Chapters Transcript Video Lymphoma ASH Highlights So I'm going to give an overview of the lymphoma abstracts that I thought were interesting and important. Um And Ash this year with an eye towards ones that have some clinical impact at present. Although I have to say there weren't a ton of practice changing abstracts this year. Although there were some very interesting I realized that that five dec I sent to the vendor did not have my disclosures uh both research funding from Pharmacyclics and Hoffman Laroche and maybe in the updated pdf that we send of these talks, we can include that. Today's agenda will review the Zuma five study inflicted lymphoma. We'll talk about three studies in diffuse large B cell lymphoma before moving on. two new agents in development in B cell malignancies. Uh and then eventually finishing up with Hodgkin lymphoma and T cell lymphoma. And it seems like at the moment my uh my keyboard has frozen. So maybe if the folks behind the scenes could advance the slides, that would be tremendous. Next slide, please. There we go. Uh so this was the Zuma five trial led by our colleague Karen Jacobson and I promised her every time I give a talk I will disclose that she bears absolutely no relationship to me which is to her benefits. The Zuma five study design was fairly straightforward. I'm not going to really be labor, it's pretty consistent with prior carta. So studies in lymphoma, There were 146 patients treated out of 151 enrolled Patients tend to relapse refractory Grade 123, a particular lymphoma or marginal cell lymphoma and had to have received at least two prior lines of therapy that included an anti cd 20 monoclonal antibody along with a calculating agent. They receive standard limbo depletion with the caribbean and cyclophosphamide and then standard dozing of axis sell artisanal product, baseline disease characteristics. The important ones, these are reasonably heavily pre treated patients and the median number of prior therapies of three. That's not ridiculous in a low grade lymphoma patient population but certainly were fairly heavily pre treated. Um We do know that, you know, in general, particularly follicular lymphoma, of the vast majority of people do very, very well. Um But there's a small subgroup of patients who have progression of disease within 24 months of completing chemo immunotherapy, you seem to have a particularly poor Prognosis. And certainly this patient population on Zuma five was enriched for those patients. So 55 of the follicular lymphoma patients that had progression of disease Within 24 months of Chemo immunotherapy. And although the numbers are much smaller, similarly, about 50% of patients with Marshall cell lymphoma, it also had early disease progression. The overall response rates work Quite astounding actually. So in the study population as a whole, there's a 92% overall response rate with the 76 spent complete response rate Uh almost mirroring the numbers uh in follicular lymphoma. So in that population, 94% overall response rate with 80% complete responses The. c. and the overall response rate for a little bit lower in marginal zone lymphoma. So there's certainly may be some differences between these two patient populations in terms of their response two car t cells. Although to be honest, again, the number of marginal zone lymphoma patients was quite small in terms of durability of these responses, the follow up is still relatively short medium follow up was about a year and a half In the trial population as a whole, median progression free survival and overall survival had not been reached. Although in the marginal zone lymphoma patients subgroup, the median progression free survival was right around a year. The 12 month PFS for this entire study population was just under 75%. So, apparently good given the relatively poor risk nature of the patients were accrued on this study And the 12 month overall survival rate was 93%. So that was was quite impressive in terms of toxicity. Again, I'm a ah I saw it is not advancing there it goes. Um You know, of course, there's toxicities of interest that you've heard about. Another talks today with carty sales, one decided Can release syndrome. The incidents of cytokine release syndrome at least Grade III or higher was comparatively low. In this patient population was six Inflict your lymphoma about nine in marginal zone lymphoma course. In addition to cite a Kind release syndrome, we do worry about neurologic events which will see on the next slide. So about 15% of patients in the follicular lymphoma patient cohort Had grade three or higher neurologic events. That was that went up to 41% in marginal zone lymphoma, which is quite hi again. These are very small numbers, but that's certainly something I think to keep an eye on as we expand our experience in that particular patient population. Overall, I thought these data were quite encouraging. The response rates were extremely high, including very high cR rates and particularly in follicular lymphoma. Think a little bit less encouraging in marginal zone lymphoma. But we need more of an experience. Not the toxicity was quite manageable. Certainly. This is not a therapy that's going to be applicable to every or even most patients with follicular lymphoma who generally can be managed quite well with less intensive therapies, but certainly for the higher risk of groups or the heavily pre treated patients. This is very, very encouraging. And the expectation