Austin Kim, MD, discusses Mantle cell lymphoma and the current treatments, as well as where treatment is going.
Okay. Alright. Can everyone can see my slides. Okay. Um so I'll be talking about mantle cell lymphoma. I have no disclosures. Um So we'll just talk quickly about the history, some epidemiology, current treatment, a couple of trials that we have available and kind of where the field is going. So um I think mantle cell lymphoma is lymphoma. Formerly known as um It was a waste basket intermediate lymphocytic lymphoma. Central civic lymphoma. It looked in between small cells and large cells. Um It was called mantle zone lymphoma. So it's like the lymphoma formerly known as Prince. But in 1992 that's when it was accepted worldwide as a distinct entity. And it was primarily because of the discovery of the um cycling D. One gene with the translocation 1114. That is um expressed in over 95% of mantle cell lymphomas. Um And in terms of phenotype that you C. C. D. Five positive. Um and cd 23 negative with Cycling D. One and sox 11 that are positive um that distinguish it from Cll or S. O. L. So the three different subtypes we see our classical um where you see them kind of more homogeneous small to medium nuclei. Uh And then you see polymorphic which are a little bit larger. And then the plastic which are the sheets of small to large um Small to medium sized blast 10-20% of patients at diagnosis have liam or phycor plastic um subtypes. So um mantle cell lymphoma is 6% of all non hodgkin lymphoma. So that's about 4500 to 5000 cases a year um median age like a lot of non hodgkin lymphomas that we see are 68 we don't know why but it is there's a clear male predominance 3 to 1. Um 85% of mantle cell lymphomas behave aggressively. Um with the majority of them presenting at advanced stage 10-15% have a more indolent behavior. And for some of these patients, initial observation can be appropriate. Um So in terms of clinical presentation the majority of patients actually have a good performance status when they come into your clinic. Um They have usually bulky non bulky lymph nodes. Um 30 to 50% have the symptoms with weight loss being the most common. And I think one of the unique aspects of mantle cell lymphoma is um that it does involve the G. I. Tract in 60 to 80% of cases. Um The bone marrow is also commonly involved um spleen and liver less. So I would say mantle cell lymphoma is kind of, I feel like if you treat mantle cell lymphoma you know how to treat all kind of non hodgkin lymphomas in general because they stands the very it can be very indolent to it can be very aggressive and then kind of in between. So um So the first case is a 65 year old male history of night sweats. He had decreased endurance. He was short short of breath. Um he had anemia and from beside a pina and then peripheral blow flow blood Sai Kama tree was sent. That showed cd five positive cd 23 negative. And a bone marrow biopsy was done with 80% of the marrow involved by mantle cell lymphoma. Um Cycling D. One and sox 11 were positive. So um this patient had stage four mantle cell lymphoma um involving lymph nodes above and below the diaphragm including the spleen that you can see here. Um The this staging and the pet scans are not the same patient but just for visual effect. Um The LDH was normal performance status was zero. Um And you see the white blood cell count. So one risk um category that we use is the mickey mantle cell International Prognostic index. Um You get scores for your age, economic performance status, LDH and white blood cell count. So this patient had a score of four which is intermediate risk. So frontline treatment um in 2022 for patients who are um below the age of 65 or 70. Um and are fit for autologous stem cell transplant um is still an aggressive regimen that includes riTUXimab and site caribbean. Um And each institution gives their own version of this. Um Dana Farber. Um dr Armand and dr Merriman have published on bending machinery. Taksim map for three cycles followed by Osama Bin said to rabin for three cycles. Um I know it's mass general. They often use the r um dahab but with oxalate platini instead of the platinum and that's often used. Um So generally as long as it has a site Arabian backbone with buttocks map and then this is followed by autologous stem cell transplant and maintenance riTUXimab. So the data from this is this was a european M. C. O. Younger trial that compared um are dehap which is sex and heather's own site caribbean and a platinum vs. Are chopped. Um and the time to next treatment and overall survival word improved with site a ravine um and significantly improved. And this was an update at 10 years out. Um That was presented this year in ash. Um So here Dana Farber. The regimen we use is the fender, mustang Taksim a Taksim website Caribbean. Um And this was a study published by dr Merriman where a three year progression free survival was 83%. Um And three year overall survival 92% with a complete Remission rate of 90%. Um one of them things that is nicer about this regimen is that it can be given out patient. So um so why do we still recommend or do autologous stem cell transplant for a mantle cell lymphoma. Um The european M. C. L. Network. This was in the pre riTUXimab era. Um randomized patients to receive autologous transplant versus interferon alpha maintenance after receiving chop like induction and in the pre riTUXimab era. There was a significant improvement in progression free survival. Um as seen here as well as overall survival interestingly in the riTUXimab era. While there was a trend towards both improved progression free survival and overall survival, it was not statistically significant. So this is why you can make an argument. Um Either way for you can say neurotoxin McNamara doesn't improve overall survival in the pre buttocks. Madeira. It did. So this is why we should or should not do it. So um why do we do maintenance for toxin mob after transplant? Um This was a