Graham Collins:

Hello, and welcome to this VJHemOnc Lymphoma Session. My name’s Graham Collins. I’m a hematologist in Oxford. I’m delighted to be joined by my friends and colleagues, Professor Andy Davies from Southampton, who is a Professor of Medical Oncology, and Wendy Osborne, Consultant Hematologist in Newcastle. Thank you very much, Wendy and Andy, for what I’m sure will be a stimulating discussion as we review some of the perhaps more recent data presented mainly over the summer congresses, and particularly think how this might apply either now or in the near future in UK practice. So I think let’s work through Hodgkin, aggressive non-Hodgkin and indolent non-Hodgkin, so let’s start with Hodgkin lymphoma. And we saw in both the EHA and ASCO, and it’s been published now, the overall survival data from ECHELON-1, which certainly surprised me when it came out as positive with an overall survival of A²VD, so AVD combined with brentuximab versus ABVD six cycles. It’s not something obviously that is reimbursed in this country. It is licensed for stage IV. So Wendy, I’d be interested to hear your thoughts, both on what you thought about the data, were you convinced by it, and do you think there is a niche, a role, for this regimen in UK practice?

Wendy Osborne:

So, I mean, I think we are all very excited when we hear of any overall survival data in any lymphoma trial, because often we are just looking for PFS benefit rather than OS benefit. So seeing an OS benefit is very encouraging. I think that I was very interested to look and see what the actual causes of death were because obviously small numbers can allow a survival benefit where we see that deaths are maybe unrelated to the lymphoma or the treatment, but actually when the data were presented, I was impressed that these did truly show an improvement in the A²VD arm. I think that the caution will be that the randomized arm with giving six cycles of ABVD wouldn’t be our standard approach in the UK. So in the UK, we would follow a RATHL approach if we are starting with ABVD and if a patient is PET negative, drop the bleomycin because we know that there is no benefit from giving all of the bleomycin and we know that there’s toxicity with bleo.

So I think that when the randomized arm isn’t our standard approach, that will lead to some discussion, particularly amongst when this is maybe looked at reimbursement. And I think that the other thing that we have to be mindful of is that both arms were still significantly lower in their PFS compared to an escalated BEACOPP approach, and in the UK, we would use escalated BEACOPDac replacing the procarbazine with dacarbazine following HD18. So I think that when I saw these data, I’m encouraged. I think that if, for older patients, that I wasn’t using an intensive approach, using an HD18 approach, and I wanted to use a RATHL approach and it were to be reimbursed, then yes, I would use A²VD approach. And I think that seeing survival benefit is really encouraging.

Graham Collins:

Yeah. And it’s interesting, wasn’t it, as well? They did present a little bit of pregnancy data, which, I mean, obviously it’s not, you’ve got to take it with a little bit of a pinch of salt, but there was certainly, if anything, more pregnancies on the AVD brentuximab compared to ABVD, which is just reassuring, I guess, that there’s no fertility signal with AVD brentuximab. I mean, Andy in Southampton, I mean, I think, correct me if I’m wrong, but I think you do something similar to what we do in Oxford, perhaps give escalated BEACOPDac for the higher-risk advanced stage, RATHL approach to lower-risk. I mean, particularly perhaps for those maybe lower-risk RATHL patients, would you want to use this regimen? There is excess peripheral neuropathy, et cetera. What’s your thoughts?

Andy Davies:

Yeah, I mean, I think this is really interesting data. The overall survival, it’s a 41% reduction in risk of death with the hazard ratio, so it’s not insignificant. To my mind, it appeals to me in the situations where it’s difficult to deliver escalated BEACOPDac. So those patients who are over 50, 60, that sort of thing is where it gets challenging. And I think being able to give this, A²VD, is really something that I think would be of great interest to be able to do that. And I think not only did you say that there’s a different, the pregnancy doesn’t seem to be affected, but also we see that there are actually less second malignancies in the brentuximab patient group as well. And I think that the peripheral neuropathy was largely reversible. So I actually think it would be great to have this as an option in our armamentarium for those older patients.

