Adam Olszewski, MD, shares updates on Diffuse large B-cell lymphoma.
um from Brown University, Associate professor of medicine. Um He is um published widely on diffuse large B cell lymphoma. Cns lymphoma. Um aggressive lymphomas in general. So I can't think of a better person to uh start us off today and I'll let him take it away. Thank you very much. Thanks everyone for joining. We'll start this session uh with uh one of the most common lymphomas diffuse large B cell lymphoma um which seems like a bread and butter um issue for oncologists. But we'll talk today about some updates really really to do it. This is my disclosure slides. I'll focus on three aspects. One is how do we understand what actually is. Um Then we'll discuss first line therapy and changes in it that have occurred recently and will brush a little bit on the salvage therapy. So, if you'd like to be someone from a for the past 20 years has been recognized as a heterogeneous entity um subdivided primarily using the gene expression profiling. Which was described by several groups in the early 21st century, splitting it into the germinal center B cell like and abc like lymphomas as well as a small unclassified group which contains perhaps many cases of primary ministerial B cell lymphoma. This classification has never really translated into clinical practice because of the difficulty obtaining gene expression profiling. So it was widely approximated by the so called hands algorithm. And there were some important clinical differences between these lymphomas. Germinal center B cell lymphomas were somewhat similar to transform follicular lymphoma with typical ibc of the transportation of the genetic lesions were supposed to have better prognosis and the A. B cell lymphoma had worse prognosis and so attracted a lot of attention especially after it was discovered that the relied heavily on the T cell receptor signaling and signaling and were shown to be responsive to targeted agents which emerged in the two thousands in Britain. That pretty clearly also became evident that these entities are heterogeneous in themselves. Among the germinal center al lymphomas, the mc rearranged double hit lymphomas were subdivided as a particularly aggressive group and then the abc subtype, the so called dual express er and tumors expressing Mc and D. C. 02 were recognized as particularly poor prognosis. Unfortunately, this paradigm has not successfully translated into therapy despite multiple randomized large trials and a lot of effort over the past 10 15 years and neither partisan nor in Brittany no really linda linda mix has shown benefits in the uh subdivided abc like subtype. Although the data and is somewhat controversial with two studies, one of them being smaller but showing some improvement in the abc subtype but the larger study not showing an improvement. So unfortunately with a lot of effort we are not able to use this information for adequate treatment selection for patients in the current wh o classification. The germinal center B cell and activated B cell subtypes are still the principal forms of diffuse large B cell lymphoma but a lot of other histological subtypes have been subdivided now and recognized as separate entities which for which separate treatments could be investigated. Uh And importantly the high grade B cell lymphomas were separated from the future of B cell lymphoma organized a different disease characterized by Mick rearrangements with in combination BTO to NBC 06. But in reality there is now a whole map of high grade B cell lymphomas which need to be considered when making a diagnosis in a patient. The world is moving however towards genomic classification which seems to be somewhat more feasible although at this point it is still not possible in clinical practice because of requirements for multiple technologies to be deployed at the same time for this sacrifice sub classification including not only the typical single point mutations but also copy number alterations and large variants, large chromosomal variants and rearrangements. But there are now at least seven subtypes. There there's also some heterogeneity on how they were defined by different groups. But I think the N. C. I. Designation showed here is becoming used more commonly at least as a terminology um of these subtypes. Perhaps the M. C. D. Subtype is gaining again a lot of attraction and interest because this is the step type recognized clinically for many years as this lymphoma with strong predilection for extra nodal sites. This is the majority of testicular breast lymphomas. Majority of primary cns lymphomas as well as some aggressive histology is like intravascular or leg type cutaneous lymphoma. It is driven by Mighty 88 mutations similar to others. Transportable anemia in combination with other features that predicted aggressive course. Um as the first glimpse into how this could work in the therapeutic arena, a recent study has shown that sub sites or dynamically classified sub sites of the lymphoma do have differential response to in Britain. It. These are this is this was a subset subset of the phoenix trial of a randomized trial between our job versus arguably Brittany. And while in the overall population sub selected for abc one famous, there was no significant improvement. You can see that in the M C. D subtype. In fact, there was 100% events for survival and similarly in the N one subtype characterized by notch one mutations, well, there was no difference in the B N two subtype. So it's possible that if we will be able to translate this economic classification into some workable scheme