Samuel Ng, MD, PhD, gives updates on the management of Peripheral T-cell lymphomas.
a colleague of mine from Dana Farber um Dr Samuel ng um instructor of medicine at Harvard Medical School will talk to us about uh T cell lymphoma. Thank you Austin. Um Let me just be sure I get this going. Um So yeah so so uh thank you. Uh As Austin said I'm an instructor. I have both a clinical and research interest in T cell lymphoma. Um And I'm gonna tell you a little bit of a case based by no means comprehensive um sort of overview of some interesting advances if you can call it that in T cell lymphoma that have made over the last several years. Um Just getting over the formalities. Um I have no conflicts of interest to declare myself but I will be discussing off label use in this talk of crescent romy depths and oral a society Indeed as well as do Felicity in combination of the roman depths and I'll also be discussing some interesting clinical trial results that come about with the Easy H. One and H. Two inhibitor of Alameda stat. Um So just to get this out of the way um the most uh distributed slide in T cell lymphoma. Um I will particularly be discussing um the major types of peripheral T cell lymphoma. So that's an a plastic large cell lymphoma that is everyone out there knows comes in generally an anti plastic lymphoma, chinese positive and negative flavor. Also peripheral T cell lymphoma. Not otherwise specified. P. T. Cell N. O. S. Essentially a waste basket term for T cell lymphomas that don't really fit any other category. Um and angio immuno plastic T cell lymphoma whose cell of origin is the follicular helper T cell which supports uh germinal center B. Cell development and proliferation. Um So these uh kind of three general main entities combined as you can see here in the international peripheral T cell and NK. Uh the lymphoma cell lymphoma study comprised the majority of cases that we're seeing both in the study and I think generally worldwide. Um so diving right into the case, this is a patient that I met a few years ago at the time she was 29 years old, 14 months earlier, she had presented to the Faulkner Hospital with left lower quadrant pain. Um had a cat scan in the emergency department that showed pelvic and retro peritoneal a Ganapathy she got admitted uh and got the academic hospital work up. Uh that was negative for most infectious disorder. She did have a low tighter a DNA but no other positive radiologic studies or frankly symptoms. She was empirically treated for lymphatic notice the the public, you know, basically inguinal nodal pain primarily and discharged over time. Uh the the pain resolved, she continued to be followed and while there might have been some minor mild subjective reduction in the size, it never completely uh particularly inguinal lymph node, It never particularly resolved. Um Ultimately, about a year after her initial presentation, the decision was finally made to go ahead and biopsy this thing. Um and it revealed all positive and a plastic large cell lymphoma one mildly complicating factor was the fact that she was in her second trimester of pregnancy um at the time that this diagnosis was made uh and then showed up in my office uh in my clinic room about a week or two later. Um At the time I referred her for M. R. I. Staging. It reveals stability of the pelvic and RP Adan apathy. So, the question of what to do at this point was a very salient one. Before we go further into kind of details of the case, um just wanted to go over the subtypes of systemic anaplastic large cell lymphoma. So, as you all know that they're defined by expression of the strong expression of the cd 30 protein. Um you know, at this point, no one really diagnosis ALk positive A. L. C. L. With fish because there's very strong concordance of hC detection with more molecular uh sorts of means of detecting it. You can see here from this very nice slide, including review from the Vancouver group. Um and the stark difference between al positive and negative subtypes a little bit more recently, uh the the mayo pathology group published that within out negative A. L. C. L. So, so excluding the positives, there were a further couple of uh structural variants that were detected uh in both cases rearrangements, you can see up here in blue a dust 22 I. R. F four rearrangement that is detected on chromosome six. Uh And in the green on these Kaplan meier occurs a tp 63 generally TBL are one XR one rearrangement that's detected on chromosome three. Um And the interesting thing about these, as you can see here is that the presence of these uh structural variants is associated with prognostic prognostic information. Where the Dust 22 seems to provide an overall favorable prognosis that's comparable to out positive A. L. C. L. Well, um T P C S TP 63 rearranged. A LLL has a very negative prognostic implication. Um The Dust 22 doing better than uh cl CLS that carried neither rearrangement and tp 63 doing worse. Uh And very interestingly, you can see in panel C here from the publication that um in patients that were not transplanted, just 22 seem to do just about as well as a positive LCL. So anyway, turning back to the case kind of what to do uh within within a L. C. L. And I think most of you out there are aware of the kind of landmark at least for t cell lymphoma clinical trial. The echelon to trial that tested the addition of Brent Taksim