cycling dy but not all multi cell in since the early days, we knew that not all the multi cell were created equal. There was classic lymphoma what I call garden lymphomas Andy aggressive man lymphoma. There is large cells, a lot of mitosis. So those those those patients needs treatment. There is no chemo immunotherapy. 1990 paper, you mentioned nodular and diffuse. Yes, I've never seen that expressed in a pathological report today. So how does that fit in? So it was initially, you know, initially in the Yeah. In the initial report, we used to call man, no, used to be the classic variant and also diffuse that there are no more like a pleomorphic aggressive variant. So no is is slow progressing uh diffuse either you are dealing with this blaster or this ali so that term is not used anymore. So we are moving more into this sort of new terminal and now we we use 67 high K I 67 is probably more like a diffuse. Yeah. Good, good question. I mean, so uh so yes, I described that Pat did a good job. So what about clinically? So what about treatment? Uh when man lymphoma become a new entity? So as a clinician, we say, oh man, lymphoma is an aggressive subtype of lymphoma in need of treatment right away. Uh I think we were wrong at that time. So then we said, OK, we need to start therapy and then we said, OK, let's use chemotherapy hyperba. This was developed in the Anderson is a others. All the patients respond high response rates, but all the patient will relapse. So we said, OK, we need to do something else. So then rea was approved in 1997 and then say, OK, let's the anti mono antibody. So then we have our job, our hyper our, we give rema maintenance. Yeah, we improve our response rate but still all the patient relapse. So then we say, OK, more is better So what if we do chemo immunotherapy induction and then we take the the patient to transplant in remission. And this is the work by the European Man Informal Consortium Martin drilling. Yes, we have longer remission duration improved P A. Some patients perhaps were cured but is not for everyone as you know. So remember, so cell lymphoma is a disease of the elderly, 60 70 years old. That's when the patients are going to be and those patients have coord and therefore they are not going to be for auto. And so what about factory? So this the data was already front line rela refractory and this data from uh uh when I was at. So we look at all rela refractory patient in the early 2000. And as you can see, this is not a pretty picture. So we are not doing well in terms of. So therefore, the conclusion was mantes lymphoma is the most aggressive subtitle lymphoma higher resistant to treatment incurable. So therefore, as a lymphoma doctors and researchers, so we need, we needed to do better. Just you just speak up a little bit. I think some people are having a hard time. Oh OK. Yeah. Right. OK. So, so that's when we established a man selling for my initiative workshop and consortium in 2003. So you're going to get my age. But that's OK. And this was the first meeting, the workshop in Washington DC, I think. And I just want to highlight Mike Williams. He was involved in the early work in Monte firm. So at that time, he was working, OK, why ox him up? He's not working all patient with multi lymphoma. Uh My group at start to dream about cancer vaccines and say, hey, yeah, if we do vaccines, we are going to be able lymphoma wrong. So, but we did some work. Uh and now vaccines are coming back by the way, the RN A vaccines. And so this is a disease in which cycling D one is over expressed. So people was trying to develop in 2003 cycling D one inhibitors and none of them made into the clinic because they didn't work because that we, we were very simplistic. We said, OK, we target cycline D one, that's it. We are going to cure me in wrong. So there are other molecular normality P 53 and others that are more important than cycling D one over expression. And then we discuss the role of transplantation, right? More is better and we had a session about transplant. And also it was interesting in 2003. So why we see lymphoma more in males than in females, 4 to 3 to 1 ratio. And still we don't know. And at that time, that presentation was perhaps there are differences in the why chromosome or because males don't express two X chromosome. Perhaps that's the reason and that was the study still. We don't know, we don't have a clear idea why males uh have increased uh predominance in multi. So a couple of months, well, last month is still. So we have this uh in a consortium meeting. I was the chair of the consortium and we decided to focus on 20 years of advanced discoveries and treatment because we start in 2003 meeting. This year was in 2023. So 2 20 years and and this is the lymphoma and this is extremely important. So you really want to make an impact all the people working on that specific disease. CLLNCL AQ leukemia needs to get together and create this type of consortium. I mean, we were lucky that there was a very grateful patient that gave $30 million to this initiative and we were able to support research, basic translational clinical trials. So we received half a million dollars for our vaccine trial in 2003. And we support uh a senior junior new investigators so that the number of members increased significantly uh from 66 members to 133. A lot of publication. But more importantly, most of the significant advances in the man in form that I'm going to refer briefly came from, from grants that were given by the man from a consortium to a specific uh uh investigators in in the field. So in 20 years, so now we know cell lymphoma is not one disease, it is a heterogeneous one. So now we know that there are patients with multi cell lymphoma that we present with indolent, clinically indolent disease and we do watchful