is that the FDA will render an opinion on this product for approval or not? Probably sometime in March. The general expectation uh is that actually so will be approved for follicular lymphoma. But of course we need to await the final determination. But I thought this uh bias aside with Karen leading the study, I thought this is one of the more interesting and important abstracts at the Ash meeting this year, we're gonna move on from follicular lymphoma to the other end of the spectrum, more aggressive lymphoma diffuse large B cell lymphoma. Again, if we could advance, thank you. Um I believe we talked about this study last year uh and there was an update of the study this year at Ash. This is the L mine study, which is a Phase two study that led to the approval of the combination of Tafa cinema and let alone a mind and patients with relapsed or refractory DL BCL as a reminder, patients received one year of lenin dynamite on this protocol. I'm sorry on this regimen uh 25 mg three weeks on one week off as a standard schedule and then patients receive tapas cinema incompetent with thalidomide. But after 12 cycles, if patients are continuing to benefit and not having not have unacceptable toxicity, they can continue on top a cinema of every two weeks until disease progression, Median follow up on this study is now almost two years. The overall response rate was 57.5%. The complete response rate of 40%, which is quite impressive. The median duration of response was about 34.5 months and has not yet been reached for patients who have a complete response, So, undoubtedly quite durable responses for a subgroup of patients. Yeah. And the study population as a whole, the progression free survival is about one year. This study looked at various subgroups of interest and I think really no major surprises, I would say. Not surprisingly. Uh patients who have had one prior treatment had higher responses. Um and better 24 months overall survival than patients who had two or more prior therapies, patients who had primary refractory disease had shorter responses on average. Although the likelihood of responding was similar, whether you had primary refractory disease or not, there certainly was a trend towards higher response rate and non G C B. D. L. B C. L. It's always been postulated and theorized and proved and disproved to varying degrees of thalidomide itself. Uh And certainly overall survival also trended better in patients with the non GCB subtypes And certainly uh and unsurprisingly patients who were lower risk on the PS four and better outcomes than patients were higher risks. I think. I mean not any major surprises. I think the reassuring thing is that most of these patient populations had fairly good response rates of this regiment. I'm going to save comment or summary on to pass it and they have little light of mine and kind of combine it with this next abstract which was longer term follow up mm Very angry. Advanced to slides ahead. There might be a little bit of a delay between my button and the and when I see the advances adam, are you able to ah You go backwards a few slides for me. I need to have a disconnect between my computer and advancing the slide. Maybe go back one more slide, please. Thank you. Um So the updated results of BR Polo Twos have included the Phase one B safety run in The Phase two randomized trial that really led to the approval of the regiment and then previously unpublished experience from an extension cohort of that trial. Uh and the median follow up for a lot of these patients now is quite long. It's 56 months. The safety run in in about 3.5 years. Uh For the randomized cohort a little bit shorter. The extension cohort, which forms the bulk of the patient. Uh As was noted in the first analysis that randomized cohort Children improve progression free survival with the are full of crap compared to be our alone. Overall survival was also superior with pr politics. Um And over br alone and there's a small subgroup of patients as six patients now, Well received. Be. Our politicians haven't had durations of response greater than 24 months, very long term remissions in a relapse refractory Dl BCL population in the extension cohort, the data really still needs to mature a little bit, but the cr rate was about 53% of the median PFS of six months and median overall survival of 11 months is starting to look fairly comparable to what was seen in the randomized br polo Tuesday mob cohort. Next slide, please thank you. Uh Similarly to Leno Letterman. Leno Letterman and tapas cinema. There was some subgroup analysis in this protocol. Again, similar results. Primary refractory patients, patients who are refractory the last treatment and patients who have had more prior therapy had worse outcomes than their counterparts. I think none of that is really fairly surprising. A frequent question that I field and I'm sure and and others in our group field is you know, how do you choose between br policies, a map and and led to one of my toughest in the map. It's somewhat difficult. Obviously in the options of a head to head comparison, we're always hesitant to make cross trial comparisons. I would say, you know, both regimens. I think the majority of my use anyway has has been in older frailer or more heavily pre treated patient populations. I think with both regiments, the partner drugs can sometimes be problematic. Sometimes the vendor must mean can be problematic in this patient population and