Graham Collins:

Completely agree. Yeah. Thank you. So just sticking with Hodgkin briefly, there was a really interesting, I thought, sort of proof of concept study. It was quite small, but looking at patients with relapsed Hodgkin lymphoma being treated with the PD-1 inhibitor, the PD-1 inhibitor starts to lose its efficacy so patients are progressing and then they are given some radiotherapy to one lesion and the response at a distant lesion is measured, the so-called abscopal response, which we’ve heard about this abscopal, I was going to say mythical, I shouldn’t call it that, but this abscopal response for quite a long time, and I thought maybe here we are, this may actually be a study that demonstrates it. I mean, Wendy, were you excited by this? Did you think there’s mileage?

Wendy Osborne:

Yeah, I do. And so I don’t think you can call it a mythical response now. I think when we looked at those scans in the presentation, they were very impressive. So the site’s distance to the target lesion that was treated with the radiotherapy clearly having a response, and these were very high-risk patients who had progressed on checkpoint inhibitors. So very small numbers, but the response rates that they had, I think, are very clear that they’re good enough to take this into a larger study. And we’ve certainly had discussions in our MDT when we’ve had patients who are progressing on checkpoints, whether if it’s a low-risk site, thinking about giving them 20 Gy radiotherapy to this site. We haven’t as yet, a small study, there isn’t really good data behind it. But I think it’s something that I’m very interested in looking at in the future.

Graham Collins:

Yeah. Yeah, no, absolutely. Almost once you sort of irradiate a lesion, doesn’t it, in one of your patients who’s slowly progressing on the checkpoint inhibitor, but so maybe we’re not quite there yet. Let’s move on to aggressive non-Hodgkin lymphoma and perhaps go straight to what I think was probably, I think it’s fair to say, probably one of our highlights, which was the presentation of two pivotal studies of bispecific antibodies, glofitamab and epcoritamab in relapsed/refractory diffuse large B, Andy, if I can maybe come straight to you, because I know this is a real area of interest for you, would you mind summarizing the data? And perhaps what I’m really interested in thinking is, assuming we get reimbursement availability, where are they going to fit, pre-CAR-T as a bridge, post-CAR-T, CAR-T ineligible, all of the above?

Andy Davies:

So, I mean, it was really exciting. Two studies presented back to back, two different CD20 by CD3 bispecifics. There are some differences in the format between epcoritamab and glofitamab and there are some differences in the way they were delivered. For example, epcoritamab subcutaneous delivery and was given until disease progression. Glofitamab which is a bispecific with two binding sites for CD20, you have an obinutuzumab pre-dose on it, but this was given for a fixed duration of therapy. Now the studies were in third-line plus diffuse large B-cell lymphoma. A third of the patients in each of these studies had previously been exposed to CAR-T cell therapy and the studies were roughly the same size. There’re about 150 or so patients in both single arm studies. And I think the primary endpoints of both of the studies was response and complete response, and the complete response rate was identical with both bispecific antibodies in this setting, and that was 39%.

So I think that’s really an impressive figure for an agent at the third-line and particularly in patients who are post CAR. And we can see that actually this response was pretty much uniform across all the different risk subgroups. So I think interesting data and what was very clear was the durability of those complete responses. So we saw some data demonstrating patients with really very long duration of responses and indeed in some of the earliest patients who were treated in the glofitamab study, we saw a duration of response of over 34 months median. Now that’s third-line DLBCL, failure of lots of other treatments. I think this is a real game changer. It looks to be safe. I think there’s going to be some challenges operationally around delivery. There are still some hospitalizations for some of these drugs around the time of sort of maximum dosing. And there are some risks of cytokine release syndrome, about 50% of patients had cytokine release syndrome. But generally these were grade one, grade two and were pretty rapidly reversible with intervention. So I actually see this as a really important game changer in relapsed/refractory diffuse large B-cell lymphoma. And of course, what we’ve got here is a T-cell engaging therapy that’s off-the-shelf that can be delivered in a hospital that the patient doesn’t have to travel to the nearest big city to go and have. So I think this is going to be really interesting as we move forward.