waiting. So I remember one patient years ago, I mean, remember that the idea was lymphoma is the most aggressive in what you are going to die tomorrow. And I had a patient that traveled all over different places and he came to see us and then I said, look, you have a man, I'm going to do watchful waiting. I mean, the patient couldn't believe so he went to different places and uh and and, and so the recommendation was the same and this patient is still alive, no treatment in lymphoma. So doing well. And these are patients that present with high white blood cell count but they have very little of minimal. Nobody they present with this but they are doing well. Watch waiting is an option. But also we have in the other extreme patients with p 53 abnormalities and daughter Nike working with. And uh and he's going to mention this is a special group of patients that are uh in which the disease is very aggressive. So, so they don't respond to chem immunotherapy, they don't respond to tramp. So, but now we know that they respond to target therapy in combination with immunotherapy. So that no immunotherapy doctor is going to refer to that group of patients in his. So this is the way that I, when I talk with the fellows, I refer to lymphoma is a heterogeneous disease, the spectrum of clinical presentations on the. So we have a presentation 10 to 20% I do visual waiting, then you have 20% aggressive which I do treatment. And then in the middle, you have patients that is they are close to in, I do watch waiting if they are close. Over here, I do some type of treatment. And now we know about the molecular basis of indolence cell lymphoma. There is a transcription factor called, you use a low or absent patient with clinically indolent cell. So in the classical and the aggressive. So 11 is we ought to be positive. But in this aggressive group, we have p 53 abnormalities. KT two D mutations. But also in this group, we have patients with plastic pleomorphic variant patient with K I 67 of 30%. So those are patients that are in the, in the a aggressive uh in the aggressive group of uh uh patients with this disease. A major paradigm change. So remember, so I we treating patients with chemotherapy more chemotherapy transplant. And then when someone mentioned, oh, there is a pill, it's a BT K inhibitor. Basically going to take this pill once a day. Uh Maybe it's going to work in lymphoma II. I mean, I laugh, I said OK, yeah, be my guest, right? Well, Michael prove prove me wrong. And he published this paper in New England Journal of Medicine in 2013. And here we have this non chemotherapy is a very target drug targeting A BT K. There is a and overall response rate. Real laugh refractory. Remember? So that, that that's like not a pretty picture factory before this treatment. 62% complete response rate. 21%. Are you kidding me? Right. 21% and durational response almost, you know, 81 year and a half. Unbelievable. When this data was presented, everybody said, oh my God, it works. And of course, now we have more in a long recommendation but this this was a change. So and this is why I want to tell you about the therapeutic evolution of 1974. So first generation, 1992 to 2005 chemotherapy ox. The consolidation, second generation meat is an effective drug 10 only in the European Union. Third generation. Now we have different flavors main. Now we have too, I think it does in the fourth generation 2020. Now we have T cells for non covalent inhibitor T cell engaging antibodies, bio specifics, chemo free combination duplet triplets. Again, cell vaccines, especially messenger RN A vaccines, moderna vaccines making a huge impact in the treatment of patients with a melanoma that recent presentation brain tumors. And so we are planning to to to bring one of these vaccines for uh patients. So what is the old concept of lymphoma always aggressive, highly resistant to treatment incurable in need of immediate treatment. Is that not true anymore? What is the current concept in is not always aggressive? There is an indul variant, not always resistant to treatment, sensitive to target therapy, inhibitors to inhibitors and immune therapies, monoclonal antibodies, T cells by specifics. I mean some patients watch waiting is an option. Ok. So at the end of this meeting in 2023 so we had a special session session number seven, just to create a road map to the cure of mantle cell lymphoma in the next 20 years. What are the opportunities? What are the challenges? So first, so we have basic translational clinical lymphoma and senior leader for pharmaceutical companies that have products in this for this disease. Also patient advocates and we just brainstorm, how can we cure man lymphoma? And these are the key recommendations. So of course, improve the understanding of the pathogenesis. Keep finding more about the different NCL subtypes. P 53 abnormalities, KMT and and so on. So risk AAP therapeutics, biomarkers continue progress in achieving deep and durable remissions using MRD protocols, partnership between a strengthening and communication between industry and physicians through our clinical trials planning to improve visibility, especially around enrollment criteria in post selection. But one of the conclusion was we are moving in cell lymphoma, we are moving away from chemotherapy, conventional chemotherapy, we have better treatments now and then we say ok, in order to get to a cure, let's get it first into the functional cure, which means cell is becoming a chronic disease. We have treatments that are effective and the patients can continue to have a quality, a good quality of life. So what I say, in other words, patients with multi lymphoma should die of other reasons rather than their diagnosis of Monte lymphoma. That's a functional cure. And it's ok with me, I can retire with