Welcome to The Lymphoma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Stephen Ansell and Graham Collins, who debate key topics in the treatment of lymphoma from the ASH 2020 virtual Annual Meeting.
The topics of discussion include the latest updates in targeted therapies for lymphoma as well as the management of Hodgkin lymphoma and Non-Hodgkin lymphoma including central nervous system (CNS) lymphoma, follicular lymphoma and T-cell lymphoma.
“And I think what really, I think is becoming more clear now, which perhaps we didn’t have clarity on before, is how these agents are optimally delivered, particularly in terms of reducing CRS, cytokine release syndrome. And also we’re starting to see some durability data now as well, and the responses and durability at decent doses. Because there’s quite understandably been dose-finding studies and it’s quite hard to interpret the response rates when you’re at low doses like that. And I was actually really struck. I’d be interested to get your thoughts Steve, but I was really struck by the consistency in the response rates in diffuse large B.”
– Graham Collins
CNS lymphoma & follicular lymphoma
“I think the thing that for me was very interesting is, are we going to see that tail on the curve, because we end up seeing patients with follicular or low-grade lymphomas that are cured with CAR T-cells. I think that’s going to be a total game changer, because we’ve always been a little hesitant of allo-transplants in these patients, because of the long-term, graft versus host disease and those sorts of problems. But, now if a CAR T-cell with its attendant problems and again, your selection comments are well taken. But if we suddenly now see that we actually have a subset of patients who are potentially cured, I think that may change our algorithm for treating follicular lymphoma patients look.”
– Stephen Ansell
“I’ve always been slightly surprised by the duvelisib data. It’s been quite good really. . . . A PI3 kinase is an important enzyme in T-cells as well as in B-cells. So perhaps it’s not that surprising that we are seeing with the duvelisib’s of data around 50% sort of response rates, which in relapsed T-cell lymphoma is good. I guess the caution is, there’s a number of agents we’ve seen reasonable Phase II data on which when you take two larger Phase III studies have failed to show improvement. So I think, yes, absolutely I think it’s a green light to develop this drug further. And I think we will see it develop further, but I’m open-minded I think, as to where we’ll be in five years time with it though.”
– Graham Collins
Hodgkin lymphoma & final remarks
“Speaking of immune-related effects, there was obviously other data which was in the post-transplant kind of consolidation space, similar to what brentuximab vedotin tested in the AETHERA study. Now it was brentuximab vedotin plus nivolumab, in that space. That was interesting because there’s been some data on pembrolizumab, if I remember correctly in that space as a kind of a consolidation. And all of those results look quite interesting and promising.”
– Stephen Ansell
Stephen Ansell: Well, welcome everybody. Thank you very much for joining us. My name is Stephen Ansell. I am from Mayo Clinic. I’m delighted to be joined by Dr. Graham Collins, who is the lymphoma lead at Oxford University. And we’re really just delighted to be here together, talking a little bit about the lymphoma data and specifically for VJHemOnc. And at the ASH meeting Graham, I think all told, it was a different meeting to usual. I think we had to get used to watching things virtually and responding, but there was some important data and I thought together we’ll kind of chat a little bit about that and maybe we’ll start, if it’s good with you, with -iffuse large B-cell lymphoma. Just before we got started here, you were saying bispecifics are coming of age, so I’ll let you pick up right there and tell us why you thought that.
Graham Collins: Yes, no thanks. Thanks Steve, very much. Yes, it was a different ASH. It was slightly unusual watching ASH in slippers with a hot chocolate on the table, but it had its perks. So yes, I mean, bispecifics, there was a whole session on bispecifics as you know, at this year’s ASH. And I think what really, I think is becoming more clear now, which perhaps we didn’t have clarity on before, is how these agents are optimally delivered, particularly in terms of reducing CRS, cytokine release syndrome. And also we’re starting to see some durability data now as well, and the responses and durability at decent doses. Because there’s quite understandably been dose-finding studies and it’s quite hard to interpret the response rates when you’re at low doses like that. And I was actually really struck. I’d be interested to get your thoughts Steve, but I was really struck by the consistency in the response rates in diffuse large B.