Graham Collins:

Yeah, absolutely. And Wendy, I mean, I was really struck by the similarity of the data and in fact so much so I think the CR rate for both was 39% on the button, which I really like. I really like it when there’s one number to remember. But that means if we’ve got two agents, again, assuming we can get hold of them, were there differences significant enough, do you think, where you would pick one over the other, subcut, fixed duration, that sort of thing? What would be your thoughts on choosing the appropriate bispecific?

Wendy Osborne:

Yeah, so I mean, I share Andy’s enthusiasm for bispecifics. I think that these data are fantastic and these were really high-risk patients. In such a patient group, to me, giving it subcut or IV is not going to be the decision maker between the two. I think with more durability of follow-up, then maybe one would have an advantage over the other but I think that’s certainly too early to say. I think there’s definitely a lot of discussion between bispecific versus CAR-T and as Andy mentioned, it’s the off-the-shelf availability because it’s so hard waiting for the CAR-T manufacture and bridging patients, and we’ve all seen patients not get to CAR-T infusion because of progression during that month of manufacture. So I think that yes, as time and longer follow-up tells, there may be some decision between bispecific agents, but at the moment with these data, I would be equally enthused about both of them.

Graham Collins:

Yeah, no, absolutely. Thanks. And Andy, can I just ask you a specific question as well? Because I hear this sort of talked about quite often and that is, in terms of sort of the sequence of bispecific and CAR-T, would you be sort of theoretically concerned about using a bispecific before you sort of apherese your T-cells, because you’d be exhausting your T-cells and therefore reducing the efficacy apheresis product? Is there any basis, do you think, in that concern?

Andy Davies:

I think, Graham, we don’t know that. What I would say at the moment really, based on the data that we do have, we have the best efficacy data and the best long-term follow-up data about CAR-Ts. So if you’ve got somebody who’s fit for intensive therapy, to my mind, that’s the right decision, and of course you are not causing global activation of T-cells. You’re talking about specifically primed T-cells, and then actually you save your bispecific for failure of the CAR-T. Now that may be in the future proven to be wrong, and of course these are individualized treatment decisions because there are some patients who may not wish to have CAR-T cells and would like to go straight to try bispecifics first of all. Whether we end up bridging with bispecifics, well, let’s wait and see, and let’s look at some of the data that’s going to come out of the trials. But I think we’ve got a lot to learn about sequencing in DLBCL over the coming years.

Graham Collins:

Yeah, yeah, absolutely. Fascinating stuff. And Wendy, let’s stick with CAR-T for the moment as CAR-Ts have been mentioned. Interesting to see some CAR-T data in T-cell lymphoma. I think you’ve been involved in the AUTO4 study using TRBC1-targeted CAR-T, which seems to be a really rational thing to do. So you target the tumor which expresses that particular antigen, but you also are likely to only deplete one subset of T-cells leaving another subset to sort of do the job that we want T-cells to do. Obviously early data, but what are your thoughts on the early data that was presented?

Wendy Osborne:

So again, these do look encouraging and our options for relapsed/refractory T-cell patients are so limited, so it feels encouraging to finally see something where we are seeing possible benefit, although it is small numbers, and the AUTO4 study and the AUTO4 product is very tolerable as well. There’s minimal toxicity for these patients. They were infused with minimal CRS and neurotox, and small numbers, but encouraging efficacy. So again, I think this is one to watch and maybe this could finally be an option for patients in the future.