a functional cure, but the functional cure is going the first step towards a cure of lymphoma is doable. So, but one special recommendation from from this workshop was keep investing in the next generation of investigators in cell in form. And I am proud to say that I am a proud grandfather because so in this picture are three generations of man selling from investigators. So doctor was my fellow and he is a man selling from expert. I mean, he's better than me in many, many, many areas and but then trained who is now with the th cancer institute uh and is now becoming an expert in farmer. And so now so let me introduce doctor Nikes who is going to tell you about all the exciting treatments that are happening in the in the field of antic. So in the case, we will take questions after let me get my drink, important things for. Thank you. Thank you doctor. So Yeah. Yeah, while we're transitioning, sorry for the loud noises outside, but the mic is for the recording that we're doing. So it's not with the sound in the room. So I apologize about that. Thanks. Ok. Right. The all right, everybody refilled their wine. We're good. Ok. Thank you doctor. Thank you, Doctor Sotomayor. That was a great introduction kind of talking about the history of man cell lymphoma. You know, he introduced me as his grandson. So I'm glad when we set up talking about this meeting and having this talk, he volunteered to talk about the history of mantle cell lymphoma because I wasn't around for most of it. And it's kind of sobering. He, you know, he had a slide in 1991. Mantle cell lymphoma was defined as its own entity, right? And I may or may not have been in diapers in 1991. So with that, I'll keep moving on Dr Sotomayor did a fantastic job reviewing the history and the current treatment paradigms for mantle cell. I'm going to kind of take that one step further and really talk about a little bit more about P 53 mutated mantle cell lymphoma, this really high risk subgroup of patients that we worry about a lot and then just talk about newer therapies, you know, he mentioned trying to move away from chemotherapy based regimens. And so I'll talk a little bit about that as well tonight, these are my disclosures not related to what we're talking about tonight. And then we are going to be talking about some off label treatment because we're talking about clinical trial updates. So Dr Sotomayor mentioned this, you know, about 15 to 20% of patients with mantle cell lymphoma will have a TP 53 alteration. So either a deletion in the P 53 gene or a mutation, we know kind of across the board in cancer. In general, p 53 alterations are bad. They promote, you know, increased proliferation, reduce the checks and balances on the cancer cells and they tend to be chemo resistant. And so this is the same thing in mantle cell lymphoma. We've seen that this is a very high risk subgroup. So the curves on the top right are from the Nordic MCL using high intensity cytarabine based induction chemotherapy followed by stem cell transplant. And you can see the curves in blue. There are patients with P 53 mutations. And despite extremely high intensity upfront therapy, these patients unfortunately did really poorly, you know, two year overall survival was about 20% for this high risk patient population. And so clearly, we need to do better. We did some work when I was in fellowship, looking at kind of non chemotherapy based immunomodulatory regimens. One in particular being lenalidomide and riTUXimab or R squared, which is an immune based therapy. And you can see our curve here in black patients treated with R squared in the front line setting. With these really high risk mutations had significantly improved outcomes. This is a progression fee survival on the Y axis here compared to the blue curve, which is high intensity chemotherapy with autologous stem cell transplant and kind of standard a chop or beam must RXA intermediate therapy in the red line. And this is kind of novel, right. You're saying this is the aggressive subgroup that Dr Sotomayor had on that figure on the right, generally presenting with high risk features, high proliferation rate blas or pleomorphic morphology. And we're saying, hey, we're not going to give you really intensive therapy and give you the highest intensity therapy that we have. Instead we're going to give you this therapy that is no chemo and really FDA approved mostly for patients that are older with mantle cell lymphoma. But we have some early data that it works again. This is retrospective, not randomized data. This is not a huge group of patients, but I think it still brings a lot of a lot of interest and excitement that hey, maybe we can do better for this high risk patient population with novel therapies that are immunomodulatory. The curve on the right is looking at a retrospective review recently presented at the Lugano Conference in Switzerland, looking at patients treated with cart therapy with P 53 mutations in the relapse factory setting. Unfortunately, kind of the two year overall survival was still around 50%. And so definitely we can still do better than that. So really, I strongly believe that all patients with an mantle cell lymphoma diagnosis should be tested up front for a P 53 mutation. It significantly impacts our choice of treatment regimen and it impacts prognosis for sure. And I think that's important for patients to know and for this subgroup of patients, kind of our standard therapies are really lacking right now. And so we should really be exploring clinical trials for all of these patients to improve therapy. So we can't talk about mantle cell lymphoma without talking about BTK inhibitors. Dr Sotomayor mentioned this, you know, I Bruni was first approved with that any paper in 2013 and that's been followed by two other Covalent BTK