mob To a chop like backbone in this case. BB chip dropping of in Christine due to peripheral neuropathy considerations. Uh in this trial, more than 400 patients were randomized in a 1 to 1 uh ratio um 75% of the enrollees were systemic anaplastic large cell lymphoma. The other way you can look at is that 25% were not just to include those patients in this analysis recently the five years, the long term follow up of this trial was was presented at ash and shortly thereafter published. Um and it basically shows that for all comers, the progression for your survival benefit that that had been established is maintained um with the hazard ratio of 0.7 and very strong significance. Uh and the overall survival benefit was just which is what kind of blew everybody away initially back in 2000 and 18, I believe is continues to be maintained with long term follow up. Um The toxicities that we're seeing in this trial are those that I think everybody who has used Brent toxin math, particularly for Hodgkin's lymphoma likely uh is our familiar with many human logic toxicities as well as peripheral neuropathy, substantial number uh a decent number of grade three uh which sometimes limits the ability to give the full dose. Um In in this case itself, one of the issues, the salient issues um is the fact that Brent proxima B is a category X. Um in pregnancy and we'll talk about that injustice further in just a little second. Um here I skipped ahead to um the subgroup analysis from the long term follow up data from echelon to ignore the top for now we'll get to it but we'll get to the other subtypes later. But in uh systemic anaplastic large cell lymphoma, you can see both the progression free survival benefit as well as the overall uh and to a lesser degree the overall survival benefit was seen most strongly in systemic LCL. Perhaps not surprisingly. Uh And uh salient to our case and the positive there really did seem to be quite a substantial benefit with the addition of Brent Taksim ad. Um And so with Brent Taksim um as a Category X. Drug um you know, just kind of had to swallow hard because you couldn't in the second trimester, we weren't gonna be able to give it any time soon. Uh As many of you out there no chop can be given and has been demonstrated to be safely given during pregnancy, the 2nd and 3rd trimesters. Um But so the question was do we wait to deliver or or do we think about um starting with chopped now? I think one of the salient issues was, well if we um uh you know wait if we wait and then burn front Taksim at, you know, what are the kind of the salvage options afterwards? Um I uh So without positive A LCL, especially with an out positive solid tumor malignancies that many of you out there are aware of. Um you know why not try that in A. L. C. L. Uh the best kind of published data that we have comes from pediatric cohorts. Uh you can see here that in one of the cooperative group studies that there's an 80% cr rate with single agent presented at two different doses for just about 26 patients. Um If a patient were to kind of relapse or or be refractory to first line therapy um you know can you salvage them uh and and maintain durable remission with auto transplant? Um This is an older C. I. B. M. TR study uh and focusing in on basically a. L. C. L. Uh There there is a benefit in the majority of patients. Um This benefit was maintained if not shown here but if you exclude um the patients or only include patients excuse me, that are beyond first remission. Um So auto transplant for if you do burn Brent Taksim map does seem to to be an uh an option. Uh And so maybe it was worth waiting to uh for this patient to deliver to give Brent Taksim at. Um One other interesting thing that I wanted to bring up was that in the long term follow up of echelon to there actually were many patients who were treated with Brent Taksim mob in the second line um even after failing BV chip as you can see here and focusing in on the systemic anaplastic large cell lymphoma patients, there's a surprising amount of activity as a single agent. Um And so so it is a possibility if you do have pain patients who relapse after BB chip to give a single agent riTUXimab. Um I think many of you are aware that single agent Pentax ahmad uh in anti plastic large cell lymphoma before the echelon to trial have been demonstrated to have an 86% overall response rate and a complete response rate of greater than 50%. That's both an out positive and negative population. Um The uh you can see here that perhaps in the chopped arm of Beebe of the echelon to trial that the single agent response rate to production mob is lower than the numbers that I just uh noted. Um It's really hard to draw firm conclusions obviously because it's it's small numbers. Uh And and there's no real prospective means of figuring out how patients are gonna be treated in this case also. Um A little bit disappointingly. Uh They did not give the kind of transplant um statuses of these patients before they went on to salvage. Um And so that might have been a complicating factor as well. Um so anyway uh what ultimately happened with this patient um is that I decided to bite the bullet and given the long-term stability of of her um disease decided to wait for her to deliver. She delivered at 37 weeks. She immediately got a pet CT after that showed that the disease was mainly infra diaphragmatic um there was