Graham Collins:

Yeah, absolutely. It’d be so lovely, wouldn’t it, to get something decent in T-cell? I mean, we need to wait obviously to see if this provides it, but yeah, quite. Let’s stick with aggressive and go to Burkitt lymphoma because wasn’t it great to see a randomized study in Burkitt lymphoma presented? It could only really, I think, be done with an investigator-initiated study, which this was, and all credit to the investigators. I mean, it was underpowered for the question it was trying to answer because the recruitment sadly was not what was hoped for, for various reasons, but it was still a reasonably large frontline study in comparison with other Burkitt lymphoma studies comparing R-CODOX-M/R-IVAC with DA-EPOCH-R in high-risk Burkitt lymphoma patients. Andy, I guess the bottom line was no difference, but yeah, how would you expand on that? And is this going to change the regimen that you reach for in patients?

Andy Davies:

Sure, I mean, so I think the stats are important in this. It was powered for superiority of dose-adjusted EPOCH over CODOX-M/IVAC and unfortunately there was only 40 patients roughly in each arm when the study closed, which was necessary just really because it was never going to be feasible to achieve the numbers that had been set out. But we see that the curves of progression-free survival for both regimens essentially overlap each other, which I think is really encouraging. What we don’t know, however, is we don’t know about the events and we don’t understand the sites of those events. And I think that’s really important because you think about how much CNS-directed therapy there is in CODOX-M/R-IVAC compared with how much CNS-directed therapy with just lumber punctures with dose-adjusted EPOCH. So I think it’s really important for us to understand that more.

And I think if you are a believer in dose-adjusted EPOCH, then that gives you strength in your argument. However, if you have concerns about dose-adjusted EPOCH, then this study doesn’t really help you with that. So for my money, really, I’m going to continue to use in my younger patients with Burkitt lymphoma, the CODOX-M/IVAC regimen, but I would feel more comfortable in my older patients where our risk of therapy-related mortality is higher to be more comfortable at using dose-adjusted EPOCH in those patients. So I’m very keen to see more of this analysis. I’m very keen to see a bit more about the sites of disease and a bit more about the profile of the patients. But what was very striking, of course it is obvious really, is the amount of time people spent in hospital was much less if they had dose-adjusted EPOCH, and of course the blood product risk support requirement was also significantly reduced. So I think this is really encouraging data. It does leave very many questions, but I certainly think for those patients who are older, I feel more comfortable with the equivalence of dose-adjusted EPOCH.

Graham Collins:

Yeah. Thank you, Andy. And I mean, one thing that struck me about the trial as well is I think it did include HIV positive patients, which is fantastic. I think that’s really good, isn’t it, to enable these patients to be enrolled. And Wendy, let me ask you, in terms of Newcastle practice, do you follow a similar sort of regimen protocol decision as Andy’s just outlined? And if so, do you have an age under which you are comfortable with R-CODOX-M and over which you’re not?

Wendy Osborne:

I mean, this study in terms of numbers was impressive. I mean, we don’t see Burkitt patients very often, fortunately, and so to get these numbers in a randomized trial, again, I agree with you, needs congratulations. It hasn’t changed our practice, and that’s, again, because of the fact it’s underpowered and my previous concern about CNS relapse rates, which have been shown with previous DA-R-EPOCH data. And I, therefore, for my patients who are fit enough, would prefer to treat them with R-CODOX-M/IVAC. We’ve seen from other, so the high IPI study showing a significant mortality for patients over the age of 50, so we are cautious giving CODOX-M/IVAC to older patients, although there is the reduced sort of higher age reduced dose protocol which we would tend to follow. So I would tend to reserve DA-R-EPOCH for older patients because of that risk of the CNS relapse, because I just think that we know that these patients are at very high-risk of CNS disease.

Graham Collins:

I agree. It does slightly go against the grain, doesn’t it, using a regimen with very little in the way of CNS penetrating agents in younger patients with high-risk disease. I’m in complete agreement with both of you. Now we’ve mentioned older patients. Andy, I think there was some data of ZUMA-7, so CAR-T second-line diffuse large B in older patients. What was your take on that?

