Welcome to The Lymphoma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Graham Collins & Wendy Osborne, who debate the latest updates in the treatment of lymphoma from the ASH 2020 virtual Annual Meeting and share how the new research and clinical updates can help improve patient management strategies in UK clinical practice.
The topics of discussion include the latest updates in targeted therapies for diffuse large B-cell lymphoma, CNS prophylaxis, CAR-T therapy, BTK inhibition in mantle cell lymphoma, the management of Hodgkin lymphoma and more.
Diffuse Large B-cell lymphoma and other aggressive lymphomas
“So I think we’re all probably even more excited about bi-specifics now than prior to attending the sessions at ASH. I mean, the bi-specifics, which worked with a CD3, CD20, so bringing those T-cells together to have tumor target and tumor cell death. They appear to be efficacious and there were four bi-specifics that were presented. And, you know, one of them was even used in a frontline setting in older patients, so the mosun was used in that setting. And I think that really, what was so encouraging about the bi-specific data were the safety, we know that they do cause cytokine release syndrome, we know that they do cause tumor lysis syndrome, but there didn’t seem to be much in the way of neurotoxicity, which we worry with using this immune effector mechanism. And my feeling was that I want to see longer term follow-up, but really quite encouraged by this off the shelf treatment for patients mainly used in a relapsed/refractory setting.”
– Wendy Osborne
“And then I think we saw some very interesting data in mantle cell lymphoma in particular with the LOXO agent, which is a non-covalent BTK inhibitor, which very much impressed me. I thought really quite good response rates for a BTK inhibitor failed population. And I find, Wendy, that post BTK inhibitor space very challenging.”
– Graham Collins
“I was really surprised by these data if I’m honest. It doesn’t make sense that somebody who’s failed a BTK then goes on and has this non-covalent BTK and has such a good response. And almost everybody in the trial had failed a previous BTK – 60 odd patients, so reasonable numbers. So, this was an example of I was really excited and encouraged by this.”
– Wendy Osborne
“And older patients with Hodgkin. I mean, we’re aware that, that’s an area of real unmet need with patients struggling sometimes to get ABVD-like treatments into them. As a UK, we delivered on the BREVITY study so brentuximab monotherapy, and those not deemed suitable for standard combination chemotherapy. And the outcomes were, I think it’s fair to say fairly disappointing. But interesting results using brentuximab in combination, I thought. And again, do you, it’s always difficult, isn’t it? Because we can’t use it at the moment in combination upfront, but what would your predictions be? Do you think that’s going to have an as an agent in these patients?”
– Graham Collins
“I think possibly it is. I think that the data presented were encouraging with brentuximab used with dacarbazine and with nivolumab as well. It was interesting that when used in combination with bendamustine that was too toxic and I think they either had to close the arm or they certainly didn’t recruit further into that arm. But the efficacy was better than we would have thought. And obviously, as you said, that single agent brentuximab, we were disappointed with the outcome from BREVITY, although they were really high-risk patients that went into that study. So, I think using these targeted therapies, whether it be checkpoint inhibition or antibody-drug conjugate upfront, I think will be of benefit to patients because it’s difficult to tolerate ABVD for many patients once they get 70 or over. And then we have this big discussion in the MDT about what do we give them.”
– Wendy Osborne
Graham Collins: Okay, well, thank you very much, everyone for joining us for this Lymphoma Session, post-ASH for VJHemOnc, I’m delighted to be joined by Dr. Wendy Osborne, who is a consultant hematologist from Newcastle. My name’s Dr. Graham Collins, a hematologist, and lymphoma lead from Oxford. So Wendy, let’s dive straight in, shall we, to diffuse large B. I guess perhaps slightly disappointing, there were no big trials that were reported. But we did see some interesting data, I think on bi-specifics. What was your take on that?
Wendy Osborne: So I think we’re all probably even more excited about bi-specifics now than prior to attending the sessions at ASH. I mean, the bi-specifics, which worked with a CD3, CD20, so bringing those T-cells together to have tumor target and tumor cell death. They appear to be efficacious and there were four bi-specifics that were presented. And, you know, one of them was even used in a frontline setting in older patients, so the mosun was used in that setting. And I think that really, what was so encouraging about the bi-specific data were the safety, we know that they do cause cytokine release syndrome, we know that they do cause tumor lysis syndrome, but there didn’t seem to be much in the way of neurotoxicity, which we worry with using this immune effector mechanism. And my feeling was that I want to see longer term follow-up, but really quite encouraged by this off the shelf treatment for patients mainly used in a relapsed/refractory setting.