and diagnosis, then we might be able to use these targeted agents in a much more rational way in the germinal center or Visa lymphoma, there are also significant developments apart from subdividing the typical hydrate Visa lymphomas. Two large studies now have shown that probably about 10 to 25% of the Visa lymphomas depending on how they're defined and whether you focus on the germinal center subtype can also be identified as molecular high grade b cell lymphoma, a much more aggressive disease that is associated with a similar gene expression profile to either Burkitt lymphoma or Double hit lymphoma. This subdivision still requires. Unfortunately, gene expression profiling so again, probably not available in clinical practice. But now several studies are showing that hybrid molecular high grade B cell lymphomas have a much worse prognosis. Compared to standard diffuse large B cell lymphoma, including the abc lymphoma. They may contain make rearrangement but not all do. Uh And some are characterized by the combination of the Mc rearrangement or the So called double his signature and the combination of P 53 mutation which appears to be particularly this knowledge in terms of the prognosis. So how should practicing clinician think about an aggressive B cell lymphoma. Now I think it is really important to recognize that these four entities exist and and think about their management. So there's this the largest group of generic the few therapies, Helen thomas in the subgroup of it. However, the dual express er population characterized by Mc and D. C. 02 expression defined by immuno history chemistry. I emphasize it because I still see sometimes people mixing the two concepts. This population has significantly prognosis is enriched in the M. C. D. Subtype uh and can be unfortunately we currently do not have a standard therapy that could improve on the outcomes but there is a large clinical trial running adding metal plaques to our job hoping to improve outcomes of these patients. The Double hit lymphoma is really now termed high grade B cell lymphoma with meghan B. C. 02 or BCL six rearrangement and as a separate disease we do not have good progress prospective data to guide its management. However, most centers have moved on to using more aggressive regiments, particularly those adjusted EPA car for the subtype. It remains unclear whether the other hybrid diesel lymphoma should also be treated differently. This this is is poorly defined, poorly recognized. One of my concept problems in clinical practice is discussing with our pathologist who might or might not have hybrid discipline from the N. O. S. Among the diseases of the soul from the cases because the threshold of pathologists is very variable. But this disease also appears to be more aggressive and we probably will have to separate it to properly treat patients and really differentiate them from standards. The facility cell lymphoma. So the first line therapy for different reasons OMA and us if you wish has not particularly changed in the 1st 20 years of the of the century. Despite large efforts, not only these two targeted therapies showed no improvement but also substituting redox map with astigmatism Map showed no benefit Intedifying the schedule of art shop to bring it to every 14 days which is clinically feasible and I have to say I still offer it to some patients who want to treat finish treatment early but with the understanding that this does not change any cure ability or other outcomes and of course the large study and did not show improvement of those adjusted Abakar over generic diffuse large B cell lymphoma. The problem with these all these studies is that as you know, they try to um focus on patients with poor prognosis about the Kaplan. Meier curves on the studies do not show poor prognosis. These are particularly well behaving patients in the Alliance study as you can see and there's a 70 years survival at five years. This is actually not what is observed for high risk patients. So there's a selection in these trials that have obscured and potential benefits. We are more successful with defining a treatment for early stage diffuse large B cell lymphoma. There are now several but particularly those three studies that have defined improved therapy for the subset many people are familiar with the flyer trial which selected patients with no I. P. I. Factors. So that includes age less than 60 as well as non bulky disease. Although interestingly allowed extra nodal sites and treated patients either with six cycles of our job or four cycles of our job with two doses of toxin map instead showing absolutely no difference in outcomes. So this is an excellent treatment approach for patients who do not have any KPI factors that relieves most patients with diffuse that beat Alabama who are over the age of 60 in the United States without a clear option. Uh So I think pet directed therapy has driven to other studies. Face to swap study which took patients at ST one and two with non bulky disease. However, it did exclude all extra nodal sites or at least a high risk extra nodal sites. And used pet negative disease to limit therapy to four cycles versus providing additional radiation including radio immunotherapy for patients with positive disease. The french study, which has so far been shown in the abstract form, I was somewhat similar in concept back to patients up to the age of 80. So the age of sensibility of art shop without any additional risk factors, but allowing extra nodal disease. And based on the basis of negative pets, which occurred in most patients after two cycles of