Andrew D. Zelenetz, MD, PhD, identifies the classification of lymphoma and recalls standard of care. Dr. Zelenetz also explains why targeted therapy based on cell of origin added to R-CHOP has not been successful for improving outcome, and describes new emerging therapies.
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it is now my pleasure to introduce Dr Andrew Xylene. It's medical oncologists with special expertise in lymphoma from the Memorial Sloan Kettering Cancer Center. He will speak to us today about diffuse large B cell lymphoma subtypes and therapy doctors. Ellen. It is well known in his field for his work with lymphoma, and we thank him for taking the time out of his busy schedule today to talk to us about diffuse large B cell lymphoma. Please welcome Dr Drew Andrews. Alan. It's and do Please use the chat function. Ask a question. If you do have questions during his presentation, we'll be able to address them afterwards in the panel discussion. I want to thank you for the invitation to talk to you today about diffuse large B cell lymphoma, different subtypes and treatments. These are my disclosures, Um, I have research support from a number of different companies. I consult with a number of companies. I'm on the scientific advisory board of Adaptive Biotechnologies and Lymphoma Research Foundation. Um, and I do not hold any individual stocks other than what could be in a mutual fund. So let's start off with classification because you know, that's changed. Well, if this was equine medicine, then treatment is really pretty simple. And you don't need a whole lot of detailed information. However, in the new era of targeted therapy, we need a lot more information about specific subtypes of disease so that we can make more accurate and precise treatment recommendations. And this requires very close collaboration between pathologists and clinician. So, uh, we have a revision of the W H O classification that dates back to 2016. Um uh, in 2000 and eight, we introduced the concept of cell of origin. Uh, this was an optional addition. Uh, two reports on diffuse large B cell lymphoma. But if we look at the 2016 now, sell of origin is required to be reported by best available technology. Um, and we know that the technology will evolve over time. Uh, for the most part, today, it still remains Communistic chemistry and mostly using the HANS model. We've actually seen several additions to the aggressive lymphomas, Um, including the recognition of the H H V eight associated diffuse large B cell lymphomas. Um, high grade lymphomas with trans location of Mick and BCL two or and or BCL six. Um, And then we have B cell lymphomas that are unclassifiable, um, with features intermediate between diffuse large B cell lymphoma and Hodgkin lymphoma. What are sometimes called the gray zone of phones. So let's talk about the biology. Um, well, sell of origin, um, has been a little bit controversial as to whether it really predicts outcome. However, here in a very large prospective randomized study using a state of the art um uh, method for determining cell of origin, the lymph to see X s A. Um, what you can see is that this supported the original observation that germinal center tumors treated with r chop or in this case, are chop or G chop had superior outcomes to the activated B cell lymphomas when treated with our chop chop. Unclassified lymphomas, which represent a minority of the tumors, have outcomes that are similar to the activated V cell tumors. Now, when we look at our understanding of germinal center and activated B cell tumors, one of the things we realize is that, um, precision medicine is going to be really dependent on understanding exactly what's going on. We have multiple opportunities to inhibit different parts of the key pathways in germinal center tumors with a variety of inhibitors. Um, and the activated B cell tumors, which ultimately end up signaling through NF Kappa B, have multiple, um, different signaling method methodologies, including signaling through the B cell receptor, um, as well as the mighty 88 complex and again, multiple opportunities for an inhibition. And so we really need to understand what's going on in these tumors if we're going to enter the era of precision medicine. Diffuse large B cell lymphoma is composed of multiple entities. This is a gene expression profiles showing, uh, that, uh, the activated B cells, germinal center and P M B l all have different gene expression profiles. But when we delve a little deeper and we include, uh, genomic information, we see that there are even more sub groups in the analysis from the ship lab. Um, uh, we see the six categories C zero to C five. Um uh, from the stout lab, there were