Graham Collins: Yeah. I was quite struck by the fairly consistent CMR rate of about 50% in high grade, at least in the pre-CAR-T setting, which was really good, actually, I think, wasn’t it? Because I guess we’re all after that holy grail of CRs in these difficult patients. Yeah, no, so it was interesting. And there were some interesting strategies, weren’t there? Like, one of them, I think it’s the glofitamab was using a subcut administration, which seems to maybe be associated with reduced toxicity. Then there was this step-up dosing that seems another way of reducing the toxicity. So it’s interesting strategies, I guess that started.
Wendy Osborne: Yeah. I think they’ve recognized that one of the main thing is trying to reduce the toxicity. I think we’re all happy that they are efficacious and the glofitamab being given sort of a day minus seven, had been a obinutuzumab as well to try and block that CD20 to try and mitigate the CRS risk. So, all quite different often in terms of how they were given, whether it was sub cut, whether it was step-up dosing. But yet very similar in terms of efficacy. And then this often led to a lot of debate and then the question and answer sessions this for and against bi-specific versus CAR-T, and I think that this debate will continue until we have longer follow-up data, because they’re both very different and both, I think have pros and cons in whichever approach you use.
Graham Collins: And talking about CAR-T data, we saw some of the ZUMA-12 data, which was quite interesting, wasn’t it? Using CAR-T in that high risk setting. What were your thoughts on that? Wendy Osborne: Yeah, so I think really interesting, I mean these days, you mean small numbers and patients with the ZUMA-12 had to be both high risk and they have to be iPET-2 positive. So they were given two cycles of standard R-CHOP treatment. And if they were iPET-2 positive, then they were given axicel as part of the trial protocol. I think we need to be cautious that these patients truly are high-risk. So, half of these patients were Deauville score of 4. So, we don’t know what that means, that may be that, that’s a false positive. We don’t know what the partner genes were in the double hit patients who were considered high risk. So, I think that a brave strategy for how they selected these high-risk patients. But it makes sense, we know that these patients often don’t do well with R-CHOP. So, I thought that these data were really interesting.
Graham Collins: Yeah. Yeah, absolutely. And one of the really interesting things I thought in diffuse large B this year was the sort of very controversial area of CNS prophylaxis, which is always seems to get people’s hearts racing and opinions spouting, me no less than anyone else, I guess. And there were two very interesting presentations, weren’t there? Of retrospective analysis with all the caveats that they come with, looking at the efficacy of intravenous high-dose methotrexate in high-risk patients with frontline diffuse large B treated with intravenous high-dose methotrexate. And I guess the take home message from both of those was, it didn’t seem to be associated with a reduced CNS relapse rate. So I mean, Wendy, will this change what you do in Newcastle, or what were your thoughts?
Wendy Osborne: I mean, we’ve been arguing, oh, well, for years it feels like about the benefits of CNS prophylaxis and we know who the high-risk patients are, I think that’s clear. We’re using the CNS-IPI, we know who the high risk are. But we don’t know if it is beneficial to give any intrathecal, any intravenous methotrexate. A recent good practice paper led by Pam McCain, colleagues from the BSH has been really helpful and their conclusion was that we should actually move away from intrathecal and start using intravenous methotrexate as a prophylaxis. And there has then been arguments about whether we give it intercalated or whether we give it at end of treatment. With my concern, giving intercalated is causing delay of the proven R-CHOP therapy and we know data to show that it does cause a delay. So our practice at the moment in Newcastle is to give it at end of treatment. Now these two datasets from ASH, one showing no, no difference in IV or IT, and then the other one’s showing actually no benefit from the IV methotrexate. But there were some problems with this retrospective data. There were, when you looked at how the data was collected and how in one of them, a third of the patients who had a high CNS-IPI didn’t receive any prophylaxis anyway. So, having analyzed the data, I think that probably this won’t change our practice. So, we would still discuss the risks and benefits with the patients with high CNS-IPI and give it at end of treatment. I’m still not sure whether I’m fully a believer that it’s doing ofany benefit, but you have to be brave to stop it completely. But I’m very cautious about giving it to patients over the age of 70, because it does cause harm. And there’s definitely no evidence that it causes good. So it was very controversial and there was certainly a lot of discussion over Twitter following those two presentations, I think.