our shop, provided only four cycles of therapy, which also showed no difference between this strategy and the strategy of six cycles of our shop. So all these studies were somewhat conceptually combined in the current NCC and recommendations for early stage disease therapies. A lymphoma which actually recommends pet scan after three cycles of our job. Um and then deciding about shortening treatment to this for for doses or using radiation as well in this work study or extending therapy. If the pet is positive, is a positive, Most patients have about 80, of patients will have negative pets and can be nowadays spared longer therapy, limiting their treatment to four cycles of our jobs. Um Finally, there is um a new first positive study in advanced stage lymphoma which we took all comers. The polaris study randomized patients between six cycles of our chopped versus six cycles of our chip income with in combination with politicians, Vidovdan, the FDA approved antibody drug congregates which is used for a relapse and refractory disease. In this case patients received its first line. This study did not involve patients central nervous system involvement or who have transformed lymphoma. And the common opinion follow up is slightly over two years With well balanced arms which included double hidden triple hit lymphomas across the world as well as about 38-40% of patients with dual expression of lymphoma. And as you have heard at Ash and now shown in New England Journal and the recent publication, there's about 6.5% difference in long term progression free survival favoring the polar our chip arm with a statistically significant hazard ratio without any overall survival benefits. At this point for this short follow up, there was a lot of hope that substituting increasing with apologies. Map will lower the neuro toxicity of this regiment but actually this has not panned out. The rates of personal neuropathy are the same in both arms as well as most other toxicities. There has been a lot of attention paid to the subset analysis might take on. It is primarily that this is an exploratory subset analysis which actually should not be paid too much attention to none of the variables including this analysis had significant interaction testing. However, because of how we all want to figure out who should get one regiment or the other. It was noted that younger patients did not have particular benefit from additional polytheism up basically with lower I. P. I. Score did not. And interestingly, maybe the most striking difference is this defense by cell of origin which was here divided by gene expression profiling so unfortunately cannot be used in clinical practice to differentiate patients. And the use of dual expression by I see has not also panned out as a adequate substitute, but it does appear that activated B cell lymphoma derived the most benefits from polytheism of in combination with our ship. So will the study become a new standard of care remains? I think an open question and there are mixed opinions, I have heard strong arguments for and against. We certainly need a longer follow up to find out if there is going to be any overall survival benefit. This may not ultimately pan out because of multiple available second line options. Perhaps there is some hint that the biology might dictate potential benefits from polytheism and this is somewhat surprising. We think of this as a targeted agent to all the future resale lymphomas. I think the staggering cost of this therapy may play a role in how it will be accepted in the community. We also worry about how this trial will impact ongoing randomized trials which all have our job as a control arm. Um and perhaps in the end sam paradigm were younger patients with a B cell lymphoma might receive in Britain it if the results of the phoenix trial are somehow confirmed or more corroborated while other patients might benefit more from addition of polytheism of. But this is still very speculative and at this point I have to say that this is an overall positive trial which did not show at least any detriment of giving polytheism occupations with germinal central lymphoma or any other subgroup. These subgroup analysis can be highly misleading against cell of origin was um studied by gene expression profiling. So and not by I H. C. So we cannot really approximate it easily by hands algorithm. And again, there doesn't seem to be any clinical detriments to giving this regiment to all patients with the field of research and pharma essentially, I should also warn all um attendees and and people who will be thinking about is that experts may give an opinion and they often will have a conflict of interest. I personally do have conflict of interest with Genentech and Roche. So you have to really use your own judgment for interpreting this data. There are some other directions where the field is going and one of them is incorporating other novel agent and strategies into the first line therapy. We have a in combination with thalidomide as well as long and the other A DC available for different reasons. And from and both are being studied in first line treatment in combination with our shop or in combination with limited treatment with riTUXimab alone for the subgroup of other patients. There is great interest into bringing the first line immunotherapy. You will hear later today by the results of the Zuma 12 trial which used car T cell therapy as part of the first line treatment for diffuse large B cell lymphoma and hybrid B cell lymphoma. Um and as and there's also interest in bringing by specific antibiotics into the