certainly The 25 mg of adrenaline Ahmad can be problematic in a trailer or more heavily pre treated patient population. I do find myself adjusting these regimens not infrequently. I often prop the bend a must in from br polo to some um is a patient of frail or in my lower the dose of adrenaline hmeid. You know obviously we don't know what implication that has and the response rates that I just showed you. Certainly there are some comorbidities that may differentiate. Well it is a bad can cause neuropathy. So if a patient has significant pre existing neuropathy they may not be the best candidate. Uh Polo twosome at BR does have the advantage of being time limited therapy. Whereas tap a cinema certainly could be indefinite therapy. And I guess you could argue whether maybe there is a benefit to indefinite therapy as well. And then there remains A theoretical consideration that may be giving and 99-19 basis antibody therapy prior to anti cd 19 based party cells could affect uh the ability of car T cells to recognize and attack their targets. There is some preclinical data and some limited clinical data to suggest that exposure to tapas that mm does not Adversely impact the efficacy of anti CD 19 cars. But I do think that concerns still persists rightly or wrongly amongst people who treat these diseases. No, now I say I use a fair amount of reduction and pull it to stab bridging therapy to car T cells. I think in a patient who clearly is not the car T cell candidate, I may end up using a little more level in a mine and tapas cinema. But first, but I think uh for many situations you can view these as roughly interchangeable and in for patients who are not candidates for cellular therapy. Probably sequential regimens for a lot of those patients. At the moment. To be honest, we really can't stay which if either is is superior. I'd like to move on to the next slide. So this is an interesting study from Canada uh for a long time. And to be honest still we debate the utility of cns prophylaxis in patients with these large B. Cell lymphoma. Um And and we'll get into why we debate that, why we'll still debate that. I think even after this study next slide please. So the C. N. S. I. P. I. Is a good predictor of cns relapses basically the I. P. I. Score with a point added for renal or adrenal involvement. And you can see on the right data from Canada and from the german group. Really super imposible and really showing that patients who have a score of four or higher At the highest risk of cns relapse hovering right around 12% next slide please. We've of course been interested in in cns recurrence and how to prevent it. A number of strategies have been explored. Uh I. T. Chemo really does not have a clear benefit to my mind and I think most publications would support that. Certainly there is a decreased risk of cns relapse in the riTUXimab era. Probably for two reasons. 1 better control of systemic disease and two there is some penetration of riTUXimab into the cns. Um older studies show that the addition of the top aside actually uh may decrease the nsb left rate with that is not borne out in the riTUXimab era. So that was only in the pre riTUXimab era. And then our strategy for the most part for cns prophylaxis has been to utilize high dose methotrexate which may decrease the industry laughs. Although you can see in the in the study that cited the cns Relaxed rate with methotrexate historically is about 3%. You can see with our chop, it's about 4%. So I'm not sure there is as much daylight against a ballot necessarily head to head comparison, but if there was a benefit doesn't seem to be tremendous. Excellent. So in that context, the Alberta group, a fairly nice study with the limitations of a retrospective study in the province. They had fairly uniform guidelines for who would or would not receive cns prophylaxis patients of the cNS I. P. I scored four or higher receive prophylactic at the track state. The guidelines were a little bit different from 2012 to 2015 were basically patients with uh I. P. I square three or higher would get uh cns prophylaxis patients of double hit lymphoma and testicular lymphoma also received methotrexate prophylaxis. Whereas patients had a high P score or double hit lymphoma either received intensive chemo, immunotherapy is the regiments more aggressive than our shop or were consolidated with autologous transfer. That's fine. So of course the objective was to see if prophylaxis mattered. Key inclusion criteria. So these are patients are 18 to 70 years old, treated between 2012 and 2019 70. Once you get above 70, it does become a little more challenging to give high dose systemic methotrexate. So I think this was a reasonable age cut off next time. So they identified 906 diffuse large B cell lymphoma patients treated in the province. During the time frame reference median age is 59 which is younger than the usual dl BCL population. But also that's because the age cut off was the 70 median follow up was about three years. Which is pretty good within within this overall study population of 906 patients, they identified 326, about a third who met the Alberto and form a group high risk criteria for cns recurrence. Uh About about a third or roughly overlapping group had a C. N. S. I. P. Score for hire with the rest having either double hit lymphoma or a very small percentage with testicular involvement with is a lymphoma next time. So here's um you know here's where I think some of the