some mild size progression based on M. R. I. Compared to the M. R. I. That that that I had gotten at her initial presentation to me. Um she ultimately completed completed six cycles of the v. Chip. Um She's currently in remission taking care of a healthy two year old daughter and I just heard that she is expecting a second. So I think a good overall. So um I'll move on from there to talk about Um my second case um look covering hopefully the other two subtypes. Um this was a 69 year old lady who had a history of diabetes. She wound up presenting to an emergency department with fever and hypoglycemia. Um there she got a pan scan that didn't really reveal uh the cause of her symptoms but did reveal some small volume diffuse retinopathy. Um She was admitted recovered and was discharged from there um and ultimately proceeded to have an exceptional lymph node biopsy that did show that there was an infiltrate of atypical cd four positive T cells co expressing cd 10. And obviously with the Ashanti results in mind were positive for cd 30. Um in this case um Ybor so E. B. V. Infection was not detected. So this was signed out as peripheral t cell lymphoma best classified as anti R. B. And elastic T. Cell lymphoma. Um Pretty Heggie the hedgehog I think mostly um Turning on the E. V. V. Status. Many of you will know that um depending on the cohort you look at E. B. V. Is detected in 72. Greater than 90% of patients in A. I. T. L. Cohort. Um Anyway um this patient wound up being referred to as a second opinion to me. Um and the question was how do we treat these patients in the front line? Um And I think um one thing one regimen this backbone of chopped that that has been out there has largely been despaired like you know it's 2022. I can't at this point maybe 2018. I can't believe we're still treating patients with with chopped backbones in this age. But I think as many of you know in the T cell lymphoma space it's been really really difficult to show that there's been any benefit with intensification of chop. Um One uh publication that demonstrated maybe some benefit was the octopus. The addition of a tope aside to chop. So this chose regimen whereto beside 100 mg for meter squared is given on days one through three um of treatment. Uh And this uh edition and benefit for in t cell lymphoma was based on an unplanned subgroup analysis of six different trials from the german high grade non hodgkin lymphoma study group that basically showed in their very very uh meticulous analysis uh That there was an event free survival benefit for younger patients. So under 60 and also normal ldh. Um Also somewhat interestingly um the significance of the benefit was was lost if the positive patients were removed from that analysis, although it was something like 600.6 for the p value if memory serves correctly. Um This analysis was further confirmed by a Swedish registry study and show up is Generally given to patients under 60, although if you look at the NCC on guidelines, that clinical trial is the preferred first option, both the front line and in the second line for for most ptcl cases. Other attempts at intensification of treatment in the past. Uh, some of you will remember on tak uh the diphtheria toxin um Conjugated, I'll to uh I'll to agent also camp path anti cd 52 antibody, the notorious AIDS and a bottle. Um these basically a chopped plus on tech um enrolled 49 patients. It did have some activity in the chopped based activity, but there was a 6% ultimately treatment related mortality that really damp enthusiasm for that uh, for chopped plus cam path. After the 1st 20 patients were enrolled, there were two deaths that were deemed as associate associated with um tribunal excuse me to treatment. Um and this trial was halted early. Um, So another disappointing attempt an intensification of chop chop plus lanolin hmeid has been studied more recently um in a cohort of pay of 78 patients in a largely European study, 45. This was little mind at 25 mg added to chop. Um on days one through 14 of treatment. Um and uh was planned eight cycles of chop. 45% of these 78 patients did not wind up completing a full dose intensity full dose treatment. Um And at the time of analysis uh the the cr rate was 41% which did not meet its specified 60 pre specified excuse me, 65% predicted uh hypothesis. Um And so this was essentially a negative trial. Um I think many of you were aware that chopped plus romi dev epson was was being studied as frontline treatment again largely in european patients. This was presented at ash um in 2020 um and published subsequently in the J. C. O. Um And uh to to everyone to the disappointment the investigators and I think too many um t cell lymphoma clinicians. Um This wound up being a negative trial. Again similar to echelon to over 400 patients were enrolled in this trial. Roaming epson at 12 mg uh per meter square was was given um days one and eight of of uh of chopped basically. Um And uh again uh excuse me, this was limited interesting to patients 60-80 years of age um and patients were not allowed to proceed to transplant. Um So really just looking at at the at the effect specifically of roman Dobson plus chop. Um You can see here based on the capital Meier curves that the the pre specified PFS endpoint was not met. Um There was not an overall survival benefit that was shown. There was an exploratory analysis looking at patients