Graham Collins: Yeah, I thought it was very interesting. And I was interested with the reactions – I think they ranged from therefore we should stop giving CNS prophylaxis to actually we need to give more CNS prophylaxis because what we’re giving isn’t enough. And then probably the majority reaction, which I think is what you’re saying went in, certainly is where I am with it. Is that, look, these are abstracts, retrospective, we haven’t even seen a peer reviewed paper yet, so we need to wait. And it’s, as you say, you’ve got to be brave haven’t you just to stop something that you believe is might be, at least might be preventing a really catastrophic complication of [inaudible].
Wendy Osborne: Yeah. And one thing that I think was really important is that I think that we know how important that first, that R-CHOP treatment is and making sure we’re getting dose intensity, right for that. And obviously, in some of these retrospective data, they didn’t talk about what the true dose density achieved of the R-CHOP was, which is important. But, there’s so many confounding variables. So for me, it’s too early to change. Although, I’m sure that some people have looked at these presentations and decided they’re stopping all CNS prophylaxis.
Graham Collins: Yeah. And actually one, a case I’ve been thinking about just this week. I think these data has influenced me because this was a 72-year-old. So, over the sort of age, not as an age cut-off, but over the age that perhaps we feel comfortable giving this with. Who really had quite difficult stage four disease, involved uterine, involved uterus. So, many would regard that as quite a high-risk sight. But actually, she’s quite poorly during the R-CHOP and is quite deconditioned. And she was heading for IV methotrexate, that was the sort of decision at the MDT at diagnosis. But I think now actually we almost certainly won’t. And part of that is, I think from my perspective is slightly influenced by this data, saying if there is a benefit, it’s probably not huge. And you’re right. It can cause harm content can’t it, in some patients. So, yeah. Interesting.
Graham Collins: So perhaps what about sticking with the theme of aggressive lymphomas? There was a randomized trial presented with T-cell lymphoma, which is a rarity and really nice to see. I mean, it was brilliant. I thought fantastic of the LYSA group to run a large randomized trial of CHOP versus romidepsin CHOP, but a negative outcome. I mean, was there anything we can take away from that trial, do you think, Wendy?
Wendy Osborne: Well, first of all, I think it is really important that we present these negative trials, because I think that sometimes they’re brushed under the carpet and they’re still valuable. I think that what we’re… There was some suggestion in the presentation that maybe the angioimmunoblastic patients did have some response from it. I think that the numbers were too small for that. Really, my feeling is that I think it’s, with such a rare disease, and now we know it isn’t just one disease. We know all of the different subtypes behave in often a very different way that probably we’re going to have to start looking at trials, looking at different, the subtypes of the T-cell lymphoma. So, for example, the oral azacitidine data that were presented in combination with CHOP, there was a suggestion that maybe T-follicular helper cell subtypes should be again, managed in different ways. That if we now going to design trials with different subtypes of an already rare disease, it’s going to have such large international collaboration. And really my take home is it’s difficult to do a trial in T-cell lymphoma. We need to get those numbers up, particularly with all of these different subtypes. And therefore, we’ll need to work internationally to get, to try and find an improvement in this otherwise very worrying disease.
Graham Collins: Yeah, absolutely. I guess just to plug, there is an international rare cancer initiative that Matt Ahearne from Leicester has helped set up and I think that’s brilliant, isn’t it? As you say, get this international collaboration. And how about the, there was a much smaller study, wasn’t there? Combining CHOP with oral azacitidine. Interesting concept. Do you think that’s got legs?
Wendy Osborne: Yeah, I think an interesting concept. And does it have legs? I do think that. I mean, there was maybe 20 patients in this trial. So small numbers, but a response rate of, very high unexpectedly high response rate. And so for me, this was a signal and my understanding is that this is being taken into the next ALLIANCE study, looking at CHOP plus oral azacitidine. Because, the responses were better than we would have thought for this group of patients.
Graham Collins: Yeah. Yeah. I guess again, that would be, it was quite enriched, wasn’t it, I think for TFH lymphomas that, and you do wonder if that should be really where this drug is, finds its home, with the myeloid-type mutations tend to and IDH…
Wendy Osborne: I mean It makes sense biologically, doesn’t it? And this is how pulling out that subgroup within the different trials is the answer, because targeting the different biological approaches does make sense. And with these responses, it was certainly something that I would agree that we would, should be taking forward.