study by the french group Where patients received four cycles of R. D. Happy And then they went autologous stem cell transplant 240 patients were um randomized half of them to observation and then the other half to retract from that maintenance therapy. And um the primary endpoint was event free survival at four years which was statistically significant. Which is not surprising. I think we would expect to see um a longer remission with maintenance riTUXimab as seen in many other lymphoma subtypes. I think the surprising thing was that there was a significant improvement in overall survival at four years 89% vs 80%. So this data was hard to ignore. And so this is now standard of care where maintenance riTUXimab is given once every eight weeks um for 18 doses or for three years. So it is um treatment is a long time. So so this patient we'll be getting Brent bending machine riTUXimab for three cycles. riTUXimab cetera been. Um And then a standard would be consolidation with autologous stem cell transplant um And three years of maintenance riTUXimab. Um So this current patient um is getting fender, mustang mattocks mab and they will be coming in between the then the mustang right toxin antitoxin site caribbean. Um to enroll in this intergroup study of autologous stem cell transplant plus maintenance riTUXimab versus maintenance riTUXimab alone. Um So this is a study that we are participating in. So um so patients who are in a complete remission and have negative minimal residual disease which I'll talk to you about the next slide are Randomized to receiving the toxin alone for three years or transplant plus right toxin. Um So the primary endpoint is a six year overall survival. So this is um they're not done accruing so um But they are getting close. So this is data we will have maybe in 3-5 years but they're trying to show that um There is an improvement in um autologous stem cell transplant 86% vs 76% So with minimal residual disease is essentially looking at the igh rearrangement um in the B cell that can be detectable in the peripheral blood even if, let's say the pet scan was negative. Um It's using a s. A. From adaptive called clone ASIK which is supposed to be sensitive and up to one in a million cells. Um And Over 85% of patients with mantle cell lymphoma have a detectable igh rearrangement. Um it appears with the Kelowna seek essay. They over 95% of patients do have a a clone that they can track for minimal residual disease. Um And it has been shown in studies that peripheral blood negativity is associated with improved progression free survival. Again, this is not something that is done in clinical practice. This is on a clinical trial basis at this time. But this is the basis for that trial, which I think will be a very important trial to help answer the question. Um Do patients need an autologous stem cell transplant in first remission. So um the second case is um maybe what we see more of as well, 81 year old female um with mantle cell lymphoma who has bone marrow involvement. Ah And we talk about this patient is definitely not eligible for autologous stem cell transplant. Um So we would consider uh frontline therapy with bending machinery. Taksim mob alone for six cycles, which has been shown to have a progression free survival of around three years. Um Compared to our shop, another option is limited to mind and buttocks And the abs So this is I would recommend this more in patients who um I would consider it for patients who are lower risk. So patients have a lo que I-67 index on the pathology specimen have fairly indolent disease, a loam IPI score. Um This is a good option for a patient who is not a transplant candidate. Um and an update from 2020 Ash showed a seven year Progression for the survival 60%. However this is a regimen where patients are online a little my for at least three years um and with the option to discontinue after three years. So it is um long term continuous therapy so we'll continue um with case number one. So the patient did um Get four years of remission after B. R. And R. S. C. And now has relaxed mantle cell lymphoma. So before 2013 our options were not great. They included Fortis Amev Which did not have a significant response rate over 30%. And Glenallen hmeid um was a response rate of 26%. So we didn't have great options at that time. Um however, since 2013 um the B. D. K inhibitors are, it's a pretty standard for second line therapy. Uprooted was approved in November of 2013. Um a calibrated have been 2017 and then Zanna Bruton in 2019. Um all with kind of improved side effect profile with each generation. Ah The median progression free survival with a broader nib is 15 months and I'd say in general with the B. T. K. Inhibitors is somewhere between 1 to 2 years. Um So a significant improvement over Borquez amendment analytic mind but still um something left to be desired um in terms of the durability. So um more recently in 2020 was a publication in the FDA approval of car T. Cell therapy. Um In this study it was for patients who had received a. B. T. K. Inhibitor as part of their prior therapies. Um So brooks to capture jean Oskaloosa aortic arteries. So Had a very impressive complete response rate of 67%. And at one year 61% of patients were in a complete remission. So this is a patient population before car T cell therapy had a median survival of 6-8 months. So this was a significant advance in how we take care of patients with mantle cell lymphoma I think as with diffuse large B cell lymphoma. The struggle comes with if there's relapse after car T cell therapy. Uh So one agent, banana clacks. Um This was a study done by matt David's here Dana Farber. But these were all patients who had not received the B. T. K. Inhibitor beforehand. So it had a um impressive overall response rate in a complete response rate of 20%. However recent publications in the real world, um most patients who will be getting banana klax have relapsed post B. T. K. Um so the response rate seems