Graham Collins: So, three out of the four presentations included patients with relapsed/refractory diffuse large B, and the complete response rates, which I think is what we’re most interested in, were around 50 to 55%. Whether you were looking at the odronextamab, whether you were looking at epcoritamab or glofitamab, we’ve also got to get used to these new names, I think. So I was really struck by the consistency in CR rates and those CR rates did seem pretty durable. I mean, the follow-up is still relatively short and there are those caveats. But to have an over 50% response rate in a difficult to treat population was impressive. Now, a lot’s also been made about responses, post CAR-T and I think some of the data that were presented showed there was activity, but perhaps less good. I mean, not surprisingly, that the CR rates for some of the agents were down to about 20, 25% in that space. But I was struck by that, Steve.
Stephen Ansell: Yeah, I would agree with you. I think for me it was very interesting as you said, how consistent the data look. So to be honest, and I’d love to get your thoughts, there’s been a lot of discussion about the design of these bispecifics and whether it’s really good to have a smaller molecule versus a bigger molecule. Multiple binding sites, whether you give it subcutaneous versus IV. Do you think any of that matters, or do you think it’s really just a class effect and we’re going to get the same from all of them?
Graham Collins: Yeah, well I think for the optimizing or reducing, perhaps I should say the side effects in particular, the cytokine release, there seemed to be a sort of general consensus emerging that subcutaneous may be the way forward. I mean, it’s all, again, difficult to be adamant about that, but there does seem to be sort of lower cytokine levels in patients that are given subcutaneous dosing, and also this whole concept of step up dosing, particularly for the intravenous. So start at a low dose and gradually work up, does seem to ameliorate the more severe at least, cytokine release syndrome is. And I was interested, there was a bit of… It wasn’t presented formally, but in the discussion there was some perhaps thought that the glofitamab, although you’re looking very active, might be associated with some excess toxicity. So maybe the two CD20 binding sites who knows, but maybe that’s adding to that toxicity. So there’s lots of hypotheses around isn’t there, but hard to be sure about these things.
Stephen Ansell: Right. But I do agree with you that I think the response rates look very comparable to CAR T-cells, but how do you feel about the durability? One of the things about CAR T-cells is we think there may be a tail on that curve. We’re pretty excited that maybe there are a subset of patients that may be cured. Do you think we can start getting excited about bispecifics and having a similar curve?
Graham Collins: Yeah, I think it’s really difficult. I mean, ZUMA-1, I think was presenting his four year data at ASH and it’s pretty convincing that there is a plateau, quite a high plateau on the tail layer. So, if I’ve got a patient in clinic with relapsed/refractory diffuse large B, do they go for a bispecific? Do they go for a CAR-T? I think if they’re eligible, I would still be recommending a CAR-T, simply because we have that longer follow-up. So, it’s really tantalizing the CR data and the early durability results, but I’m not convinced yet there’s a plateau. There may well be, but time will tell.
Stephen Ansell: So how in your practice, do you, as you say, do you decide that, so I mean, basically, are you still going CAR T-cells are the thing. And only if you fail that or if you can’t get that or whatever, then bispecifics, or are you’re starting to say if you’re in a hurry to get treating, we’ll just jump in with bispecifics, because I can give that to you today. How do you manage them?
Graham Collins: Yeah, it’s a good question, Steve. I mean, we have to say, we have quite limited access to, bi-specifics in the UK is purely in the context of a trial and often they’re slot driven and, so it’s can be quite difficult to sort of just give it quickly to a patient, but you’re right, Steve. I mean, these patients who are progressing quickly, perhaps bulky disease that relapse, these are the ones that we’re getting more and more of a sense of that actually CAR-T may not be the optimal approach. However, in the absence of those things, if you’ve got a standard patient, if that patient exists with relapsed/refractory diffuse large B, we have access to CAR-T as long as the patient’s eligible. So I do, that is what I would counsel a patient.