Andy Davies:

Yeah, so Graham, I wasn’t going to let you leave aggressive lymphoma without talking about this data from ZUMA-7. It’s a pre-planned analysis of older patients on this study. These are high-risk patients, relapsed within 12 months, randomized either to receive standard of care or to receive CAR-T. This was 109 patients. They were above the age of 65 and up to the age of 81, really, and what this demonstrated was that the trend of the trial was followed. In fact, there was a greater effect. So we recognized that in older patients who were fit enough for this type of intensive therapy in the second-line setting, there’s significant benefit to be had, and indeed event-free survival was some nearly 50% in those patients who received CAR-T cell therapy at 24 months compared with just 15% for those patients who went down the conventional treatment route. And actually, what was very interesting about this was, although the study hadn’t demonstrated globally an overall survival advantage, there was a clear overall survival advantage in these older patients. Now, the toxicity was perhaps a little greater in the older patients compared with the study as a whole. But I think actually what it really demonstrates to us is that should we be approved to use CAR-T cells in the second-line therapy, we certainly shouldn’t be denying our older patients access to this approach, assuming that they are fit enough for it.

Graham Collins:

I mean, the thing that interests me about that as well, Andy, is an 81 year old, would you put them in a trial where you could be randomized to an autograft route? I mean, did the older group randomized to chemo and autologous transplant, did they still get the auto as frequently as the younger patients who were randomized to that route?

Andy Davies:

I can’t tell you that figure off the top of my head, but I think you are right. The number of patients who had the autos was a little less than it was in the study as a whole, but I can’t remember the figure off the top of my head.

Graham Collins:

Yeah, yeah. Because my takeaway from that is there really is this group that we would judge as auto unfit who are CAR-T fit and who’d benefit substantially. Yeah, no, it’s compelling data, Andy. Thank you.

Wendy Osborne:

And we’ve seen from a lot of the other real-world data sets how effective third-line CAR-T is in older patients and from the UK data, it’s clear that if they get to infusion, the outcomes are as good as a younger patient, but we do see a higher dropout rate of the older patients, so progressing or not managing to get to infusions. So I think that, again, patient selection is important, but we should not be selecting on age, we should be looking at other comorbidities and disease factors as well.

Andy Davies:

I think that’s really important Wendy. These were a select group of patients, so although they were refractory and had relapsed or were refractory within 12 months, actually these were patients who didn’t have bridging therapy and who had good organ function. So this is a highly selected group of older patients. And if the kinetics of their disease were such that they couldn’t wait for the manufacturing process, then they weren’t entered into this study. So I think we look at this with a little bit of the caveats of understanding the disease kinetics.

Graham Collins:

Yeah, yeah. Thank you both. Let’s move on to indolent non-Hodgkin lymphoma and probably the one to go to first of all, the presentation to go to is the SHINE study. So large randomized trial, frontline mantle cell lymphoma in older patients. So again, great to see randomized data in this group, not necessarily an easy study to deliver comparing rituximab and bendamustine given in pretty much the standard way with rituximab, bendamustine in addition with ibrutinib that continued until toxicity or progression. And the take-home message from my perspective was PFS benefit, I think, is about 2.3 years, no overall survival benefit, potentially a toxicity signal, surprise, surprise, if you’re adding in another agent with chemotherapy.

Yeah. It’s proven slightly controversial, I think it’s fair to say this study, certainly in the Twittersphere, there’s been a lot of debate about its design and the relevance of the results. Wendy, can I come to you? I mean, is this something, obviously it’s not approved by NICE. I understand it may be going down that route. So who knows, it may become available. Yeah, would this be something you would consider in older patients?

Wendy Osborne:

Yeah, so I think it’s always interesting when designs are openly criticized when we know that you have to design many years before you can actually deliver the trial and things change and we understand more about the data and to have this randomized data, I think, is helpful. At the moment, as you know, we’ve been able to use upfront ibrutinib during the pandemic to try and reduce patients’ admissions to hospital and their toxicity. And we’re also awaiting data from the UK ENRICH study, again, looking at upfront ibrutinib. So I think that these data wouldn’t change my practice. There’s no survival benefit, and if we use second-line ibrutinib, we still get this similar outcome. So at present, I would still, whilst we are allowed in terms of the funding, to use ibrutinib frontline, if not second-line, for my mantle cell patients.