inhibitors, ARB and X. Really the data that I'm showing here is just a comparison among the seminal trials for these, for these different BTK inhibitors. And really they have a little bit different toxicity profiles. But these really changed the game for how we take care of patients with mantle cell lymphoma and with CL now as well. But they are approved in the relapse refractory space for mantle cell lymphoma. There's a new class on the bottom, see kind of the compounds here that are called reversible or non covalent BTK inhibitors that are looking to try to see if we can improve on outcomes for patients that have been previously on a covalent BTK inhibitor, both from a toxicity standpoint and from an efficacy standpoint. Later today, I'll be talking a little bit more about PNI, which was originally called loo 305 that recently had an FDA approval for relapse fray mental cell. So to tie things together with kind of talking about four or five different recent clinical trial updates. Today, I kind of made up a few patient cases to just help keep things clinically focused and relevant for us. So this is an 80 year old gentleman with newly diagnosed mantle cell lymphoma. He presented with symptomatic multi not disease and unfortunately, was not one of these indolent patients that we could watch. He needs treatment. Thankfully, he doesn't have a P 53 alteration and doesn't have any cardiac history. This is a clip from NCCN guidelines for older patients, you know, less aggressive induction regimens that NCCN recommends you can see are really mostly chemotherapy based still at this day and age benda must riTUXimab r chop kind of intermediate intensity chemotherapy. And then I mentioned, you know, Leidy and riTUXimab or R squared is a chemo free regimen that is approved as well. But let's talk about another non chemo regimen for elderly patients. This is a trial that was presented by Dr Jane at the recent Lugano conference last month, really spearheaded Andy Anderson and I have to be a little careful here because they said elderly patients, but they incorporated patients greater than 65. And so I feel like now that my parents are getting older, I have to be really careful about using the word elderly for patients older than 65. So. Ok. Ok. So I'm just going to say patients greater than 65 who are very wise, but this is, this is for front line patients newly diagnosed, not yet treated with anything else greater than 65 with adequate cardiac function. The trial schema was they treated patients with this double it regimen of a calibri which is a BTK inhibitor and riTUXimab which is an antibody against CD 20. They had this combination for two years and then followed by a calibri and maintenance therapy by itself for as long as it worked. And as long as the patient tolerated it, they enrolled, I want to say 50 some patients, 50 patients and you can see that the majority of patients at either intermediate or high risk by the score, the mantle cell prognostic index and almost 30% of patients were high risk had TP 53 alterations or AC. And so this was definitely a fairly high risk population to give a new non chemotherapy based regimen to the median follow up at the time of this presentation last month was 17 months and their median progression free and overall survivals were not yet reached. But you can see out of the 49 patients who are valuable for efficacy. At this 0.92% had a response. And all of those 92% had a complete response, which is really remarkable for a non chemo regimen with a BT inhibitor and riTUXimab. And you can see actually 60% of those patients at last follow up were negative for any measurable residual disease, which is a surrogate marker for progression free and eventually overall survival as well. This is really impressive data for a non chemotherapy based regimen in the front line setting, you can see on the bottom left toxicity. You know, the regimen was really well tolerated. There were very few high grade three or four toxicities. Unfortunately, there were a lot of grade 1 to 2 toxicities that we expect with the BTK inhibitor, right, fatigue myalgia bruising, surprisingly not a lot of atrial fibrillation. This was done in the COVID era. So you can see 32% of patients have low grade COVID infection. But the curves are really representative of the response rates essentially flat, you know, at 17 months follow up, very few patients progressed or had a death. So this is definitely in my mind, it's definitely not approved by the FDA yet. This is very early data, but this is certainly a reasonable option in my mind. Again, off label, but for older patients who want to avoid chemotherapy, right? And please feel free to interrupt me at any time. Questions, comments, anything I want this to be as interactive because that keeps it fun. So this is a new patient. This is a newly diagnosed patient as well but young and fit. He is also symptomatic multi not disease needs treatment does not have P 53 aberrations. NCCN guidelines. Very complicated on the right. But essentially these are all high intensity chemotherapy regimens with some sort of combination of cytarabine and anthracycline based chemotherapy. Many of these are followed with autologous stem cell transplant. Really, you can see all of these regimens are high intensity for young and fit patients. So let's talk about the triangle study. This is a really big study that was recently published, recently presented at Ash in December by Dr Martin drilling from Germany. And this was one of the plenary, one of the big plenary presentations at Ash that made a lot of waves in the mantle cell lymphoma space for young patients. So definitely worth talking about here. So they enrolled young fit patients less than 66. So now young is less than 66 in this trial from Europe, you know, in