the initially four categories, but I'm about to show you there are actually a number of more, and these further subdivide, um, they sell of origin into different groups and that may explain why sell of origin as a simple marker has not been a useful tool for treatment selection in large cell lymphoma. So here is, uh, a more up to date model. Um, for, uh, this is Agent. This is an algorithm that can be used on a sample to try to characterize what subtype of diffuse, large B cell lymphoma patient has. And what we see is that there are not four subgroups. But in fact, there are seven subgroups, um, and the germinal center B cell lymphomas. Um uh, do have their own subtypes, but this being to class, actually, some of them are ABC tumors. Some of them are gcb tumors. A number of them are unclassified tumors. So what? And each of these subtypes have a specific set of mutations that lend itself to inhibition by different targeted therapies. So if we want to use a B t K inhibitor, for instance, um, in all ABC tumors, like, was done in the Phoenix trial, um, uh, if you're in a three tumor, you're being too tumor. Your and one tumor. Uh, it may or may not work as well as it does if you're an M C D tumor. Then we have other types of diffuse large B cell lymphoma, including P m B L p M B l. If you look at gene expression, profiling is actually more akin to Hodgkin lymphoma than it is to germinal center B cell lymphoma. Um, and we see either amplifications or breakpoints at, uh, I'm chromosome 16, p 13 and chromosome location nine p to four. The 92 4 is particularly important because this is, uh we see over expression of PD l one in pd l two as a consequence of either the amplification or break point in this area, and it results in sensitivity to checkpoint inhibitors. Uh, the Epstein Barr virus associated diffuse large B cell lymphoma is also another important entity. Um, uh, this tends to be an aggressive lymphoma. It's associated with chronic HBV infection, um, and often has a poor prognosis with standard chemo immunotherapy. Um, e B V can be associated with a number of large cell lymphomas and the differential diagnosis, um, includes things like P t l d. Um, uh, immuno suppression, lymphoma, toy granuloma, ketosis, lymphoblastic lymphoma, plasma, acidic lymphomas. Um, diffuse large B cell lymphoma with chronic inflammation spells and classical Hodgkin lymphoma associated with HPV infection. Uh huh. One of the things we need in diffuse large B cell lymphoma is, uh, how to, uh, conduct trials with earlier endpoints. Um, and it turns out that event free survival at 24 months is an excellent, uh, endpoint. Um, if we look at overall Survival Act diagnosis, patients with diffuse large B cell lymphoma, not surprisingly, have a substantially inferior outcome than those people in the general population. Um, though at 12 months, this gap is dramatically reduced. It's still highly, statistically significant that there's an inferior outcome of patients who are even event free at 12 months. But at 24 months, the event free survival is equivalent. And why does this happen while this happens? Because even though there is a risk of death of about 5% um, from diffuse large B cell lymphoma For those patients who event free at 24 months, it's not the dominant cause of death. The dominant cause of death becomes competing events, Um, that are typical of the general population. Another important thing to remember and this is as we interpret data um that delays from the initiation of treatment, ironically, selects for favourable patients. So in this curve, we can see that people who were uh diagnosed and treated within the first 14 days of diagnosis had an inferior outcome. And if you think about your own practice, those patients who walk in the door with explosive disease and you know immediately get hospitalized and started on treatment. Those are the patients who don't do very well. Why is this important? Because those patients who come to your practice with explosive disease there frequently not the ones who are getting on clinical trials. Um, oftentimes to finally get on a clinical trial, there could be a delay, and we're selecting patients with better outcomes, and that's really important in interpreting data. So what about first line therapy? And I'm not going to spend a lot of time about early stage, Uh, Lord cell lymphoma. I'm really going to focus on advanced stage. But, um, one of the major things is to determine whether someone has P M B l or not. Um, if they have P M B l. Uh, the, uh, best treatment available is either dose adjusted epoch R or R chop 14 for four cycles, followed by ice or rice for three cycles. Both of these regiments are associated with high probabilities