Graham Collins:

Yeah. Thank you, Wendy. And Andy, your thoughts on SHINE?

Andy Davies:

Yes. I agree with Wendy’s comments. I mean the one thing to note is that the time to next anti-lymphoma therapy was significantly extended in those patients who were at risk in the ibrutinib arm. So for older patients who may have comorbidities, it might provide a potential option. But I do think it’s important that we think about the toxicities of ibrutinib. We think about some of the low grade toxicities of ibrutinib, of continuous therapy, and I think from my mind, I continue to wish to sequence them by giving induction chemotherapy followed by maintenance rituximab and then wait until progression then to give ibrutinib in the second-line setting. And of course the whole kind of sphere of BTK inhibition is changing, isn’t it? We’ve got next-generation BTK inhibitors, we’ve got different BTK degraders coming on. And I think there’s lots of things that we’re going to see changing over the coming years. So I think actually in terms of sequencing for mantle cell lymphoma, I think we’re going to have more options in the future. So probably my take-home on SHINE is no change in UK practice.

Graham Collins:

Yeah. Yeah. I think you’re right, Andy. I mean, one thing I found difficult interpreting the data was to understand the toxicities because like most studies, the maximum grade of toxicity was reported and we want to see that data, but it’s also very relevant if you have a grade two adverse event, for example, if it lasts for two months versus 20 months. And of course, if you’re on a continuous therapy like ibrutinib, you may well guess it’s a fairly low grade that lasts for a prolonged time. And I didn’t really get a sense of that. And one way of maybe getting a sense is to look at those who discontinue therapy and there was a significant minority who did discontinue ibrutinib due to adverse events. So there clearly is a toxicity signal, as we all know there is with ibrutinib. So yeah, likewise I think it probably wouldn’t change my practice at the moment. Okay, thank you. Again, let’s go back to bispecifics. So Andy, mosunetuzumab data, I think, was presented in indolent non-Hodgkin lymphoma. Interested to hear your thoughts on that.

Andy Davies:

Yeah. A smaller bit of data, really. It was posters, it was a subgroup analysis of some of the things that we’ve seen already, but I think there was just two key take-home messages. I’m not going to go into much detail, but one of those was that the efficacy of the bispecifics was similar between those patients who are older, i.e. over the age of 65, and those patients who are younger, and therefore this concept potentially of immunosenescence and risk that the T-cell activation may not work in older patients probably is something that we don’t need to worry about. The other observation that we saw was that re-treatment with bispecifics in patients who’ve initially responded, relapsed, and then are re-treated actually appears to be a very effective approach as well. And again, something that’s really, very interesting. And I think that story, it’s a small numbers of patients, but will sort of unravel further. So although that’s not going to change practice now, but actually we are looking at potential approval of mosunetuzumab within the coming months and we will potentially think about some of these analyses really.

Graham Collins:

Yeah. Yeah.

Wendy Osborne:

And that, I think that re-treatment data is really encouraging, because we know from patient reported outcomes that they don’t like to be on continuous therapy. So the option of having a fixed duration therapy, knowing that they could have re-treatment if there is further progression, is really encouraging and with various approvals now being obtained, we will, if there is UK approval and funding, need to learn how we deliver these treatments of bispecifics safely within our NHS setup, because we want to make sure that we can deliver it safely for these efficacious options for our patients.

Graham Collins:

Absolutely. Thank you. That’s a good point. And sticking with indolent non-Hodgkin lymphoma, perhaps let’s move on to, maybe I shouldn’t call mantle cell indolent, but there was longer follow-up data for CAR-T therapy, in particular axi-cel in relapsed mantle cell lymphoma. It’s good to see that because obviously it was pretty early data, which the license and reimbursement was based on. I don’t know about you guys, but I thought really good data. I mean, it’s very good data, but I wasn’t yet convinced there’s a plateau. I’m not sort of saying to patients who I refer for CAR-T yet that it’s potentially curative, whereas I do for relapsed high grade, and there was some interesting data as well on sort of T-cell fitness and prior bendamustine. Andy, what was your thoughts on that?