Graham Collins: You often lay out the options don’t you, to the patient and the patient often turns around and says to you, “Well, what would you do?” And, genuinely speaking in that situation, we’ve got licensed products, CAR-T products with pretty good durability data now. Plus, obviously longer safety data, which is also reasonably encouraging in the post CAR-T space. So yes, it is that. I mean, if bispecifics are available. Yeah, fantastic, I mean, to have an off the shelf product that would get that sort of CMR rate would be great. But again, I just need some reassurance about the durability, I think.
Stephen Ansell: Right. The other thing I was thinking about, was just when you were talking about practice and how you actually manage things. There was three or four presentations, publications on CNS lymphoma. And again, I don’t know what your experience with CNS involvement, secondary involvement and prophylaxis and how you manage that. But there was some sobering data to suggest that maybe we do things to treat ourselves rather than actually in a way that’s beneficial to patients. So I don’t know what your thoughts were, from seeing some of that data.
Graham Collins: Yeah. So I love that data Steve, because I think anything that challenges what we do is really welcome and stimulates such great debate, doesn’t it? And you’re right. Yeah, two presentations, quite big numbers of patients, looking at the efficacy of single IV methotrexate. So, most of them excluded patients also getting intrathecal, and lots of caveats, it’s retrospective. So some of the data that wasn’t available, was the IV given over three hours or 24 hours might be important. So, lots of missing gaps but, the bottom line was there did not appear to be even a whiff of benefit for those given the IVs. So that is challenging. That’s not to say that there might not be a significant benefit that’s masked in that data set, but it’s fascinating. And again, what was, I think interesting in the discussion is I think people are falling into three camps.
Graham Collins: They’re falling into the, perhaps the neolistic camp, can I put it like that? As in, it’s not working, let’s stop. And IV methotrexate can cause problems. So there is a rationale for not giving something that’s not working and that may cause toxicity. But then the other camp is, well what we’re doing isn’t working, so we need to do more. We need to give dual prophylaxis, we need to give novel agents. Who knows, maybe a cycle of thiotepa containing chemo at the end of treatment.
Graham Collins: So there’s that camp, but there’s also the camp, which I think I’d put myself in still, which is that this is intriguing. It’s probably not enough to stop what we’re doing, because when you’ve got such a devastating complication as CNS relapse, it’s very hard to withdraw a treatment that might even have just a small chance at reducing their relapse rate. So, we tend to recommend it in CNS-IPI four plus and in high risk sites, testicular, kidney, adrenal, breast, ovary, that sort of thing. And I think we’ll keep doing that. Certainly it’ll be interesting to see the publications when they come out, but boy oh boy, it’d be nice to have prospective data.
Stephen Ansell: I couldn’t agree with you more. I think we really need, we need some prospect of data. I’m in your camp too. I mean, I tend to test CSF to be sure that it’s not positive, because obviously that changes everything. But in the people that are negative, it’s only really for me, the highest risk population are the ones that I use prophylaxis. The rest I basically explain the risks and say, “I think we’d be doing something to make ourselves feel good because we’re doing something, but I’m not personally convinced that in the lower risk patients we actually make a difference.” So I think that data was informative. The only problem was I wasn’t sure how that changes my life and my practice just yet.
Graham Collins: Yeah, yeah. Yeah. And did you see the presentation, Steve, as well on the cell-free DNA in CSF? I thought that was quite intriguing.
Stephen Ansell: Correct. I mean, and to be honest, that was like 100% likelihood of showing things. So I do see that as a potential tool in the future, particularly because it may be difficult to get parenchymal lesion tissue from parenchymal lesions. And if you could get that from CSF, that would actually be very helpful. So I’m watching that space with interest.
Graham Collins: Yeah. Yeah.
Stephen Ansell: Maybe moving us on to follicular. So again, we kind of had the themes of bispecifics and CAR T-cells and it’s kind of like a version 2.0 when you get to follicular lymphoma. But again, some really interesting data with CAR T-cells and follicular. So I wonder what you thought about that information, particularly the axi-cel data?