problem comes in with interpreting this data. And it's just the nature of retrospective studies. There are 326 high risk patients Of whom 115 roughly a third received high dose methotrexate. And not surprisingly, those tended to be slightly younger patients with higher risk disease of multiple extra nodal sites, renal and adrenal involvement or double hit lymphoma. The one of the problems to me comes in the bottom group. Uh in that for most of those patients we don't know why they didn't receive high dose methotrexate that's obviously a con founder. Uh The other thing you could identify in the top group is you know the standard plan or the intended plan was for these patients generally to receive three cycles of high dose at the trixie. You can see here that the median was too. But certainly if you're not receiving the full intended therapy that could diminish the efficacy of eric next slide please. So here's what they derived as a recurrence risk based upon the I. P. I. Score in their patient population. It's really super imposible over prior data from another group in Canada and from the german group where patients with the C. N. S. I. P. I. For higher overall had about a 12% chance of cns recurrent next line. So the overall risk for all 906 patients was 6%, again very comparable to what we saw in the preliminary data. On average, the cns recurrence happened within about six months seven months of diagnosis, which is super imposible with other data. Again reflective of other data sets. Most recurrences. Either parent camel, we're both paranormal and left them in a jail with comparatively fewer isolated, left them in a deal relapses, which is probably why intra fecal methotrexate datas or in tropical chemotherapy is of limited utility for prophylaxis. And again, not surprisingly, the median survival after relapse was four. Next slide please risk factors for relapse. Again, everything that's been seen in prior studies at high risk by the LG criteria which largely translates to a high density testicular involvement, uh double hip coma. All those uh either significant predictors are strongly trended towards now. Here's where the rubber hits the road. In terms of did prophylaxis matter? You know? The short answer is no. So patients receive prophylactic titles. methotrexate had the same risk of recurrence as those who did not. If you look at those who received intensive chemo immunotherapy or consolidation with auto transplant individually, those did not impact risk, pull those together and there was a trend towards decreased risk of cns recurrence began only a trend next line. Uh multi variable analysis for progression free survival and overall survival, administering prophylactic high dose methotrexate did not influence uh progression free or overall survival. Um intensive chemo immunotherapy did not affect uh PFS for os consolidation with a dog is transplant has been shown in other studies to improve progression free survival but not overall survival. Um In this study again, retrospective consolidation with auto transplant and high risk populations did show improved overall survival. I think there's enough other studies that have not shown that this is really not practice changing. I think the interesting point of discussion in this trial is the influence of prophylactic method tracks next slide please. So you know the data for this trial and risk of cns recurrences really super imposible from other data sets and um administration of high dose methotrexate did not seem to decrease the risk of the NFL current. Again I highlighted some of the shortcomings. It's a retrospective analysis. We don't know why the two thirds of high risk patients who didn't receive high dose methotrexate failed to receive high dose methotrexate. So all those things are confound ear's and I think how you interpret this trial really is influenced by your bias going into the trial. If your bias was prophylaxis is not helpful, you can certainly use that. You use the results of this study to reinforce this bias. If you think prophylaxis is helpful, you can say, well retrospective study, you know, the consequences of cns recurrence are devastating. It's hard to withhold that based upon retrospective data personally, my feeling is in most settings. I I don't think we're doing a whole lot of benefit with cns prophylaxis. I think there are some exceptions. You know, Burkitt lymphoma. Obviously it's not included in this patients with testicular involvement with aggressive lymphomas. I do think need and thats prophylaxis. And I still I think would continue to favour prophylaxis in the high risk double hit lymphomas. But and really think for most of these patients who don't fall in those categories, prophylaxis is not a benefit. And I think personally I'll be more comfortable pulling back from prophylaxis based upon this data as imperfect as it is. But I think there's going to continue to be a lot of debate in the field and I think people still may remain relatively entrenched in their prior practice, interesting grist for the mill, so to speak. And I thought a very well done an interesting retrospective study. We're not going to move on from there uh to new agents and B cell lymphoma. And if I could have the next slide, so odra next the mob is uh C B 20 C B three by specific antibody. There are a number of by specific antibody presentations and I list them at the end of this section, I picked this one largely because he participated