Andy Davies:

Yeah, so it was great to see. We see our 36-month follow-up data, and as you say, the original publication, we only had 12 months and we can see that those patients who achieve a CR really do very well indeed, but I agree with your guarded analysis of it. I mean, I remember when we first saw the reports of the Nordic MCL 2 regimen, everyone was jumping up and down and saying, these are cures for mantle cell lymphoma, but of course there’s that continued attrition with this disease and those curves as the years go by do start to drop off. So I think we have to wait to see longer data. But I think the number of events that were counted after 12 months actually was very small and actually the other important thing was that the number of new adverse events with long-term follow up was pretty limited as well. So I think that the caution about long-term toxicity is there’s nothing new compared with what we’ve learned from diffuse large B-cell lymphoma.

But I think what was interesting was about going back to sequencing in mantle cell lymphoma, because there were some important lessons about fitness and the fitness of the T-cells. And I think if you looked at patients in sort of an analysis that was done in an ad hoc way [inaudible 00:31:22] post-hoc way was that those patients who had bendamustine more than six months ago and those patients who’d had bendamustine less than six months prior to T-cell collection were analyzed. They were relatively small numbers, and for those patients who had had bendamustine within the six months before collection of the T-cells, both the expansion and the peak expansion and the area under the curve of those T-cells was significantly reduced compared with T-cells collected from patients who’d had bendamustine more than six months ago. So there’s no doubt that bendamustine affects your T-cell fitness.

I think it’s quite reassuring to see that those patients who were treated some longer period of time beforehand, actually you can still get effective expanding T-cells. So I think we probably don’t need to be completely guarded about bendamustine in those patients where there has been a significant disease interval, but I think we do really need to be very careful about using bendamustine in those patients where we think CAR-T cells are going to be something that we’re going to want to do relatively soon. So those patients with poor-risk disease features clearly will want to stay well clear of bendamustine.

Graham Collins:

I find it really interesting how a new therapy impacts the therapies you’re going to give before it like this. I mean, Wendy, do you think we can extrapolate this to high-grade lymphoma as well?

Wendy Osborne:

I think that we are all very cautious about using bendamustine. At present, we would consider, certainly in the UK, even though it isn’t the approval with using rituximab, bendamustine, polatuzumab as our bridge as standard, that’s the standard approach, and we would be very keen to not do that before we’ve apheresed the patient because of concerns about bendamustine on the T-cell fitness. Now that does lead to problems if you’ve delivered the bridging therapy and then there’s a failure of manufacture and you’re going to have to then re-apherese for the patient to try and get those T-cells. So I think that we are trying to avoid bendamustine as much as possible, but we don’t know clearly how much it does affect our ability to manufacture a CAR-T product.

So I think that that understanding of sequencing, understanding of effect on subsequent therapies really needs to allow us to then guide our choice of selection. So in mantle cell, would we be better if we are using an R-chemo frontline approach to use the bendamustine frontline, save the BTKi for second-line, or rather than using CHOP frontline and using bendamustine later? I don’t know yet, but I think as Andy has said, it appears that the longer duration between the bendamustine and the apheresis is really important. And I also think you are right about not calling mantle cell indolent. I think it is the one in between that can behave either in an indolent way or a high-grade way. So it doesn’t fit in either of the categories.

Graham Collins:

Absolutely. I think we all struggle sometimes getting our relapsed mantles to CAR-T, don’t we, for that very reason. It can really blast off sometimes, which is hard for everybody. Yeah. Okay, thank you. Well, look, I think that’s been a really fascinating conversation and a tour de force of Hodgkin aggressive and indolent non-Hodgkin lymphoma summarizing some of the key data from EHA and the summer meetings. So thank you, Andy, very much, and Wendy, thank you very much for your contributions to the discussion. Really interesting. Thank you.