Graham Collins: Yeah. Well, and this is very welcome, Steve, I think because, follicular it’s interesting, isn’t it? It’s most of the time fairly straightforward as a lymphoma doctor treating follicular lymphoma, but you get the odd case, which is really difficult. And BTK inhibitors a bit underwhelming really in follicular. Venetoclax monotherapy, not great in follicular. So, whereas CLL has lots and lots of options in this sort of relapse/refractory space. I find myself running out of options in these high-risk patients. PI3 kinase is inhibitors work ok but we’re all very familiar with the toxicities. And in Europe we don’t have PI3 kinase or inhibitors licensed. So we struggle a bit. Lenalidomide is sort of where it stops. So to have the CAR-T and bispecific data coming through and looking so encouraging. And CAR-T seems to work pretty well in relapsed diffuse large B, but it seems to work very well in relapsed/refractory follicular.
Graham Collins: I think it’s all going to be about picking the right patients though, isn’t it? And defining that high risk group where you can use a product, which has reasonable amounts of toxicity. A third of patients roughly with axi-cel are getting grade three, four neuro toxicity, maybe a bit less than that, but a substantial number. So sort of to justify the expense on the toxicity, it’s about picking the right patients, I think. But really encouraging high response rates and good looking durability.
Stephen Ansell: I think the thing that for me was very interesting is, are we going to see that tail on the curve, because we end up seeing patients with follicular or low grade lymphomas that are cured with CAR T-cells. I think that’s going to be a total game changer, because we’ve always been a little hesitant of allo-transplants in these patients, because of the long-term, graft versus host disease and those sorts of problems. But, now if a CAR T-cell with its attendant problems and again, your selection comments are well taken. But if we suddenly now see that we actually have a subset of patients who are potentially cured, I think that may change our algorithm for treating follicular lymphoma patients look.
Graham Collins: Yeah, no, I completely agree. But I guess the other question though, is how long do you need to wait to find that plateau? Because the autograph data, some people would say you’ve got a curator at 10 years, others don’t believe it. They would say it’s going to keep going down with longer follow-up. Is it the same with CAR-T? Are regulatory authorities going to buy the fact that there’s a cure rate with these after, I don’t know, four or five years follow-up. Yeah, no, it’s an interesting question.
Stephen Ansell: I do think though that we’ve done a little better job in more recent years to work out who the higher risk patients are and those people, I think the end points come up a little sooner. So I think we may well get some of those answers, or at least some clarity in shorter kind of order.
Graham Collins: Yeah, absolutely. And it is, I was struck by the original idelalisib trial that used this concept of double-refractory alkylating agent CD20. And obviously we’ve got other things now POD24, et cetera, but completely agreed. Yeah.
Stephen Ansell: When you mentioned earlier venetoclax and ibrutinib, I was kind of curious, there is a regimen around the NCI called VIPER. Kind of thought it was an interesting name. I’m not sure whether it’s good or bad, to have a name like that. But really bringing in venetoclax, bringing in ibrutinib, steroids, rituximab all into the initial therapy. Any thoughts about that combination?
Graham Collins: Yeah. I mean it was a bit like opening the dictionary of novel agents, wasn’t it? And picking out.
Stephen Ansell: Putting them together, right.
Graham Collins: Putting them together. So yeah, I mean, interesting combination, active combination, time limited as well, which is, I think probably beneficial in this sort of space. I mean, again, I was struck in the questions when somebody… One of the first questions I think was on cost and the presenter actually had an answer. So I think he was clearly ready for that question, and argued that it was actually significantly less than potentially one dose of CAR-T, which is I’m sure right. But yeah, I’m personally still a big fan of good old immunochemotherapy in the frontline space. And I think it’s going to take quite a lot to push that out. So yeah, great to do it. Great to see the activity of that combination, but I’m not sure it will affect my practice for some time to come.
Stephen Ansell: Right. Right. I thought also, as we’re thinking now maybe a little bit about T-cell lymphomas, there was some interesting data, again, disappointingly, a lot of the interesting data in T-cell lymphoma was negative data. But a big randomized study on romidepsin CHOP, Romi CHOP if you like. Want to give us your thoughts about that?