of long term cure without the need for radiation therapy, Um, you can potentially get good results with our chopped followed by radiation. But many of these patients are young women, and you would really like to avoid the use of radiation in that patient population. Um, in the non p m B l patients, the question is, is there bulk? Um, and, uh, if there's bulk, uh, then they get treated as advanced stage. Um, though radiation, uh, should be incorporated based on the results of the flyer study. Um uh, in non bulky patients, treatment should really be defined by their, uh, all right, stage modified. I p I, um, either stage modified I p 01 or two or two or three risk factors. Those with two or three risk factors. They get treated as advanced stage disease. Um, the very limited or, uh, stage modified I p I zero can get our chop times for if their pet negative um, they can be observed, Um uh, in a limited stage I p I, uh, for four cycles of chop again pet for if negative, um, could be observed, otherwise they would go on to six cycles. But let's focus on advanced stage disease. And, uh, this, uh, slide probably can sum up very easily the international standard of care. Category one recommendation is R chop chemotherapy. Um, these are mature data from the original, uh, villa study. Um, looking at our shop, Um uh, and, uh, the, uh Oh, After a very long follow up, we can see that there's a maintenance of a survival advantage. Uh, remember that the patients in this trial were originally aged 60 to 80. So with this long term follow up, they're in their late sixties. Um, too late eighties, Um, and, uh, with a persistent improvement in outcome. So this is the international standard of care, but obviously we would like to improve upon this. Um, there are some caveats. This does not apply to P M. B. L. It doesn't apply to high grade lymphoma with trans location of Mick BCL two and or BCL six, and it does not apply to primary CNS lymphoma. So we've tried different drugs or different regimens, so we have to show up and show up. Uh, had neither a better progression free or overall survival are a CVP Um, uh was a positive trial for both progression free and overall survival. Um, the one caveat about this study is it was performed in highly favorable patients with AP one disease. So, um, and the reasons for that are complex. Um, But this study, um, this regimen has not been very widely adopted because for these highly favorable patients, um, it's been difficult to justify this more difficult and toxic regiment. Um uh, short accelerated, or does stints are chopped? Unfortunately, it was not successful in improving improving either progression for your overall survival. Um, opening Tuesday map as I showed you in that earlier slide, um, from Nagoya. Study again, no improvement. And the, uh, alliance study of art shop versus dose adjusted epoch again showed no improvement for the dose adjusted epoch regiment. So what about adding maintenance to our top 21? And this has been studied? Rituximab, uh, has been tried a few times. Um uh, in one instance, there was a small improvement, um, in progression free survival, however, there was no difference in overall survival. Uh, ends a store in was negative lead to minimize. Um uh, again, uh uh was slightly better and progression free survival, but no impact on overall survival and older patients, Um, and every Lima's was also negative for both progression free and overall survival. So maintenance does not seem to be the ticket to improving art shop. Um, and if we look at a meta analysis of all of the maintenance trials that have been undertaken, you can see that there is no impact. Um, that really that significantly favors maintenance. So there is no role currently after the trials that have been done for maintenance and Laura cell lymphoma. Well, if you can't beat them, what about joining them? So how about adding something to our chops? So are chopped plus X. Well, a couple of different studies have tried adding vortices MIB uh, the two, um r chop it. Unfortunately, no difference in either progression free overall survival. Um uh, based on results from the stout lab and, uh, the evidence that a brute nib was better for, um, activated B cell tumors. Um, there was a prospective trial selecting for patients with activated B cell disease, and there was no difference in progression for your overall survival. There is a caveat in this study that there was a subgroup analysis showed an overall survival benefit for patients under the age of 60. Whether that was biologic or that was ability to deliver dose is somewhat controversial. Um, and this study is being recapitulated using al calibrate nib. But in that younger patient