Graham Collins: Yeah. And there was a very nice, wasn’t it, retrospective presentation or retrospective study on a allografting grafting in T-cell lymphoma. And I guess the bit that struck me was the very small number of patients who had a hepatosplenic T-cell lymphoma. But about a 50% long-term survival, which is better than I’ve ever, sort of seen. And my limited experience of that diseases it’s horrendous. But there were a lot more patients than that. Does that influence where you see the role of allografting, Wendy, in T-cell lymphoma?
Wendy Osborne: So, I mean, these data are good because of the numbers. I mean there were 500 patients and I think that maybe more than 250 were taken into allo in a CR, and the rest in a partial response. And so that in itself answered one question is, should we be taking PR patients into allo? And my conclusion from these retrospective data would be, yes, because we’re still seeing that graft versus lymphoma effect. So therefore taking them in a PR makes sense as we would with a Hodgkin lymphoma patient, for example. And again, I mean, if you look at the data for hepatosplenic T-cell, internationally is poor and the outcomes are poor. And there could be an argument, would you put a patient through such an intensive procedure as an allo for such an aggressive and poor outcome when you’re consenting the patients. So again, when we looked at that subgroup in these retrospective data, it was better than I thought it would be. So, to my practice still would be to try and take a hepatosplenic T-cell in frontline to allo, whereas for other T-cells I would consolidate with auto and only allo them in a relapsed/refractory setting. And it probably hasn’t changed my practice, but it’s given more information when we’re talking to our patients about allo and about the consent process, so I thought this was a really helpful presentation.
Graham Collins: Absolutely. I was quite struck by the quite high percentage of patients who were having their allo without having had an auto first, though. It did make me think in the US, is that more of a accepted practice? Because like you, I knew it would nearly always autograph first apart from the rare, very aggressive subtypes. So I did wonder if maybe that’s just a difference in practice.
Wendy Osborne: I was surprised by that as well because I think that there’s always so much argument about, do you auto up-front or not? And then there’s many people who don’t believe in that approach. So, it was surprising that so many patients actually allo-ed upfront for this. So, but you know again, this shows the importance of collecting these data. And obviously, if we could start to collect it prospectively, then it’s more accurate and we could have more informed discussions with our patients.
Graham Collins: Yeah, absolutely. And just briefly on Burkitt lymphoma, I mean, it was great to see this massive dataset that had been collected really across the globe, US and ex-US, was the way it was sort of split. Very nice in validating the Burkitt lymphoma-IPI that they’d previously described. But, I think that making really good progress on identifying a high-risk group of Burkitt – so over 40 LDH, over three times upper limits of normal, CNS involvement which I thought was really helpful. I think performance status two or more was the other criteria. Any other sort of take-homes that you took from that data, Wendy?
Wendy Osborne: So again, a rare disease, we maybe see one patient a year in Newcastle with Burkitt lymphoma. And our standard approaches are CODOX-M/IVAC. And I think that there’d been some concern as to whether, we know that in the US that they use a lot of DA-R-EPOCH. And there were other data presented about Burkitt showing that the outcomes were equivalent. And actually there was less CNS relapse in the patients who had the CODOX-M/IVAC. So, I think that really from the Burkitt data presented at ASH, the useful things were this prognostic index, which seems more, which has been validated and is more accurate than just the standard IPI. So again, useful to discuss with patients. And second, I think continuing with the CODOX-M/IVAC approach, particularly for those CNS risk patients. And what we need and is actually open and recruiting is a randomized study for us to see whether DA-EPOCH which is much less toxic and better tolerated is as equivalent compared to CODOX-M.
Graham Collins: That’s a really good outcome of that study, isn’t it? Because I think some people may have even said it, it’s not really ethical to randomize. But I think that the data suggests, yes, it is. It is unclear which is better, if one of them is better. So yeah.
Wendy Osborne: So, I think it’s made that study more relevant than ever. So again, when we think about what we’re bringing home for the UK, when having looked at all of these data. Really wanting to put patients into this trial, knowing that both are efficacious.
Graham Collins: Yeah, absolutely. So moving on to indolent non-Hodgkin’s lymphoma, a reasonable amount presented there, I thought. Again, some more data on CAR T-cell looking very active. Do you think it’s going to find a home in indolent lymphoma, Wendy?