Graham Collins: Yeah. And hats off to the French, the Lisa group for doing that study over 400 patients randomized. And I think one of the main take home messages there is we can do randomized studies on T-cell lymphoma and isn’t it great to see one of those randomized studies coming through and being published, but of course disappointing. And that the curves were tantalizing, because if you follow the survival curves for quite a while, almost a year or so, maybe even two years that the road CHOP looks like it’s doing better, but as you get to the right it comes back down and there’s really no significant difference. I was interested in the subgroup analysis. Obviously subgroup analysis you’ve always got to take with a slight pinch of salt, but it nearly, the angioblastic group nearly made it to statistical significance.
Graham Collins: And of course, there is this emerging data that the TFH group of T-cell lymphomas, with a unique mutational profile may be more susceptible to HDAC inhibitor therapy. So, hypothesis generating, but does this mean, having said we can deliver randomized trials in T-cell lymphoma. Does this now mean we’ve got to deliver randomized trials in TFH lymphoma? Boy, if T-cell lymphoma is hard, then splitting a rare disease into an even rarer disease will be even harder to do trials for. So, disappointing sure, but intriguing particularly with that subgroup analysis, I think.
Stephen Ansell: Yeah. And I must say, I think your points are important related to the subgroup analysis, because I think, if I look at where we have made progress, it’s been with brentuximab vedotin plus CHOP, but that was a subgroup right off the bat.
Graham Collins: Yeah.
Stephen Ansell: And I do think much though, it’s great to see these trials. It still does make it a little challenging, because it’s such a gemisch of people put together, we may need to, proving that we can do this kind of study. Maybe we could go a little longer and a little bigger and get it more focused, because it might’ve been that, that subset of patients could have benefited. But I guess the challenge is no one’s going to go back and do the study again. So, we’ll wait and see. There was also some data to say that you could put azacitidine with CHOP. That was a small study. So I think it was more just a, you can do this, not so much that it’s clearly, you’re going to need a randomized study to show that, but what are your thoughts about that?
Graham Collins: Yeah, well, and they were enriching. I agree, it was only about 20 patients, wasn’t it? But most of them had TFH derived lymphoma. And I think that’s where the interest is, isn’t it? With these agents, the data we’ve got so far, which is, is monotherapy in relapsed patients mostly, is very interesting. Some really quite high response rates, albeit in these small number of patients in the relapse setting. So to combine this in the frontline setting with CHOP, which of course the other thing the road CHOP study is again confirmed that the cure rate or the long-term remission rate with CHOP is about 30%, it’s now. I think we knew that anyway, but it sort of confirmed it. So, there is a minority that do well with CHOP. So to combine something like oral azacitidine in that targeted group of TFH derived, I think has a lot of rationale behind it. So it was reassuring that it can be delivered safely.
Stephen Ansell: And speaking of transplant, it made me think for a minute, what are you doing in your practice? Are you one of those who consider transplanting autologous or allo in first remission, there was some data around allogeneic. It was sort of a big registry study. And again, if you can get to a transplant, you can get into the registry, because you’re at an academic center, the numbers look better, but I wondered if those kinds of data impact what you do in your practice?
Graham Collins: Yeah. I mean, again, it’s fraught with controversy, isn’t it? What you do with transplants in first remission, particularly. I mean, we do autographed, I do it slightly guiltily, because again, when I’ve got a patient in front of me and I’m consenting them, obviously I want to tell them what the benefit is. And, I don’t quite know what to say. And often I am honest with them and say that the evidence behind this is thin, but we believe that some of the better results that are seen in the frontline setting are including a stem cell transplant. And generally speaking, we include an autologous. There was that data, the Germans produced, of randomizing autologous and allogeneic in the frontline setting, very brave study, the outcomes are the same, but many patients didn’t actually make it to their assigned transplant.