America, old is 65 and older in Europe, 66 is considered young. These were also previously untreated patients and they were really looking at failure free survival and response rates as their main outcome. The study schema really had three arms and so they had kind of the classic cytarabine based regimen based on the Nordic MCL younger trials, which is a combination of our chop and RD which is AC and platinum based regimen followed by transplant, autologous transplant. The next experimental arm was a combination of that same standard but adding ibrutinib, our early BTK inhibitor in the front line setting and then also using two years of ibrutinib maintenance after they had a transplant. And then the last arm is asking the question, do patients need transplant? And so they said, let's take the standard our chop R DB intensive chemotherapy, add Ibrutinib skip the transplant and do two years of I bruin maintenance, right? So we really kind of looking at three different questions. A few different questions here. And then they added a maintenance based on kind of the guidelines depending on the country the patient was treated in looking at just the initial induction regimen and transplant. If they received a transplant, essentially the take home message is Ibrutinib improved induction response rates in addition to standard chemotherapy, but at the cost of slightly increased toxicity. So you can see on the left, overall response rate was 98% in patients who received Ibrutinib versus 94% of in patients who did not receive ir but did receive a transplant. And the complete response rates were also slightly higher, about 9% higher. There was a little bit of increased toxicity with IRB. So all the Ibrutinib arms are in yellow here or gold and you can see they had slightly increased toxicities compared to the transplant patients. So let's keep going looking at longer term efficacy. So this is long term efficacy after patients received whatever regimen they were assigned to potentially transplant and potentially a maintenance after that. And so the curves in gray and green are patients that did receive a BRUIN. And the blue curve is patients that received stem cell transplant with no ibrutinib at all. OK. So clearly you can see with the curves, there's definitely a separation here, right? In progression free survival at the top or failure, free survival. I should say there's a clear separation between both the groups that received Ibrutinib versus the patients that did not receive Ibrutinib. There's a clear separation here. Looking at the statistical comparisons, the patients that got Ibrutinib and transplant had an 88% 3 year failure, free survival compared with 72% for patients that had an auto transplant without I patients that did have viib without the auto transplant. Interestingly had three year failure, free survival of 86%. And these were all statistically significant. It's important to note in this trial, statistically, they did not compare patients that had Ibrutinib without transplant. Two patients with Ibrutinib plus transplant that was not statistically compared. So we can't statistically say that one was better than the other. But you can look at the curve for failure free survival and kind of make your own interpretation from a non statistical standpoint, right? We can see that those essentially overlap. There were not significant differences in overall survival yet. But you can see there may be some trend towards improved overall survival with the containing arms still not enough long term follow up to make to make a statistical comparison there with the median follow up just under three years. And so really the take home from efficacy from the triangle study is that the Ibrutinib containing arms had improved failure, free survival versus auto transplant without I. And autologous stem cell transplant does not provide a failure, free survival benefit compared to auto transplant, prob or Ibrutinib by itself. So, digging a little deeper in this trial, they did a sub group analysis which is really interesting, but we have to be really careful about making big broad sweeping interpretations from this because these are all low numbers and the study is not powered for this, right. And so they did look at something near and near to my heart, which is P 53 expression and PP 53 alterations. And they did find interestingly that patients that had a high p 53 expression by immuno histochemistry may have had better outcomes or trended towards better outcomes with transplant anti Bruni compared to transplant by itself. Interestingly, the incorporation of riTUXimab maintenance did not seem to have a benefit between these groups. We know in general when we're not talking about I maintenance and just, you know, standard chemotherapy autologous transplant, we know that rebab maintenance has progression free and overall survival benefits in that setting. But interestingly with the addition of IRU maintenance, it's kind of unclear whether that's still going to hold true. Not a lot of patients thankfully died on this study with about three years of median follow up. But you can see there were more deaths in the autologous transplant arm and most of those deaths were from lymphoma, not as many from the aum containing arms and not really many deaths if any related to therapy, which is important. So the newest NCCN guidelines actually incorporates the triangle regimen as one of the recommended preferred regimens for young fit patients with newly diagnosed aggressive mantle cell lymphoma, right? We can see that here and then talking about maintenance. They actually recommend, you know, category two a recommendation for a Bruni and interestingly not based on this trial kind of extrapolating from this trial. They're saying category two B recommendation for a