Wendy Osborne: Yes, I do. So ZUMA-5 data were presented were indolent, but mainly patients with follicular within the study. And Caron Jacobson, and I think presented that. And again, it looks very efficacious. I think that this could be an interesting area as to whether bi-specifics or CAR-T. They’re both on the starting line at the same time, really. We’re looking at this data coming through at a similar time for both indolent showing for both bi-specifics and CAR-T really effective. And as I’ve mentioned earlier, the pros and cons of each approach. So, I think, we always think of indolent as easy to manage until we’ve got that patient who’s just on their third relapse or a POD24 early relapse, and we need to have better outcomes for them. So, I was quite excited by the ZUMA-5 data, to be honest. And I really want to look at longer follow-up for that and compare that with the bi-specific data.
Graham Collins: Yeah. I’ll be really interested as well. If, and when the CAR-T does get a license in relapsed indolent and NICE, or whoever looks at the data to fund it. How are they going to define, because presumably they’ll define some sort of high risk. And that’s always the thing, isn’t it? Is how do you define high-risk follicular? Would it be POD24? Will it be double refractories? I’ll be fascinated to see what the criteria is for us using them.
Wendy Osborne: Yeah, I think that’s true. And I think, as they have with our currently available commercial CAR-T they, NHS England initially looked very much on the criteria within the trials. So they’ll probably be looking as well at the ZUMA-5 criteria. But that CAR-T is not without toxicity. So we do have to be mindful that we are selecting the right patients and not, you know, maybe giving it to patients who could have gone on with a good progression through time with much lower-risk treatment. So this is going to be, I think, quite a clinical dilemma if it does get approved.
Graham Collins: Yeah, absolutely. And then I think we saw some very interesting data in mantle cell lymphoma in particular with the LOXO agent, which is a non-covalent BTK inhibitor, which very much impressed me. I thought really quite good response rates for a BTK inhibitor failed population. And I find, Wendy, that post BTK inhibitor space very challenging. What’s your go-to at the moment for post for BTK failures with mantle, and do you think this drug might find a role?
Wendy Osborne: I was really surprised by these data if I’m honest. It doesn’t make sense that somebody who’s failed a BTK then goes on and has this non-covalent BTK and has such a good response. And almost everybody in the trial had failed a previous BTK – 60 odd patients, so reasonable numbers. So, this was an example of I was really excited and encouraged by this. I know that you’ve got this trial open in Oxford, I think it’s really well tolerated with good efficacy. At the moment, what do we do? We would try and tend to give them often the R-BAC regimen and then take them to allo if they’re fit enough. I think mantle cell is becoming a disease because it’s so variable. You have, the patients have really indolent disease, which never causes any problem. And then these patients with awful aggressive blastoid disease who you want to know about almost upfront. And I think mantle cell lymphoma management is changing. And I think, we wanted to know their p53 status up front. Would that lead us to maybe use more of an intensive allo approach upfront, which I know is done in some centers. And then in a relapsed/refractory setting, we’ve got trial options, but also I think CAR-T, we know that they look really encouraging – the [inaudible] data for mantle cell looks fantastic in terms of response rates. And ASH this year, the liso-cel cell data were presented for mantle cell. Again, really impressive. Similar response rates with often can be given in an outpatient setting. So I think mantle cell particularly was a of real great interest this year at ASH.
Graham Collins: Yeah. I mean, it is a disease where I would predict, as I think you’re saying, Wendy, as well, CAR-Ts are really going to have an impact. So yeah. Hopefully, we’ll be able to use them fairly soon. So yeah.
Wendy Osborne: I hope so.
Graham Collins: Okay. Then moving on to the mighty Hodgkin, you’re and my favourite lymphoma entity. And again, no big sort of clinical trials presented, but there was some very interesting follow-up data on the AHL 2011, I mean really good results. I mean, long-term, progression-free survival of 87% in both the standard and the experimental arm. With the experimental arm, basically being a PET driven de-escalation from escalated BEACOPP to ABVD. Although I think LYSA now de-escalate to AVD pretty much routinely. Some interesting fertility data there, Wendy, is that going to influence how you might use that strategy?