Graham Collins: So it was a very hard study to do. The allogeneic data that you mentioned. Yeah, that was interesting. The retrospective study, big numbers, hundreds of patients. And, my take on that was the five-year PFS looked like it was about the 40% mark, which to be honest is what I normally quote with an autologous transplant in first remission. Although these weren’t all first remission patients, obviously. So they would have had some higher risks than that. The group that really made me look hard at though, I think it was only 34, 35 patients, but with a hepatosplenic T-cell lymphomas. Where it was almost 50% I think were progression-free at five years, which that is a hard group of patients. So, I think that’s confirmed our desperate attempt to try and get these patients to allograft if we can, even in first remission.
Stephen Ansell: Yeah. I must say, I think that was information that I found useful. I think for me, for T-cell lymphomas, I kind of put them in three buckets, the really good ones that could benefit from CHOP, or BV-CHEP. And then there are the not so good ones, but if you can do an autologous transplant that may be beneficial and then there’s the really bad ones. And those, if I can get them in remission, allo-transplant is what comes mind. So I thought those data were very hopeful to help define a little bit the third of those three categories.
Graham Collins: Yeah, completely agree.
Stephen Ansell: So you mentioned earlier about how we desperately need new drugs. And duvelisib had some data, and I know they’ve kind of putzed around with trying to get the right dose and the study was kind of giving that information. What’s your thinking about duvelisib? Do you see this as a future tool that we’re going to see a lot more of in T-cell lymphoma or is this something that’s sort of just okay information and we’ll leave it at that?
Graham Collins: Yeah. I’ve always been slightly surprised by the duvelisib data. It’s been quite good really. And the reason I say that is, when idelalisib first came around. A number of people suggested trying it in T-cell lymphoma, but the manufacturers were very down on that and said that in the lab, there’s no good rationale of treating T-cell lymphoma with PI3 kinase, but actually there is. A PI3 kinase is an important enzyme in T-cells as well as in B-cells. So perhaps it’s not that surprising that we are seeing with the duvelisib’s of data around 50% sort of response rates, which in relapsed T-cell lymphoma is good. I guess the caution is, there’s a number of agents we’ve seen reasonable Phase II data on which when you take two larger Phase III studies have failed to show improvement. So I think, yes, absolutely I think it’s a green light to develop this drug further. And I think we will see it develop further, but I’m open-minded I think, as to where we’ll be in five years time with it though.
Stephen Ansell: I think I agree with you. I think it looks, it’s a promising drug. The results were quite good and very encouraging. My test is always, do you think you can combine it with other things, because one of the challenges I think in T-cell lymphoma, there really isn’t a one drug going to fix the problem. It’s always going to be a combination approach. So does it play well with other agents? And it’s always my question in my head when I’m thinking about longevity, and I think there are going to be a few challenges with duvelisib, just with blood counts and other issues.
Graham Collins: Yeah. I’m sure you’re right, Steve.
Stephen Ansell: So, moving on into our final segment, if you like, is something that you and I have done a lot together on, and that’s a Hodgkin lymphoma. So, right in the beginning, jumping right off with the antibody drug conjugate, the CD25 ADC Cami-T. You’ve kind of pioneered this particular agent in Hodgkin lymphoma. There was more of this data available. What’s your take on? Is this going to be a tool we’re going to see used all the time or not?
Graham Collins: Yeah, I mean, it’s a fascinating drug, I think. And a real dilemma in terms of drug development, because it’s really active. So as you say, Phase II study now where the starting dose is given for two cycles and then dropped to a lower dose to try and circumvent some of the toxicities that were seen in the Phase I. And, the response rates in the Phase II are looking very high, over 80% in a group of patients where all but one patient had, had prior BV and a PD-1 inhibitor, and that one patient was a protocol deviation, so they should all really be gettiing that median, I think of five prior lines. So, a truly heavily pretreated group. So response rate of 83%, amazing. CR rate was over 40%, really good. But boy, it’s the toxicities, so I’d class them into two really, one is the sort of PBD Pyrrolobenzodiazepine associated toxicities.