population, uh, Linlin Hmeid, um, again showed no benefit in either progression free overall survival. Um, uh, the phase two study from Peacock did show a improvement in progression free survival. Um, but no difference in overall survival. And And I will say the caveat is, um, that the progression free survival was a one sided analysis. Um, and, uh, so if you do a standard two side analysis, it's actually not statistically significant. Um, we're awaiting the results of the polar X study. Um, which looked at our chop r chop minus the vin Christine. So our chip plus polar choose a mob versus is R chop. Uh, the it's all in the can. It's done. We're just waiting for the results. Um, to be reported. Um uh, our shop plus magnetic locks has only been studied. Um, in phase one and phase two, Um uh, in a recently published analysis, um, we showed that, uh, there's an overall survival advantage compared to the Goya patients. Um, if there's expression of BCL two, however, without a prospective randomized phase three study, um, that just represents a hypothesis. Um, not a treatment recommendation. What about P M B? L well, does suggest that EPA car has shown excellent results. Um, uh, I will tell you from our experience at Memorial, um, and other experience in other centres, they're not quite 100% like the original New England Journal paper. Um and, uh, these analyses are actually much more realistic with about, um a, um 75 to 85% long term disease free survival among these patients. An alternative regimen that was tested at M s K C C was a regimen of four cycles of distance, uh, chop, followed by three cycles of ice or rice, depending on the clinical response. Um, this study included a significant number of patients with P M B L, um, and the results, um, for both progression free and overall survival were excellent. Um, and we also found that these patients were highly salvageable. Um, with high dose therapy, autologous stem cell rescue. So, um, this represents another radiation free regimen. Um, uh, in addition to the dose, suggested epoch are, um so you have to remember, this is a disease typically of, uh, younger women. Um, so that radiation optimally would not be part of the regimen. Um either does suggest that EPA car or chop followed by rice um, achieve high curates without radiation. Um, and second line therapy followed by high dose therapy. Autologous stem cell rescue, uh, is effective. Um, uh, these tumors frequently express express CD 30 and, uh, for relapse. Refractory disease. Brent Tux Ahmad can have a palliative role. Checkpoint inhibitors can also have a palliative role. The high grade lymphomas were translocation of Mick, um, and BCL two and or BCL six. Um are often known as the double hit lymphomas. Um, uh, it's relatively uncommon, occurring in only about 5% of de novo diffuse large B cell lymphoma. Um, it's essentially exclusive to the germinal center. Diffuse large B cell lymphomas. Um, it's not to be confused with the double express. Our lymphomas. Um, the double expresso lymphomas, um, can express Mick and BCL two. Um, and they include both these double hit patients as well as a number of non germinal center or activated B cells. Diffuse large B cell lymphomas. Don't suggest epoch has good efficacy in MC rearranged diffuse starts, B cell lymphoma and these, um, double hit lymphomas. Um, uh, interestingly, the MC trans location partner actually impacts outcome. Um and, uh, so it is important to have the pathologist, uh, investigate with fish what the translocation partner is. So let's turn for, uh, the last few minutes to relapse and refractory disease. Um, this is the algorithm from the n c. C n for relapse refractory disease. Um, and the basic question is, is the patient eligible for high dose therapy now? Autologous stem cell rescue or not? Um, for those patients with the intention to proceed to high dose therapy, second line chemotherapy, Um, and if in a completely response, the plan would be to proceed with high dose therapy autologous stem cell rescue if in a partial response, either high dose therapy or car T cells would be appropriate. But for those people who failed to respond to second line therapy, then, uh, car T cell therapy is most appropriate. Um, we have a large number of different treatment options, Um, in the relapse refractory setting. And we don't have time to review every treatment possibility. Um, it is important to mention the c D 19 directed Corti sells. Two of these are approved. Actually, Captain Jean Silo loose. L and T is again, like loose L um Lisa. Captain Jean Marie Luce. L, um, is likely to be approved early this year. Um, and they all are similar. Um, they target cd 19. Um, um and there have a signaling