in the trial. If you closely look at the data from all these presentations, there's very little daylight I think between the The four lead TV 20 CB three by specific antibodies that are in development. They all have reasonably comparable efficacy and tolerable. Itty as far as I can discern. Next slide please. So I'm not gonna dwell too long on the structure by specifics. Again the idea is to engage a T cell long in this case with a D. Cell and induce a sighted toxic response of the T cell against these. Excellent This current study there is uh an initial split those days and weeks, one in in week two trying to mitigate some of the toxicities. Vice antibodies notably CRS and to an extent neurological syndromes. those thing of this particular agent is weekly for 12 weeks and then continued on every two weeks until disease progression or discontinuation. And patients who are eligible for this study I had to receive prior I had to have cd 20 positive. Uh Relapse refractory B cell lymphoma And had to have been treated with prior anti CD 20 antibiotic there. Next one. I'm not going to read this slide to you I think you know you can certainly review it. Um if you choose but surprise it to say This was a fairly poor risk patient population. Most almost 60% had diffuse large B cell lymphoma. Though there were other histology is included. About a third ahead prior cellular therapy, carty seller transplant, 80% were refractory Their last line of therapy and about 80% were refractory to f. i. c. 20 antibody based there. Next slide please. So in terms of adverse events of special interests um you can see the incidents of Significant Grade three or higher cytokine release syndrome was quite low except in the other B cell lymphoma category. Again very small numbers. But Great Priest Crs is 20%. Which is interesting. You know when you think about the higher incidents of Adverse reactions in marginal zone lymphoma in the Zuma five trial in terms of neurologic toxicity, the incident was quite low a couple of percent basically. And there was essentially no license syndromes overall fairly favorable toxicity profile. Next slide please. Uh in terms of efficacy. Again, these numbers are small uh certainly not as large A dataset as we saw amazon A to Z mob last year and B cell malignancies. Uh but they are encouraging so their response trade in particular lymphoma was 90% with 70% cr and uh the median duration of complete response in particular has not been reached. And you can see you know there are a handful of patients who are a number of years out still in complete remission. Which namely encouraged. Next slide, please if we look at a large cell lymphoma patients who had not received prior car T cells Against all numbers. Uh, Very small numbers, but the overall response rate 55% essentially all complete responses. Again with some of them durable lasting a year or longer proof of concept. Certainly that this strategy can be effective in this basic population support what we saw last year and even this year with data and other 53 DB 20 by specific next one. Certainly the post car relapses remain a problem. Uh you know, with an aggressive lymphomas and And not surprisingly, the response rate here was lower as about 33%,, 20% crs. But a couple of those um responses are quite durable and approaching two years in duration. So overall, um, if I could have the next slide please, I thought, and and you know, I think we continue to believe that this strategy is is quite promising. A single agent activity. Look good in this data set, favorable safety profile that the drug is continuing To be developed in a Phase two trial that could serve as a registration trial data looks good and it's being studied in combination with other therapies, chemo and and non chemo based options. And if we could go to the next slide as I mentioned, there certainly are other By specifics and development. These all targets C3 and CD 20. I gave you the abstracts here but essentially as I mentioned, the data look pretty comparable and many of these um particularly Messina Tuesday man are moving along quite rapidly and development uh both as a handle on therapies and particularly in the case of I was in a Tuesday mab as part of up front chemo immunotherapy for large cell lymphoma. So I think this is a class of agents to keep your eye on. I think at least one of these, if not multiple, might be entering the clinic in the relatively near future. The next abstract I thought it was very interesting to me. This was the most interesting new molecule that I saw at ash comparatively new. So this is V. L. S. 101 which is an antibody drug. Conjugate that targets roar one next one. The Roar one is uh uncle fetal protein that's important and embryonic development uh importantly for our purposes. Anyway it's expressed on both pharmacologic and solid tumors but not a normal post fetal tissue. Makes a very good target for anti neo plastic therapy. And the L. S. 101 is an abc that targets your one is conjugated to M. M. A. E. Which is the talks that we've seen Widged used another 80 CS. This trial included a fairly broad population of patients with T cell lymphomas. I'm gonna end up focusing on the data and mantle cell in large cell lymphoma. The median age was 70's has trended towards an older population. About a third. It had prior cellular therapy and the median number of prior therapies was four. So pretty heavily pre treated population neutropenia. Not surprisingly, it