with follicular helper T cells, uh T. Cell lymphoma. So A. I. T. L. Plus some of the PTL subgroups um there they did find a significant PFS benefit um Just barely meeting significance. Um uh So you know perhaps that's something that that you could think about giving Roma Dobson in the front, a group of patients you can think about giving them a person in the front line. Too many patients who can't go for transplant. However, you're buying that PFS benefit with an increase of grade four A. S. From 42% to with chopped to 74% with road shop. Um And again so so so not a lot of enthusiasm there I think uh some of you out there are aware that Romeo Jepsen's um FDA indication for peripheral t cell lymphoma was withdrawn as a consequence of this negative trial. Um Unfortunately for patients I would say Romy Dobson remains available based on its label for cutaneous t cell lymphoma, but again, the peripheral T cell lymphoma label is just not there any longer. Um So it might be harder to get it paid for. Um. Ah Anyways. Uh One might ask what about coop Plus Rosemead epson um That was also a studied with the ptcl 13 study that was just presented in december. Again um 86 patients were enrolled with a 18 month PFS of 48%. Um So again, this didn't quite um show any benefit, so we're still stuck here. Many of you out there um would ask, what about B. V. Chip in this population of patients? Um I told you we'd get back to it in just a second. Um You can see here the Kaplan meier curves uh for PFS and Os with the P. T. Cell and ai tl subgroups of the echelon to trial. Um recall that in echelon to uh the path samples had to have greater than 10% CD 30 expression in order to be eligible for this trial. Um and you can see here that um with the BB chip in the green and chop in the blue uh that they're basically was not a benefit for PFS or Os. And interestingly you can see here that chop actually outperformed BV chip for progression free survival in the ai tl subgroup of these patients. Um and you know, chop was I think surprisingly to the investigators associated did with, you know, close to a uh if well over 40% PFS. Long term PFS rate, which is surprising and I think underscores the need to keep in mind that uh there are a subgroup of patients that benefit from chopped, so it's really difficult as much as we disparage it to move on from chopping the frontline for t cell lymphoma because there is going to be, although it's it's it's not nearly the you know the race that we expect to see with other subtypes of aggressive lymphoma. There is a benefit um that that some of these patients derive um from from such treatment. Um So one promising uh strategy that that's been studied at the weill Cornell Medical Center and others with while leading it is the addition of as a sideline to chop. And this was primarily targeted at follicular helper T cell type T cell lymphomas. Many of you out there might know that I know that that tattoo loss of function mutations are highly prevalent in this subgroup of T cell lymphomas. And so you know, the mechanistic rationale for proceeding with this sort of combination was that if you have a hyperventilating agent uh that will be treating diseases that have strong arrangements in DNA methylation that there might be some synergy there. So in this trial um oral is decided in C c. 4 86 and 300 mg daily was given to patients as kind of a seven day leading before the cycle one of chop. Uh Subsequently for cycles two through five additional 14 days was given starting at day eight. Um and this was given for six total cycles. Um The when this was initially presented at ash 2020 there was very short term follow up but there was a 75% complete response rate for all the valuable valuable patients I guess there was some ptcl mOS is like a couple of them that stuck onto there that we're not like a helper T cell lymphoma subtype. Because if you look at the T. F. H. Lymphoma subtype, it's 88%. Overall. The grade three toxicities are kind of what you would expect for the combination of chopped plus this agent, mainly human logic and infectious. Um and then in Ash 2021 just a few months ago, um the PFS uh the the uh longer term PFS and OS benefits were presented. Um you can see here that while it wasn't, you know, the greater than 80% that was initially presented for for PFS among the T. F. H. Um subgroup, that's still 70% PFS that two years is nothing really to sneeze at. We'll see if that still holds up in in later term follow up. But overall I think this is kind of an encouraging strategy for for patients with T. F. H. Type lymphomas and kind of would fit for this patient. Um And in fact I actually recommended at the time when I saw this patient that she considered going down to new york to see if if this is something she could do, but ultimately she decided not to do that. Um So what she did decide to do was actually to go on show up despite, you know, some of the uh things that despite the limitations for age that that the german high grade non hodgkin lymphoma study talked about. Well she completed six cycles of coop. Um And um when she was being worked up for um a transplant uh we did uh the we did her her pet ct analysis which showed unfortunately F. D. G. Avid nodes in the neck and upper media steinem. Ultimately these were exceptionally biopsied and showed unfortunately evidence of refractory disease. A bone marrow biopsy at