Graham Collins: That’s the payload on the antibody drug conjugates. And these can be really problematic. Grade three rash, fusions, which can really impair patient’s quality of life. Actually, it can be quite hard to manage, particularly the rash. It’s not a simple matter of delaying the drug and giving some steroids. It can persist. Liver function test abnormalities as well. But perhaps the thing that worries most of us, is the rate of Guillain-Barré or polyradiculopathy that’s seen. Now that the study was actually paused, the Phase II study, at 50 patients because they had the protocol defined stopping criteria, that once they saw two or more cases of polyradiculopathy, there would be a pause, while the data was looked at and regulatory authorities had a good going over of it. And they have done that and it has reopened again.
Graham Collins: But again, we are seeing these polyradiculopathies, which I understand, thankfully none of them were my patients in this trial. I understand that they have been reversible, which is encouraging, but it’s a very difficult and scary side effect to deal with. And, but fascinatingly, a lot of patients with non-Hodgkin lymphoma and other tumors have been treated with this agent, but it’s only the Hodgkin lymphoma patients that have seen this side effect. So there is something about Hodgkin lymphoma patients, I guess we know don’t we? That you do see auto-immunity in rare patients with Hodgkin’s, but there seems to be some way in which that’s diverted towards the neuraxis in some of these patients. So, yeah, active but toxic. And again, going back to your combination comments Steve, can you combine this drug? I think it’s a real challenge.
Stephen Ansell: Right. Have you seen much in the way of immunological effects with this agent or you obviously taking away T reg cells, so you’re unleashing the immune system, or maybe just depleting it. Any problems that you’ve noticed when you’ve been treating patients, particularly in the Phase I, when you did that?
Graham Collins: Yeah, we did see some of what you might expect to be sort of PD1 inhibitor toxicities. So thyroid disturbance, particularly hypothyroidism, and also pneumonitis. There was a case of that reported in the Phase II, but we also had a case of that in the Phase I. Not particularly frequent, but definitely there. So I think you are seeing these other immune related toxicities.
Stephen Ansell: Speaking of immune-related effects, there was obviously other data which was in the post-transplant kind of consolidation space, similar to what brentuximab vedotin tested in the AETHERA study. Now it was brentuximab vedotin plus nivolumab, in that space. That was interesting because there’s been some data on pembrolizumab, if I remember correctly in that space as a kind of a consolidation. And all of those results look quite interesting and promising. So your thoughts on where are we going in the post-transplant space? Are we’re going to put all our drugs in that space, or have we used them up more typically before we get to transplant, or should we really not do that and keep them so we can use them later if people relapse? What are you doing in your practice?
Graham Collins: Yeah. So, well I mean, it was a very interesting study. So combining nivolumab with brentuximab, as you say, post autologous transplant, in the high risk setting. So overlapping with the AETHERA trial criteria, but I think they also included patients who’d taken more than one line of salvage and PET-positive as well at transplant. So a little bit extra in terms of eligibility. And what was good, I think about it is, it was shorter treatment. I think they were using eight cycles rather than up to 16 that AETHERA used. And yeah, it was very high PFS rates seen so far. Although, obviously followup is relatively limited. I was slightly surprised by the toxicity, in that there was quite a high use of steroids in the patients. I think it was around almost heading up for 20%, which seemed quite a lot really. And more than you would expect, perhaps if you use NIVO, a single agent in that setting.
Graham Collins: So a little bit worried about that. Now what we do in the UK, again, we’re rather restricted by what we’ve got available. We don’t even have AETHERA, brentuximab consolidation funded, which I think is a real shame, because I think if you can avoid an allograft and we still do allograft patients with multiply relapsed Hodgkin’s in England, at least. I think if you can avoid that with consolidation post autograft, then all the better. I think what we’re seeing though Steve, and I’ll be interested to see if you agree on this, is we’re seeing a shift though towards actually identifying the lower risk patients and replacing the autograft. It’s been the long-held mantra, hasn’t it? Of relapsed/refractory Hodgkin’s, you want to get them to autograft. But of course the evidence-based for that is quite thin. Two old studies, neither of which showed overall survival advantage. And we’ve got much more active agents nowadays.