first line therapy. Finally, the combinations of targeted therapies may prove more useful than just adding one drug to our job especially. They will be combined um using some kind of genomic trans classification that will be translated. And there's a number of studies combining a little intimidated BDK inhibitors in various options with different antibodies. Here's an example of a first line trial for the future of and now without chemotherapy that we were um fortunate to participate in uh specifically for all their patients over the age of 80. And um I was very happy to have this option for my patients over the age of 80 or or those with functional organ impairment, which otherwise the only people To get a mini art shop and a number of patients personality, 40% have achieved complete response. And so far many of these responses are durable. So as you can see, there are some suburbs of the future visions in which potentially could be treated without chemotherapy. Although this remains highly experimental for the relapse refractory disease. Our paradigm since 19 nineties included salvage chemotherapy and relax with about half of patients expected to respond and go on to having autologous stem cell transplantation more recently. Uh following this following failure of transportation, we had car T cells available autologous car T cells And the number of new therapies which have been approved in the past three or four years for relapse and refractory disease. Unfortunately at the beginning of this pathway we know does not really work in the current era. Um we I often used to quote about 30, cure ability potentially for patients relapsing. We now know that this is not true. even in the coral study. Um which randomized patients um To receive this standard therapy with other organisms of transplantation. Following treatment with riTUXimab. Only uh small number of patients less than 20% had long term survival if they relapse within 12 months of the initial treatment. And the same was seen in the randomized Orchard trial which used to already have versus of the mammography have. We're probably about 20% of patients have long term event free survival. And in the observational data from the Scholar one analysis, we also know that patients who are refractory to either primary treatment or any subsequent treatment had also failed the poor outcomes with just about 20 or less than 20% long term survivors. So this problem does not really work. And there has been a lot of attempts to bring car T cells into the second one trial. Um Car t cells are highly effective for um subsequent lines of therapy. 3rd and and and and and future. There are three available products uh they you know, these studies can be compared side by side and and it's done routinely although you have to think about the difference is how these cells were designed. But in general patients who progress after a second line therapy can expect about you know, 50 to 75% response rate. Probably about 40% of them will remain disease free after a year and a half. So this is really much better than the results of this standard paradigm. If you thought about bringing this to the second line trial autologous car T cells obviously associated with significant toxicities with rates of severe crs and particularly your toxicity, which may prohibit eligibility for many patients but it does appear to be the most promising treatment for relapsed refractory to start retail fomo. So just this year, we have heard results which will be discussed later today in detail. So I only uh speak about them very briefly of all three products, autonomous counties of products used as a second line. So soon after relapse reserving further therapies for future recurrences. And as you probably know, these trials have, quite similar enrollment criteria and this one is a negative study and and two are strongly positive. Um And then you will discuss during the presentation of dr Jacobson why this third study may not have worked just as well as the other two. Um and um but this this ultimately will be a practice changing paradigm. There are numerous further salvage therapies available. Uh The car T cells, the autologous car T cells are well established but there are two similar immuno therapeutic modalities which are competing directly with car T cells for potential efficacy. Uh and for the safety of the standpoint, these are the by specific city 20 and 30 30 antibodies of which there are now four in clinical trials. We'll see if all four really moved to further research as well as the allergenic parties which are available off the shelves that are already produced. And there are some differences and potential conceptual benefits of these other therapies over the car T cells. Although their efficacy is less well established. Autologous car T cells have high toxicity, high cost and long production time during which many patients require bridging therapy or even progress and never receive treatment living in a state where no center can administer autologous car T cells. I know very well about patients who are just never able to get these treatments. Um however well bi specific antibodies actually have less crs no wait time to deliver very little neuro toxicity. But the durability of responses is uncertain at this point and the rate of responses seems to be somewhat lower than with autologous car T cells. This response rate is pretty high with allergenic car T cells but again and which are available again off the shelf. But their persistence in the host is much shorter, only measured in weeks as opposed to a months to, you know, a