was one of the major acute toxicities that happens with mm maybe based therapies as does neuropathy. Uh diarrhea. A great three apparent about 9%. Little bit unanticipated. We don't usually see that with M. M. A. E. So it may be some unanticipated effect of the antibody itself and that's being investigated further and there were no infusion reactions to date which is encouraging certainly for a monoclonal antibody based therapy in terms of efficacy. Again, small numbers so I don't want to overstate this, but I was impressed by these small numbers in mantle cell lymphoma. Again, in a heavily pre treated patient population, the response rate was about 50% with to see ours. And again only five patients. But in a heavily pre treated The fuse large b cell lymphoma patient population, four out of five patients did respond. And some of those responses have been quite durable. So obviously very early data, but some of the early compounds that were at ash. This is one that caught my eye and I think certainly is worth monitoring going forward and certainly showed some progress promised both in terms of efficacy uh and tolerable. Itty. I'm sure you heard from Matt David earlier today about locks 0305 in Cll. I wanted to highlight some of the data from this abstract. I'm going to highlight mostly mantle cell lymphoma, although um the data look pretty good in Walden streams macro global anemia as well. Next slide please. So Loco is a non Covalin B T K inhibitor. Unlike the current commercially available BDK inhibitors, Vaillant inhibitors. Now we do know that patients with mantle cell lymphoma who relapse after do not respond to be TK inhibitors have a poor prognosis is currently an area of unmet medical need. Next slide please. The bruin trial uh was a Phase 12 trial with an initial dose escalation followed by a standard dose expansion. And I'm sure matt talked about the CLL arm, We'll focus on some of the middle histology is again particularly mantle cell lymphoma. So there is 61 patients with mantle cell lymphoma included on this trial and we'll see some of their characteristics on the next slide. So in particular in the mantle cell cohort, 93% of patients that had prior B. T. K inhibitor therapy, you look down in the bottom row, About 77% of patients and progressive disease and prior BTK inhibitor therapy, these are mostly B T K inhibitor resistant patients. The safety profile look quite good. Again, it's 60 patients, but this also bore out the larger patient cohort in the CLL cohort, particularly these toxicities of interest of a 50 K inhibitors, hemorrhage and atrial fibrillation seems to be a very low incidence in low severity using this agent. So, um, that certainly is encouraging in and of itself. But on the next slide we'll look at additional encouraging data on the efficacy of this drug. So in the dark blue lines are responses in patients who are progress then prior BDK inhibitor therapy, Light Blue is a group of patients who discontinued B. T. K. Inhibitors because of toxicity. And you can see that in the patient population as a whole. And in the B. T. K pre treated patients The response rate was right around 50% with about 25% complete responses. So that's let me really, really good considering that three quarters of patients who had had prior B. T. K. Inhibitor therapy were progressing on that therapy at the time of this trial. Um small groups of patients who had transplanted car T cells were included and had similarly encouraging response rate. So this this drug I think is quite promising and mantle cell lymphoma sticking with the theme of mantle cell lymphoma. I just wanted to touch briefly on car T cell therapy and sample. So this was the next slide, please. The transcend. NHL 001 study with Lissa cell. Ah An M. C. L. The next slide will will give a brief overview of the design. Again fairly straightforward. Uh Standard limbo depletion of madeira means cyclophosphamide followed by car T. Treatment. Patients tend to have at least few prior lines of therapy including a. B. T. K. Calculating Agent and Anti CD 20 therapy and prior transplant was allowed next time again. I'm not going to read this to you. Just shows that these were poor risk patient population, fairly high number of patients with elevated seven The 53 mutation. Um And you know, median of three prior therapies so consistent. What we see in another car T cell population. Next slide please. Um I think the most important finding of this study was the very low incidence of grade three crs and neurologic events. So you can see 3%. Grade three. The RS 4%. Grade three I'm sorry. 12.5% Grade three neurologic events below is the data for Brexit Captain Jean which currently approved as a car t product from relax mantle cell lymphoma. And you can see that although again not a head to head comparison to see our estimates and and neurologic events much higher. Next slide please Again, looking at the efficacy of the overall response rate was 84%. With 66% of those being complete. Response rates compares favorably. But the Brexit Captain Jean Data 93%. Overall response rate 7% cr next time. So this is clearly an effective product to me. I think there is a strong signal that it has less toxicity than Brexit Captain jean. Again with all the caveats of it not being a head to head comparison. But I think this is certainly data to keep an eye on and could be another car t product on the horizon her mantle cell lymphoma. Again, I don't think it's