calibri or X maintenance, which are other covalent BTK inhibitors. Because when you're doing the triangle reg, now do you, are you using uh that would be my preference? I haven't used it yet just because this data came out very recently. But I think extrapolating from Triangle from an efficacy standpoint that we see in other mantle cell and cl trials, I feel like Aa and Zanu have a similar efficacy profile, right? And I think lowering toxicity, it seems reasonable to try to use a or in this setting. We don't have data to confirm that. But I think kind of extrapolating from the data that seems like a reasonable, reasonable thing to do for sure. That's a good question. Triangle answers a lot of important questions for us about the role of BT inhibitors up front and in maintenance and it answers important questions about autologous stem cell transplant. But there's a few unanswered questions still. Right. It doesn't answer the question of what is the best upfront regimen? What is the best front line approach for patients with newly diagnosed mental cell lymphoma? We still have multiple options out there. I think the triangle regimen is a great approach, but we don't have comparative data to compare that with other approaches that we have. Sorry, say that one more time discrepancies between European countries and the US there is actually I was just talking about that with someone the other day. So I will say in lymphomas in general, I find that I feel like in a lot of European countries, they are OK with giving more intensive chemotherapy up front that we feel comfortable with or we try to give here, especially in other diseases like Hodgkin's lymphoma, they commonly use more intensive cytotoxic chemotherapy that most of us in the US would not even give anymore. Not really. And I think there's probably a variety of reasons for it. I don't have one good answer for why. That is I don't know if it's that like German and European patients are more fit than American patients or tolerate therapy. Better. Some of it may also be access to some of the novel therapies, right. There's different health care models in Europe is the us. We tend to use a lot of novel therapies. We try to use them farther front line as much as we can based on payers and insurance and things like that. I think in general, we like to incorporate novel therapies sooner rather than later and try to avoid chemotherapy for a lot of our lymphoma patients when we can. Whereas in Europe, I think it's still a lot of intensive chemotherapy based regimens. It's still a lot of the standard. It's definitely driven by cost. Yeah, that's definitely one part of it. Yeah. No, that's a great question. That's a great question. Absolutely. Absolutely. So moving on from triangle, we'll go back to our young patient. He was treated on the triangle study, received a chop Deb and I did not get a transplant, received. I Bruin maintenance with Rauma. And unfortunately, he relapsed just before he was finishing his maintenance therapy. So now what do we do? Well, this brings us to our next trial, which is the Bruins study. This is looking at PTO Bruni, which is a new BTK inhibitor. The Peter Bruni study, the Bruin study really enrolled a lot of patients with cl mantle cell Waldenstrom and other non hodgins lymphoma. I'm really going to be presenting mostly the mantle cell lymphoma data from the Bruin study, patients had at least two lines of prior therapy and they looked at response rate as their overall outcomes as their primary end points. This is just a map of the KOM kind of the different KOM we have the K is in the body and the red is BTK Bruton Tiro kindness that we is really important in proliferation in cell proliferation in a lot of lymphomas, but especially CL and mantle cell lymphoma. And pr is very specific for BTK. It doesn't have a lot of off target effects to other tyrosine kindness in our body. And so the brew and mantle cell lymphoma cohort had 104 patients. Vast majority, 90 of those patients had a prior covalent BTK inhibitor like I Bruni, a calibri nib xib per Bruni is a reversible non covalent BTK inhibitor and 14% of patients. So, about 10% of this trial had not received any BTK inhibitor before this. So this was the first BTK they had received. You can see patients who were older seventies which is typical for mental cell lymphoma. There were about 20% of high risk patients with pleomorphic or blass toid morphology. Again, 20 to 40% of patients were high risk by international prognostic index and most patients had received two or three lines of previous therapy. So they had a lot of therapy before this. Interestingly, the majority of patients that had a prior BTK inhibitor, 82% had discontinued the previous BTK inhibitor because of progression of disease, only about 20% or 17% discontinued because of toxicity from the initial BTK inhibitor. Prior therapies, you can see listed here. About 20% of patients had a prior autologous stem cell transplant. Some patients had an allo transplant. Some patients had cart therapy before this 20% of patients had TP 50 TP 53 mutation. So you can see about 20 to 30% of patients on this trial had high risk disease for sure efficacy. The box in the top left is efficacy for patients who had had a previous covalent BTK inhibitor. Overall response rate was about 60% for those patients with a complete response rate only at 20% for the patients that had never seen a prior BTK inhibitor. Their response rate was much higher, almost 90%. It was 85% and their complete response rate was 35%. And that holds true in this waterfall plot on the right. You can see the patients here in red and green. So the patients in green had never had a prior BTK inhibitor and the patients in red had a prior BTK inhibitor but discontinued because of toxicity rather than