Wendy Osborne: Yeah. I mean, when we’re thinking about changing practice, probably these longer term follow-up will change and has actually changed my practice just since it’s been presented. Because to be honest, for most of our advanced Hodgkin, we tend to in Newcastle, use an HD18 approach for most patients because we know that if they are PET negative, so Deauville one, two or three, we would then go on and give them only four cycles of escalated BEACOPP. So, it’s not common that we would consider saying to a patient, okay, you’re PET negative after two BEACOPs your choices are either six more weeks of treatment or four months of treatment with ABVD as in the AHL 2011 study. I think the main difference would be, when we’re thinking about fertility, because it’s the fertility, particularly young women where when we have the discussion about HD18 versus a RATHL approach upfront, although because of efficacy, we tend to move more to HD18. It’s the concern about the efficacy and the fertility for patients. So, what these data showed, where that, you know, they measured markers of premature ovarian insufficiency, and they showed there was a five times reduction in POI compared to the standard arm, which patients ended up having six escalated BEACOPP. So, not the four that you do can get to 75% of patients in HD18. So, now if I’ve got somebody with high-risk disease, I would be keen to start with escalated BEACOPP. If they reach that PET-2 negativity, which remember is 140% of [inaudible] different. So it’s like a Deauville four and a half, and five is a positive. Then I would now have deescalated to four AVDs, which is what I know that the LYSA group are doing to try and reduce that their fertility toxicity. And again, this is really useful data to be able to talk to patients about in clinic with this further follow-up.
Graham Collins: Yeah, absolutely. And I’ve certainly used that strategy in patients who didn’t tolerate the two escalated BEACOPPDacs well. I was actually quite worried about a particular patient who was admitted for sepsis on each cycle. And I was really nervous. She was a slightly older patient, really nervous about giving two more. And so I just found the efficacy data very reassuring that de-escalating, I could be as upbeat and optimistic that it was associated with a good outcome. So yeah, no, I absolutely agree.
Wendy Osborne: I think that the 87% efficacy is obviously good. You could argue it’s not as good as HD18 – there’s like 92%. But what I think we’ve got to remember is that, that is the real higher risk patient is. Because they’ve counted the Deauville score is slightly higher for their positivity. So you would expect it to be a bit lower, but again, having all of these information and data to talk to patients about and about weighing off, maybe losing a few percent PFS in order to try and preserve fertility is really important.
Graham Collins: Yeah, absolutely. And older patients with Hodgkin. I mean, we’re aware that, that’s an area of real unmet need with patients struggling sometimes to get ABVD-like treatments into them. As a UK, we delivered on the BREVITY study so brentuximab monotherapy, and those not deemed suitable for standard combination chemotherapy. And the outcomes were, I think it’s fair to say fairly disappointing. But interesting results using brentuximab in combination, I thought. And again, do you, it’s always difficult, isn’t it? Because we can’t use it at the moment in combination upfront, but what would your predictions be? Do you think that’s going to have an as an agent in these patients?
Wendy Osborne: I think possibly it is. I think that the data presented were encouraging with brentuximab used with dacarbazine and with nivolumab as well. It was interesting that when used in combination with bendamustine that was too toxic and I think they either had to close the arm or they certainly didn’t recruit further into that arm. But the efficacy was better than we would have thought. And obviously, as you said, that single agent brentuximab, we were disappointed with the outcome from BREVITY, although they were really high-risk patients that went into that study. So, I think using these targeted therapies, whether it be checkpoint inhibition or antibody-drug conjugate upfront, I think will be of benefit to patients because it’s difficult to tolerate ABVD for many patients once they get 70 or over. And then we have this big discussion in the MDT about what do we give them? And certainly, we’ve started to follow the Glasgow regime of using ACOPP where Pam McKay developed that, sort of dose reduced BEACOPP essentially without the bleo or etoposide. And these data look encouraging all those small numbers. But I think if in the future we’re able to use a targeted agent upfront, then that could be a better outcome for these patients because we know that they do badly, our patients with older Hodgkin’s lymphoma.
Graham Collins: Absolutely. And I guess that leads on to the role of checkpoint inhibition, where you know, each conference, you seem to get more and more data on checkpoint inhibition in Hodgkin, in various guises. So there was the longer term follow-up of the NIVAHL study using it frontline, which had in early unfavorable patients where they had, I think it was, there were two cohorts, one was a 98% progression-free survival. And the other was 100%, albeit every patient had radiotherapy. Incredibly good data. Then there was the pembrolizumab GVD first relapsed data – over 90% CMR rates, albeit in a relatively small number of patients. I mean, incredibly impressive. How can we incorporate these agents properly Wendy, it sort of seems that us using them post auto, post BV, single agent? I worry we’re behind the curve in the UK. Not that we can do anything else, it’s not licensed. But where should we really trying to use these, do you think?