any more efficacious but it may have a more favorable ah toxicity profile. Move on to Hodgkin lymphoma. Where the next slide, I'll show that to abstracts one was embolism ebb and DVD of salvage. And the third let me start. The second was a drug caMA daniel lab to searing which just called CAMI for short ah and relapse refractory disease. This phase two trial of Pembroke and DVD was led by Alison Moskowitz. Um and we'll give some brief introduction to it on the next slide. So we do know that pre transplant. Pet status is the best predictor of post transplant outcomes of patients who are negative going into transplant generally have very good outcomes post transplant. So that's a meaningful endpoint in salvage therapy and in hodgkin lymphoma. Next slide please. The summary of quote unquote modern second line regimens are basically chemotherapy in combination with either breast tuck, Sagamore checkpoint inhibitors and you can see highlighted in orange. The percentage of patients are negative regimens changes Typically around 70%, sometimes as high as 80. Next slide please. And in that context, you know, we'll take a look at the Pembroke GpD trial. GVG is a very well tolerated salvage regimen. It can easily be administered as an outpatient and it has potential advantages over some of the other chemotherapy backbones used in the other trials that I highlighted. Here's the treatment scheme before the trial. So two cycles of standard DVD with TIM bro added restaging it cycle too. But the option to go to transplant after two cycles. If there's a cr or continue an additional two cycles restage and then go to transplant. If there's a cr next slide please, you can see that these are high risk patients. Again, I'm not going to belabor the point but they were at first recurrence but they were very high risk with advanced stage disease, extra nodal disease. Uh Either refractory or early recurrence after primary therapy toxicity profile is quite favorable. As I mentioned, DVD is a fairly easy regimen, notably there are no pulmonary events which is a potential concern when combining jump side of being which can be a pulmonary talks one inhibitor, but there was no signal of that here And then efficacy really was astounding. I thought so, 95% er rate. Uh and all those patients going on to transplant a plant Again, small number of patients but 95% is pretty darn good for a well tolerated regimen. Are we ready to switch standard of care just now? Probably not but certainly worthy of further study. And on the next side to finish up this abstract think we'll see what's probably the most interesting finding or an interesting path forward is Cantley eliminate transplant in this patient population. Has never been a randomized trial that showed an overall survival advantage. With transplanted, relaxed Hodgkins certainly would be nice to avoid transplant in that patient population. So this portion of the study will look at at doing that avoiding transplant and using temporal is um neither the the last uh Studying Hodgkin's is this Phase two study of commie uh and and heavily pre treated patients with relapsed or refractory disease. Next slide please. So commie as an anti cd 25 monoclonal antibody of the PBD warheads, so to speak or toxin used in other A. D. C. S. And the idea is to induce direct by the toxicity but also induce an effect on the immune micro environment next time. So this was a single arm study. The Prior Phase One experience was actually halted At the time because of 6% incidence of beyond Berets syndrome. This page, this was a phase two Essentially expansion of that prior Phase one with careful monitoring for any neurologic toxicity. These were heavily pre treated patients, all of whom are required to have had Or almost all of whom had had prior Brent Tucks a mob and PD one blockade and to mitigate some of the toxicity. The patients started with a 45 microgram per kilogram dose for the first two cycles but then were de escalated to 30 micrograms per kilogram going forward. The intention was to treat for up to a year of the patients. Could continue therapy if they were benefiting, Not going to read you the patient characteristics. I think the important one is almost 100% of these patients. It had prior brand Toxin, Abdomen PDF one therapy, The median number of prior therapies with seven. So certainly heavily pre treated, including a high percentage had prior autologous and even a few and an L. A. Genetic transfer. The overall response rate. I thought it was quite astounding was 83%, with almost 40% of patients having a complete response is really remarkable and heavily pre treated asian population. Of course, the concern going into this trial was that possibility of Gillian barre syndrome because that was observed in the prior trial. and again in this brow there was a 6% incidence of of DeAndre, some of which is still ongoing, which to me at least is somewhat of a dilemma. You know, this is a patient population really does not have great options left. Uh To me, the response rates with this agent. Uh we're really quite astounding. So I think it comes down to a discussion or decision and whether you can tolerate some degree of uh you know, a small chance but a chance of a significant toxicity uh while trying to derive but otherwise is a substantial benefit from this agent personally. I think in the right patient population, this drug makes sense. But it will be interesting from from a regulatory perspective