domain. Um, either, um, through c d 28 with a c d three Zeta for, um acsi Captain Jean or the other to use a 41 BB co stimulatory domain with CD three Zeta. Um and, uh, this is, uh, the results of the label enabling studies. Um, and you can see that the objective response rates for both of these, uh, approved drugs the ACSI Captain Jean Louis L and the T generally clue cell, um are good. Actually, Captain Jean was a little bit higher. Complete response rates were a little bit higher. Um, but there are adorable ongoing responses in the range of 35 to 40% with these agents, Um and, uh, now it's a little bit misleading. It looks like there's more CRS with these again, like loose l. However, the two drugs use different scales for rating of, uh, CRS. There's actually more crs with taxi captivity. Uh, it is important to remember that there are two important syndromes associated with car T cell therapy, the side to kind of release syndrome, Um, and the, uh, immune cell associated neurologic syndrome or icons. Um, and, uh, the management of this, uh, and understanding how to manage these, uh, syndromes are very important for successful application of car T cells. Um, here is the long term follow up of the Zuma one study it follow up at, uh, 27 months and you can see, um, the overall survival in excess of 40%. Um, and this is really impressive. This is a group of patients who would have had a median survival of about three months. Um, and, uh, you know, a number of these patients are clearly cured over the long term. Um, with this long term follow up. So cortisol really represents a, uh, enormous step forward. How exactly to use it and where to use it is still a bit of controversy. In the last couple of minutes, I'd like to touch on new antibodies. Um, uh, there's an alternative targeting of CD 19, and that is with, uh, a regimen called El Mind. And this, uh, uses an antibody to fasten a mob, which is a, uh, a f C engineered anti CD 19 antibody used in combination with Lana. Lana, My, uh, Linda Linda, my augments, uh, antibody dependent cell mediated side of toxicity and also does elicit some direct side of toxicity. Um, and the combination with Tafa cinema bob increases tumor cell killed. Uh, this is the outline of the study. More Children waiting to see the mob was given weekly for the first three cycles than, uh, every other week for cycles four through 12 and then continuously after cycle 12 for responders, let alone, um, I was only given in the 1st 12 cycles initially at a dose of 25 mg days, one through 21 frequently dose reduced, um, for side of toxicities, but This was a highly active regimen, with an overall response rate of 58% and a complete response rate of 33%. Many of these patients were treated in second line, so it's not directly comparable to the results with car T cells. Um, but this is an off the shelf, easily used the regimen and represents, um, a new treatment option for our patients. Here are the progression free survival, Um, and the progression free survival looks favorable over time, and even among patients who are refractory to their to rituximab or refractory to the last treatment, the overall survival also looks good. Another important antibody is Paul Atoosa Mob. This is an antibody drug conjugate that has Vidovdan bound to, uh, a anti CD 79 b antibody. It works very much like Grant took some Advil gotten but targets C d 79 instead of C D 30. Um uh, in patients with relapsed refractory disease in the Romulus study. Uh, there was substantial activity of the combination of rituximab in Poland, choose a mob, and in a labelling enabling study, um uh bend, a musty rituximab was compared to polo twosome AB plus bender Mustang protects the mob, demonstrating improvements in progression free and overall survival in favor of adding polo to Zermatt. Now that red line with the dots that are added there that shows the rituximab plus polar to Zermatt. In many cases, I don't personally use the Bend a Mustang, because the results with politics may have been rituximab alone are actually quite similar to the three drug combination with less toxicity. So in summary, diffuse large B cell lymphoma represents a variety of diseases with unique biology. Um uh, for diffuse, large B cell lymphoma not otherwise specified are chopped remains this international standard of care for P m B l does suggest that epoch or R chop rice are appropriate treatments. Um, car T cells represent a really, uh, new therapy with a potential curative outcome, even in third line and beyond. Um, and there are emerging important new therapies, including alternative antibodies, antibody, drug conjugate and unfortunately, what? I didn't have time to talk to you today about by specific antibody