Wendy Osborne: I mean, the study you mentioned, the pembro plus the GVD, I mean, those outcome were really impressive. Allison Moskowitz presented that and I mean, they use liposomal doxorubicin. I mean, that will add significantly to the cost. But I think really what we, you know, we’re putting a lot of people through an auto transplant. And the question for me is, is this necessary? Do we really need to have that toxicity for treatment? Could we bring checkpoint inhibition in with that second line treatment, maybe with maintenance to prevent some patients going to auto? Now, the question for me is how we select which patients could avoid this. And I know that there are ongoing studies in the US where they’re using maintenance rather than autologous stem cell transplant. But I think checkpoint inhibition frontline, and I know with the AVENUE study, I think that now that we are seeing more data, it is much more reassuring. I think, to start with, because we get such good outcomes for so many patients with frontline treatment, we’ve just talked about those high percentage rate, it’s very, you have to be quite cautious I think bringing something in frontline. But these window studies are showing such fantastic outcomes. So I think that these look encouraging, and particularly for me, frontline, for the patients who can’t tolerate the standard HD18 approaches, you said the older patients bringing in their frontline. And then I would be keen to bring them in second line for those patients trying to avoid an auto for them. That would probably be where I would see them. I don’t know what were your thoughts.
Graham Collins: Yeah. So, I was also struck by, I think it was a poster that was reporting on heart failure later effects in patients who had only had ABVD versus those that had also had mediastinal or radiotherapy. And it was something like a 2%, 10-year heart failure risk with ABVD. Which, okay, it’s not a huge, but it’s one in 50 and it’s a devastating complication. It was doubled if you had radiotherapy. But I guess it did again, make me think that, as a hematologist, like you, who prescribes this chemo all day, every day, we are doing damage. Now, we’re also curing a lot of people and the risk benefits is very much for benefits in giving the chemo. But it did make me think, you know, even in younger patients, I still think there may be a role somehow in incorporating checkpoint inhibition upfront to try and reduce the chemo burden. But of course these agents have their own toxicity profiles. So, as well as sharing the sort of mechanism of action out, you’re also sharing the toxicities out. And it’s hard, I think, to know exactly how we’re going to benefit young frontline patients with this approach. But I think there may be a role in the higher risk patients. But like you, Wendy, I was very struck with the pembro GVD. And you know, if that’s… I mean, it was, I think it was about 34 patients. It was quite small numbers, but if, you know, I’ve just never seen that CMR rate before.
Wendy Osborne: It was 92% or something, wasn’t it? It was unbelievable. And you sort of think, well, if you’re going to get that many patients, even if you’re consolidating them with allo. A few of them did get the brentuximab maintenance as per the AETHERA approach. I don’t know what that is going to add, but you know, a 92% CMR, it makes us think our standard current second line treatments aren’t achieving that. And we do need to improve upon that. But as you say, in the UK, apart from in a trial setting, we can’t bring them in earlier than third line at the moment.
Graham Collins: Yeah. And I guess it did, I mean, I know we always say it, but it really did scream out to me, come on. We need a randomized trial in that first relapse setting because it’s not that uncommon around the world, particularly relapsed Hodgkin’s. It’s probably commoner than frontline T-cell and there we saw the LYSA group deliver on the [inaudible] CHOP study. So, we can do it as a global community at least. So it’s, yeah, it’s frustrating that we don’t have that sort of data to support further approvals. But yeah, but no fascinating data. Wendy, look, it’s been a really interesting conversation and thank you very much for your thoughts and applying it to UK practice. I think it’s been a fascinating ASH and it’s always great, isn’t it, to mull over the data and see where things are going to land. You know, at ASH this year, we had some controversy with the high dose methotrexate, CNS prophylaxis. We saw some interesting results from new agents – the LOXO study. Some sort of watch this space data such as the oral azacitidine and CHOP data in frontline, peripheral T-cell lymphoma and some interesting long-term follow-up from a large clinical studies such as the AHL 2011. And I think, although, it’s hard, isn’t it? To your finger on and say this was practice changing. I think a lot of this is practice informing and does give us more data to discuss these things with our patients who ultimately are the people we’re subjecting these treatments on. So, I think it has been an incredibly useful ASH, despite it being virtual. And we all missed, I’m short bumping into our friends for a coffee. But, Wendy, thank you again for joining me. And thank you, VJHemOnc for running this session.