that time also showed a very small population of atypical cells that was consistent with with ongoing disease. Um So what to do at this point um one uh interesting sort of more novel strategy to to treat this patient would be um looking at at the combination of doom elicit which is a. P. I. Three kinda gamma delta inhibitor. Uh In this trial given at 75 mg B. I. D. Um And and giving that in combination with the roasted epson. Uh They won in 15 of the 28 day cycle um at 10 mg per meter squared. Um Initially this combination trial was opened with two arms, one with Romi Dobson Dude illicit. Also one with melissa and for testament for hdX experienced patients um Ultimately encouraging results were seen with the Doobie romy combination um And this uh continued with a with a dose expansion cohort or excuse me? With an expansion cohort. Um And in this expansion cohort. Some patients these patients were given a seven day lead in with Felicity. Um before romy Dobson was initiated. Um And in in this combination again there's there's very encouraging activity that's seen particularly in A. I. T. L. You can see here a 71% of the world's response rate of 65% cr rate. There's still also his activity. And kind of the non T. F. H. P. T. Cell N. O. S albeit at slightly lower rates 47% and 29%. Um The numbers are smaller for the other subtypes so I won't really get into those. Um I think what's really encouraging about this or what's interesting about this anyway is that the combination of roman Jepson with melissa perhaps tamps down some of the toxicities that you might otherwise expect with P. I. Three chinese inhibition. Uh There's actually a decrease compared to just looking at at those patients with the with the lead in of dualism alone of trans am races as well as diarrhea. So that this combination seems not only to perhaps be improving efficacy but maybe decreasing toxicity. Or if someone's a real skeptic perhaps saying that um the ability to maintain intensity of the P. I. Three chinese inhibition because of roman might allow you to to see some of those outcomes. Um So uh that that's one more novel strategy. Uh that that's out there. Um not quite uh that that hopefully will make its way into the guidelines although it has not yet um the another uh promising agent I wanted to discuss this kalamata stat. Again, given the epigenetic abnormalities that you would see with tattoo mutated disease. Vala metastatic uh which is an easy H one N. E C H two inhibitor was initially uh tested in japan by Daiichi. Um you can see here their dose escalation cohort. Ultimately the recommended phase two dose landed at 200 mg daily. Uh and this was given to further cohort of patients both in Japan and the United States. Um looking further at um um results that were presented at the IAA last year, you can see that there is um encouraging activity that was seen particularly in an area of elastic T. Cell lymphoma. Um here with the cr rate of close to 50% as a single agent. Again with P. T. C. L. N. O. S. A more modest response rate but still activity there with a T. Uh with A. T. L. There actually is some uh responses as well in a disease subtype that needs a lot of attention of help overall. But we won't get further into that at this point. Um looking at the toxicities that you see with Kalamata stat. One of the interesting things that that one can see is that there is thrown aside a pina that develops in basically the majority of patients and many of them reaching grade three. Um The really interesting thing about this is that it occurs within the first two weeks of the media that was reported in this uh presentation. Was that about 12 days. Um However, without further modification of the dose uh you know, with ongoing treatment, the platelet counts generally recover uh with with after a few more weeks. Um So so um the marrow seems to to adapt to the presence of th one and th two inhibition. Uh similar sort of similar phenomena are kind of scene with anemia as well as um leukemias as well. Overall, this drug is very very well tolerated. Um So ultimately this patient wound up going on the Kalamata step trial, she completed for 28 day cycles, achieved a cr um She moved on to a rick uh rick uh matched related donor allo transplant and she remains a remission two years later. Um And so that's kind of what I have, thank you for your attention. Um These are perhaps two of my ptcl patients, the only two that are still alive. Um No, just kidding about that, but but you know, I think it's reflective overall um of what's going on. Um Thank you guys, thank you so much sam for an excellent presentation. Um It's 906 maybe I don't see any questions right now. Maybe I'll just ask a quick question because I wasn't aware of the friend Taksim ab data like treating after someone has progressed on BB chip, I think that is um really interesting, kind of surprising actually. Um. Yeah. Yeah no I I agree. You know I mean you wouldn't you wouldn't expect it but for systemic anaplastic large cell lymphoma um there is data out there um from from the lab that these diseases are addicted to the ongoing expression of Cd 30. Um So from that mechanistic standpoint, you know if they've got to have it it's going to be there and you can still target it. So the mechanism of resistance might be different than just playing loss of the other receptor, which obviously would be the easiest way.