to be closer to 50% um an immediate time uh in remission closer to eight months. So um it is an effective agent but not a durable agent. Um So I'll just highlight trial that we have ongoing. Um at Dana Farber which is um a combination of a calibrated the second generation BDK inhibitor veneta clacks and um open a twosome app which is this second generation anti cd 20 monoclonal antibody. Um With the rationale being synergy between um the B. T. K in BCL two inhibitor with potential resistance overcome with kubernetes a mob. Um So part of the rationale for this was patients who have a tp 53 mutation. Um If you compare them to patients who have more run of the mill mantle cell lymphoma without a tp 53 mutation very significantly decreased median time uh in remission and overall survival survival compared to those without. and um it does appear also that TP 53 mutation is um a poor prognosis and the deletion of the gene itself which is seen here. Okay, so um a phase two study that was um published in 2018 using a brutal and veneta clacks in the relapse setting. Um Most of these patients had high risk committee scores about half of them had a tp 53 mutation. Um and in this high risk population there was a 45% complete remission rate in TP 53 mutated patients Uh and a one year progression free survival 75% and 18 months of 57 and in terms of untreated mantle cell lymphoma. Um This study is being um first is currently now enrolling in relapsed refractory mantle cell lymphoma with the goal of it also being used in the front line. It's not yet open in the frontline setting But we're first we'll be using it in patients who are TP 53 mutated Um and patients who are transplant ineligible. Um and then if efficacy goals are met then we will move that forward to patients who are transplant eligible. Um and TP 53 wild type and we'll also use minimal residual disease to try to limit um toxicity and allow for a time limited therapy as well. Again M. R. D. Is not approved for clinical use. It is right now just a clinical trial tool. So future directions in mantle cell lymphoma um Other than trying to move these newer agents to the front line I think a lot of um work now is being done as is a lot of work in lymphoma in general is relapse after car T cell therapy. So so far I would say the three most promising options are a non convenient BDK inhibitor locks 0305. It's called Puerto brute nib which is shown impressive. 50% response rates for patients who have um progressed on prior B. TK inhibitors and patients have also progressed after car T cell therapy. Um As is another antibody drug conjugate against roar. 10 overtime obvious dalton. Um These are both still in clinical trials but really promising efficacy. And then as with a lot of other lymphomas, the bi specific antibodies including the other next demand low vitamin algorithm. And so just as a summary um mantle cell lymphoma is technically considered to be an indolent B cell. Non hodgkin lymphoma but it can behave very indolent lee but it can also be very aggressive. So it is thought to be an incurable lymphoma and it's pathan demonic is the cycling D. One Translocation Translocation 11 14. Uh It is a male predominant 3 to 1 Median age is 68. The majority of patients have advanced stage disease. G. I. And bone marrow involvement is very common. We use the midi score and tp 53 mutation um as prognostic tools and then there are the metamorphic and blasted variants are higher risk. Um We don't treat them differently but we do expect a more aggressive disease in those variants. In terms of treatment summary for patients. First line is still chemotherapy with three Taksim mob. If they're a transplant candidate you want to include a site Arabian based agent. Um And if they are a transplant candidate, three years of maintenance were toxin obvious standard given improved overall survival. Currently, second line is a D. T. K. Inhibitor. I prefer a collaborative or zanna brutal. Given improved toxicity profile with decreased atrial fibrillation uh and major hemorrhage compared to a broken hip. If a patient is able to tolerate car T cell therapy I would say this is third line at this point. Um And then right now the greatest area of need is um Relapse after car T. Cell therapy. Um interestingly. Um Car T cell therapy was given a label where it can be used As 2nd line as well after one prior um line of therapy. Personally I do like to still use a B. T. K. Inhibitor beforehand as we are often able to get 1 to 2 years of remission with that before needing to move the car T cell therapy. However there is some um There's definitely some data to suggest that patients with TP 53 mutations or glass toyed variants Have a shorter remission with the BDK inhibitor closer 4-6 months. Um So some patients or some providers do um sometimes skip over the B. T. K. Inhibitor and go to car T cell therapy. I still think it's worth at least bridging with B. T. K. Inhibitors before um considering car T. Cell therapy so that is my presentation. Um And I will open it up for questions as I think we are doing okay on time. We have five minutes before the next talk. If there are any questions. Um If not we can move to the next presentation which is um dr Karen Jacobson for car T cell therapy. Um She her talk is prerecorded um as she could not be here for the presentation but she will join us for the panel discussion. Um So I will take any questions if if not I think we should just move ahead to the um appreciation from Dr Jacobson. Okay. Alright. As uh it seems like there is, well there's one that popped up, How many of the 4500- 5000 cases per year are relapsed refractory. So the 4500 to 5000 are those are the new new cases a year um that are recorded into the United States. Um Most patients do relapse almost all patients eventually relapse. Um So that that number is just new diagnoses per year. Okay. Alright so I'm not seeing any other questions. Um So I think we can move on to dr Jacobson's presentation.