Graham Collins: Plus the pediatricians for a long time have been taking their low and intermediate risk patients and not autografting them, that relapsed and have very interesting results. So, I do wonder if, PD1 maybe plus BV as well, will be used more in the future of actually challenging that autograft in the first place, rather than throwing everything at consolidation afterwards.
Stephen Ansell: Yeah. I think you dead right. And I think that’s begging for a randomized comparison to actually prove that, because I think you’re right with new drugs available and higher response rates and potentially better ways in treating people, that may be kind of a more toxic agent combination that causes problems in the long-term and we may not need to do that. But I’m like you, I’m data-driven so I want to see the study to show that, if we possibly can.
Graham Collins: Yeah. And what was your thoughts on the pembro-GVD data as well, Steve? Which was first relapsed, wasn’t it? Showing a 95% CR rate or something? I mean again, small numbers non-randomized but what’s your practice for first-line salvage in Hodgkin’s?
Stephen Ansell: Yep. So that I thought was really interesting, because that was a really high response rate. And we tend, because we’re often using new agents in the frontline, outside of a clinical trial, we would typically use standard GVD, or standard ICE chemotherapy and then go to transplant and then bring the novel agents in on the back of transplant. So I thought that data was quite compelling and intriguing, but I think again, often you can get good results because you select patients well. And because these small studies are exactly that, small. I think we just need to wait for more information and potentially compare comparative studies, but it certainly was an intriguing result. And there’s some data from Josh Brody’s group, where they’ve done this immuno transplant, where doing something before you actually give a heavy dose of chemotherapy, may actually change the environment and get better results later.
Stephen Ansell: So to be frank, I think that’s another space which hasn’t really been explored much and certainly would be interesting to see what that showed, as we kind of get more data.
Graham Collins: Fascinating.
Stephen Ansell: Well, we’ve kind of gone through a bit of a whirlwind here of different topics. Anything you wanted to bring up that we might’ve missed, or something that we should chat about, because it was big news at ASH?
Graham Collins: I think we’ve just about covered it Steve.
Stephen Ansell: It was the plenary session on large cell lymphoma, more of a basic kind of approach. But I think again, really reminding us is that we’re understanding some of those large cell networks and BCL10’s role in all of it. So I’m always excited when lymphoma makes it to the plenary session, because I think that elevates the importance of what you and I do.
Graham Collins: Yeah, absolutely
Stephen Ansell: Wasn’t ready for clinical prime time I think at this point. There was some suggestion that maybe it can impact who would benefit from ibrutinib, but as you and I said, Ibrutinib’s not got quite its spot if you like, in those diseases, this was large cell. So I’m not sure if we know exactly how to utilize that information just yet.
Graham Collins: Yeah. And I thought it was, it underlines the fact that precision medicine is so fraught with difficulty, isn’t it? Because, you can define the pathway of tonic signaling from the BCR receptor. Target it, find it doesn’t work and then you or not in the majority of patients, and then you find a new mutation you weren’t expecting that explains that. And of course, my older PhD supervisor used to describe these intracellular signaling networks as pond life, everything you’d have your lily pads on the surface and then everything sort of coming down underneath it, lots of overlapping interacting circuitry. And it’s so hard to tease that apart. So, agree with you, great effort and results to find that explanation there. But whether this is going to be a really good approach for treating that small subset of patients, I think is yet to be seen.
Stephen Ansell: I think it’s a little bit like the London underground. If you’re new to London, it’s very confusing, but once you know how to read the map, you can get where you need to go. So my hope is that as we unravel the map if you like, we’ll get closer and closer to the truth and how to navigate it all.
Graham Collins: Absolutely. Absolutely.
Stephen Ansell: Delightful to chat with you today, Graham. Thank you very much for your time. Again, thank you to all of those who listened in and to our VJHemOnc session on lymphoma and a report back on the ASH meeting. So thank you for your time and attention.
Graham Collins: Thank you.
Stephen Ansell – Research funding (to his institution) for clinical trials: BMS, Seattle Genetics, Takeda, ADC Therapeutics, Affimed, Regeneron, Trillium and AI Therapeutics