year of autologous car T cells. So it is uncertain if they will be able to compete directly. We also now have four additional lines of therapy approved by FDA. Um Again, these trials can be put side by side, although the eligibility criteria here are very different and the results of these studies are quite different and really I do not think they are particularly comparable. However, the politics a map in combination with offers about half of patients response rates. Most of these responses are going to be quite to be complete and quite durable if they if they occur. But the overall permission for survival is less than one year. The is a common option for clinicians, particularly for other patients. Uh it is a system that has few toxicities. Little little mites can be easily those adjusted in clinical practice. And again, the results were impressive with high response rates. Majority of complete responses and I get a publishing for survival about the year in the general population. Um the has seemingly somewhat less response rates, but again, the eligibility criteria in the study were different and enrolled many high risk patients. So altogether I think for all three therapies like 40 patients, about half of the responding. Uh and um For those who respond potentially uh some long term survival, this is in a range of about 20, We'll have to see how the data for deficit and availability might pan out with longer follow up. There's the fourth option selling exa which has lower response rates. Uh despite including patients in the trials who have very good prognosis for relapse refractory disease. So it is not commonly used although it remains an option and there were some complete responses and some long term survivors on Southern Extra as well. So, um if you think about what we stand today um in terms of the classification, I think we're still relying on the fish basis and I see a subdivision of cells of origin. We know this is not greatly useful and hopefully we'll move on to the genomic classification imminently. If we can figure out a good method to do that. First line therapy as of April 2022 is a little bit in flux. Um the polar our ship is not FADA approved yet but um I have used it for a number of patients and it may become a standard of care. We will have to see for everyone or just for a sub group of patients for second line car T cells. I put a question mark. It may fall off this week. Uh I believe yesterday the actual cell was approved as a second line therapy for the 2000 and famous of these options now may be covered by insurance and available to clinicians. And we have this host of second line therapies um but in the future there will be more and perhaps we'll be able to use the targeted therapy in a more genomic lee rational way. Um Thank you very much for your attention and um I'll be happy to entertain any questions. Now we're during the panel discussion. Thank you adam so much. That was a really comprehensive concise and I think very relevant talk on um very rapidly changing landscape for a few large B cell lymphoma. We have a few minutes for questions before we go to our next speaker. There are any questions I guess uh If we have no questions I'll ask. Um So you have been able to use um pola are chip for some patients. Um Frontline yes and I admit that I have sub selected more aggressive non germinal center patients to receive this therapy. Um I suddenly had some insurance denials um but we were also able to successfully treat some some ridiculous if patients with this regimen so far with good response, I would caution about doing this um A blanket until it gets approved by FDA but for at least for some patients these days are quite compelling and we your as you said we are expecting it to be approved um sometime this year I'm not sure when but um yeah and I think that's something we're gonna have to decide who to use polar our chip for versus standard art shop if not everyone. So that's for me it was sometimes sometimes the you know one of the options for patients where I really feel they have a high grade lymphoma. Um and our pathologist will not assign this on the basis of morphology but with really high I. P. I. And multiple risk factors. Um This is some some hope of potentially overcoming the resistance to our jobs with the caveat that we actually don't know if this is going to work so well for germinal center high grade lymphomas. Um It does look like we have a question in the chat. Um it's asking how we are using targeted agents and practice and I'm wondering if that means more like frontline if if anyone is using brutally stabbed Will be very interesting to know how these studies influenced people's practice. They have not influenced mine. I have not prescribed in the little little minority Britain for innovation and first line therapy fortunately we have the availability of the alliance trial within 8:00. So if somebody wants to try to get an agent, I think this would be the best option to try this right now. But I do think that these genomic data suggest that adding B TK inhibitors to our shop will be beneficial for at least some some big corporations. That may be a large benefit, which will have to really document well. And I think that is kind of in our group has been similar as well. We haven't used um analytic mind or toxin map, I mean broad nib to arch up and front line. Um But you're right. I think there may be a signal there. Um I don't see any other questions. So like adam you are now off the hook. Thank you so much. Um And we'll see you in the panel discussion and I will now introduce our next speaker.