going forward and my particular interest is T cell lymphoma. And I always feel like if these updates, I give all the exciting things and B cell lymphomas. And then if you're familiar with the Disney movie inside out, that's less who represents sadness on the left? Because I feel like each year, unfortunately this seems like sadness and T cell lymphoma. I'm not going to show the abstract. I think the top one is sad. The bottom one is not. There was a final analysis of the randomized trial of Roma depths and chopped versus chop and patients with Ptcl and like so many trials before it. Unfortunately there is no benefit with adding Roma depths into chops. The for most patients as dissatisfied as we are chopped remains the standard for front line therapy. There was a five year update of the echelon to trial which randomization chop or CHD Brent tucks them really just reinforce the notion that CHP brand tucks a mob me is the clearest standard of care for and a plastic large cell lymphoma. Unfortunately I really didn't do anything to resolve. One of the major controversies which is what's the utility of CHP friend tux amount and histology is outside of LCL. There's no as of yet no demonstrable benefit with adding Brent tucked in cabin that patient population. The numbers just aren't big enough to really discern whether or not there's a benefit. There's the toxicity. The long term toxicity seems to be about the same. The initial increase in neuropathy of Brent Taksim and resolves over time. Uh Me personally I still continue to treat most non LCL histology is with Top or show up but certainly reasonable if patients have speedy 30 positive disease. The treat was CHP brand Taksim. Um It's just an area of controversy within the field. Hopefully ah someday we'll we'll have a little more data in patients with non LCL subtypes. So with that wrap up with joy from inside out thank and uh and my colleague jennifer crom being Karen Jacobson who are as well as the study, investigators were kind enough to provide slides for this presentation and I know that was a lot to cover. I appreciate your attention, thanks. Eric That was an outstanding overview of a lot of data but some very interesting um studies we have probably time for one or two questions. Um Not surprisingly, we got a couple of questions about cns prophylaxis. Would you consider liver involvement uh a number of extra nodal sites as the N. C. I. Has suggested. Um And then what would you do for high grade B cell lymphoma? I think making the distinction between if you start to b cell lymphoma, would you give cns prophylaxis to that subgroup of patients? Yeah I uh taking the first question I I really tend to follow the C. N. S. I. P. I. So if you know and certainly if you have liver involvement it's it's likely you're gonna end up having a high C. N. S. I. P. I. Score and get cns prophylaxis. But I don't necessarily prophylaxis just for you know if a patient happens to have isolated liver involvement or liver involvement and doesn't have a high risk score on the C. N. S. I. P. I. The second question and high grade B cell lymphomas. I think we really don't know. But I my practice I think will be to continue to the profile acts those patients and you know they do worry about them more. I don't know if we're doing if we're helping them by profile asking them but any time we worry more about patients we try to to try to do more for them. And then last question which is an important one. How would you sequence for a relapse patient for whom you might consider carty? How do you sequence Polar half a How do you think about that patients there? I mentioned there's some pre clinical data on a little bit of clinical data showing that tap. It doesn't seem to adversely affect party responses but it's not a ton of data and I do still worry about it. Again I don't know if that's justified or not. Ah If someone is is a car T candidate I usually start with with polytheism, a based therapy. Um You know if I'm choosing between one of those two regiments um if someone is not a car T candidate then then I think there's a good likelihood I would start with Len Tafa. Um that follow up a little bit longer. There certainly are some very durable responses. But um you know in the non carty population I think you could probably sequence them however you want but in the car T population I did preferentially use Ebola based there. I just didn't add on to that. Do you worry about giving bend a must in before trying to collect carty? I do and that's what I usually don't give the bend a part of it. So I usually give reduction, pull the tooth mm. Bend the mustang clearly affects T cells. You do see opportunistic infections sometimes after bending mustangs. Yes I skip the vendor must in part of it when we're using a pre carty's right and then maybe there was one quick last question about should high risk patients be considered for auto and first remission to reduce risk of cns relapse. Uh if you you kind of cherry pick from that Canadian data they said I would use it probably not not to profile as people of methotrexate a lot. You know, looking at the whole study you would say should consider it to decrease the chance of CNS occurrence. But um you know, there's lots of studies of upfront transplant and large cell lymphoma and including a large meta analysis really they have not shown and overall benefits. So I I do not transplant the patient. 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