progression. And you can see it seems like those patients tended to do much better. They had deeper responses in general than patients who had progressed on their prior BTK inhibitor, there were still some patients that had good responses, 50 75% reduction in tumor bulk who had been a refractory to their prior BTK. But certainly the patients that never received a BTK inhibitor or had intolerance were the ones that did better. And you can see here, the overall survival median was not reached but seems to plateau kind of around the 50 to 60% range so far. This is a lot. But I highlighted the main things here. The subgroup analysis in this trial really looking at it seems like high risk patients unfortunately did not seem to have as much benefit from PRB. And patients with P 53 p 53 mutations maybe did not have as much benefit from PNI, which is interesting. But again, this is a very low number of patients. So it's hard to kind of take anything away from that and look similar to what we saw in the outcomes data in the waterfall plot patients that discontinued the prior BTK inhibitor because of toxicity did much better than those that had disease progression, which makes total sense, right? That important to look at adverse events. In addition to efficacy, you can see the table on the right. There were very few grade three or higher adverse events. The main one was neutropenia, which is not very surprising. There was of course a fair amount of low grade side effects that we typically see with BTK inhibitors, bruising rash, joint pain bleeding. There were very few events of a fib or a flutter which we see with some of our other BTK inhibitors on the left is an interesting graph. So this is for the 90 patients that had a prior BTK inhibitor that had toxicities with those. And you can see the blue curves are patients onto that did not have any recurrence of their prior toxicity which is great. 75% of patients didn't have a recurrence of cardiac events. 90% of patients did not have a recurrence of a fib but a lot number of patients had a recurrence of grade three or higher infections and neutropenia, which is definitely something you have to talk to patients about. Again, this is a pill. It seems really easy. You're like, hey, take this pill. It's not chemo, it's a pill, but you still have to worry about infections and low blood counts. Neutropenia. Specifically, the median time on treatment was five months. But remember there was not a lot of long term follow up for this paper just yet and only 3% of patients discontinued therapy because of adverse events related to treatment. And so based on this data, the FDA recently in January of this year approved PRB for relapse refractory mental cell lymphoma if they had received at least two lines of prior therapy. Unfortunately, there were some patients that progressed or were refractory to peri. So this was a recent paper looking at mechanisms of resistance to PRB. And it seems like some of the resistance mechanisms are pretty similar to resistance mechanisms for other BTK inhibitors, right? That one in green, the C 481 S mutation is a very common mutation that confers resistance to other BTK inhibitors. Like Bruni. A calibre still seems to work for a lot of those patients, but they tend to develop other mutations in the same tyrosine domain. And so this is similar to a lot of our other TKS in other malignancies, right? We think about, you know, things like things like Gleevec and other tyrosine kinase inhibitors and we kind of see the same thing with those patients as well. And so our patient, you know, was on triangle and relapsed, got on pr next and had a partial response for a year or so and then unfortunately progressed after that. So what are we going to do for this poor young patient who kind of just keeps having very aggressive refractory progressive disease? So let's talk about glob in mantle cell lymphoma. This is a lot of excitement. You know, Dr Sotomayor talked about by specific antibodies as kind of the new up and comers in lymphomas in general. And in mantle cell lymphoma, in particular, you can see the figure on the left is there's about five or more than five. Now by specifics that are in trials. And really, I'm going to talk about glob because that has the most data and excitement in mantle cell lymphoma. In particular, all the civics have a little bit of variation. But essentially the idea is that they combine CD 20 which is an antibody that targets lymphoma cells, B cells in particular, and CD three, which is, which is a target on our host T cells, our immune system and really tries to essentially simplistically bring the T cells close to the lymphoma cells to help activate them and kill the lymphoma. I'm not going to go into too much detail about by specifics that could be like a whole hour talk by itself. But essentially this trial looking at glob and man cell lymphoma patients used a CD 20 antibody called a bea up front and then followed that with kind of this gradual ramp up or step up dosing with the by specific antibody glob. And they did this for up to 12 cycles of therapy. These were again relapse, fractal cell lymphoma patients. You can see the outcomes here for all patients. The overall response rate was 84% and actually 73% of those had a complete response, which is pretty phenomenal for patients that have received multiple lines of prior therapy and failed on the right is specifically patients who received a prior BTK inhibitor. And you can see the response rates were a little bit lower but still decent for that patient population. 75% overall response, 66% complete response rates. Um The follow up period on this study is not very long yet, but the median duration of response so far is about a year. And you can see there's plenty of patients with ongoing responses here. Safety profile. The main thing that we need to worry about with by specific antibodies in general is cytokine release syndrome and to a lesser extent neurotoxicity. This is something that we've gotten very familiar with with cart therapy in the last few years and this is no different. Definitely, the CRS rates, the grade two or higher CRS rates are definitely less common than we see in cart therapy kind of clocking in at 18% neurotoxicity at about 15%. But this is something that for now really needs to be given by people familiar with this need to be closely monitored on the trial. They were hospitalized for that first day, 15 full dose. And so that may be something that we see if the FDA approves this down the road, only 9% of patients impressively had to discontinue because of toxicity, not in mantle cell lymphoma, but in large B cell lymphoma. The FDA very recently, just a few weeks ago, approved glob for the treatment of relapse, refractory large B cell lymphoma. I expect with time and seeing more data, the FDA may approve this in mantle cell lymphoma. But there's definitely ongoing randomized trials that are looking at that. So our patient, you got all these therapies, he got glob, he was one of those 60% that had a complete response was in remission for two years and then he progressed. So what are we going to do for this patient? Now, one option that's still remaining is cart therapy. I'm going to do this really briefly so we can wrap up quickly. But cart therapy is a lot of excitement in lymphomas and cart therapy in the last 56 years or so large B cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia, and now mental cell lymphoma as well. This is kind of just a few of the constructs with the T cell receptor of cart therapy. But the idea is very similar to these bi specific specific antibodies. We're trying to essentially rev up your rev up the patient's immune system. Let the T cells of the immune system really go and find and target the lymphoma cells activate and really drive this robust immune response to kill the lymphoma cells. So, breo cap the gene auto lu cell or Tatis is the FDA approved cart therapy for relapse refractory mantle cell lymphoma. The curves here are a little bit small, I apologize. But that purple curve on the top left is the progression free survival kind of plateauing at around 50% or so. And the overall survival also plateauing at around 60% for these patients. And these are patients that are heavily pre treated. And so when this came out in the New England Journal a few years ago, this was revolutionary. This is a fantastic option for patients. Recently, a month ago, Michael Wong presented data with a different cart therapy that is already approved in large B cell lymphoma and follicular lysogen auto or LYO cell and had maybe not as robust outcomes. But still, you can see the median progression free survival in blue on the top was 15 months and the median overall survival was 18 months but really plateauing kind of around that 50% 40% mark. I think we still need longer term data to really kind of learn more about the long term outcomes with lyo cell. But that may be a potential option for patients with relapse or mental cell lymphoma down the road. So you know, that kind of summarizes the recent updates from the past year or so in the mantle cell lymphoma field. You know, with Dr Sotomayor's leadership and mentorship, we are very excited to be building a mantle cell lymphoma Center of Excellence at Tampa General. We really want to bring in, you know, top research from a translational standpoint, looking at you know DNA or a sequencing tumor micro environment, learning more about mantle cell lymphoma, what drives patients to have more aggressive disease, less response to treatments. And then with that information, how do we improve upon treatment for these high risk patients? But then also bringing in new clinical trials to help improve outcomes for these patients. So you know, we are working on bringing in trials for novel frontline combinations that are chemotherapy free, bringing in trials for patients that are relapse refractory with new BTK inhibitors or BTK de graders looking at by specific antibodies that we just talked about. And really our goal is to really try to bring in trials and tailor therapy to each patient. Because as you can see from Dr Sotomayor's talk treatment from an cell lymphoma is not one size fits all. It makes it difficult for providers. But the good thing is that we have a lot of therapy and we really have to pick the best one for the patient and sometimes with indolent disease that's watching them. But we really need to make sure we optimize therapy. We know that unfortunately, these patients are going to relapse at some point. And we really need to be cognizant about how do we sequence therapy for these patients, right? When we decide their initial therapy, we have to be thinking about. Ok, if and when they relapse at some point in the future, what are we going to use next? What are we going to use after that? And so it's important to sequence therapy in the right way. We recently started, you know, in the fall of last year, our autologous stem cell transplant program. And so, you know, depending on the patient that may be a consideration for mantle cell lymphoma, even though I told you that transplant is less exciting now with the triangle data, that's certainly something we can offer. And then we are building our cart program and we will be starting that very shortly here, which will be an option for patients with relapse refractory mantle cell lymphoma as well. And so definitely a lot of excitement going on at TGH with mental cell lymphoma. And I just wanted to thank you guys for coming out to this dinner. Um We really appreciate you being here. Published Created by
