Evolution of first-line management of advanced Hodgkin lymphoma (HL)

DR ANSELL: If one goes right back to the beginning there’s been a lot of debate about what’s the optimal treatment to give to patients with Hodgkin lymphoma. So there’s been a big discussion about is it ABVD chemotherapy, is it escalated BEACOPP, and the reason for that is the results with escalated BEACOPP show a higher response rate and better progression-free survival but not overall survival.

And the problem with that was many people that received ABVD could then receive salvage chemotherapy and a transplant and kind of catch up if you like, and there was more toxicity with escalated BEACOPP. So in North America most people felt comfortable using ABVD chemotherapy with the thinking that you gave less therapy, less toxicity, less complications, and then if it turned out you had evidence for patients getting disease coming back you could make a difference then by adding additional salvage and transplant and kind of catch up where you might have fallen behind.

But that’s been very contentious. And the reason that matters is that we’ve really struggled to find an overall response benefit from one therapy when compared to another. So that’s actually what makes the ECHELON data pretty remarkable. We can possibly come back to that in a second.

So as the trial was then being discussed the key question was will an addition of a new agent make a difference in the overall long-term outcome, or will it just add toxicities and side effects, which intensive therapies as we have found in the past could potentially do, without necessarily improving the outcome. So there was a lot of debate about that.

There was also a lot of debate about when you give the brentuximab vedotin you actually get low blood counts, and you need to give growth factor. And so I think in general folks felt like well we’ve been trained in the past to avoid growth factor because of the bleomycin and the potential that growth factor would make bleomycin lung toxicity worse. So it was good that now bleomycin was being left out of the combination, but there was still a concern that now you’re making the regimen not only more expensive with the new agent, but you’re also getting problems with the fact that you’ve not got to give growth factor to everybody. So all of that kind of went into the debate and the discussion.

Furthermore, there had been a lot of discussions and trials that had looked at the omission of bleomycin if you had a good result. So in the RATHL trial if you had, after 2 cycles, a good response you could drop the bleomycin. So now the whole conversation was when you’re comparing these 2 regimens should you be dropping the bleomycin out of the standard arm as part of the regimen. So there were a lot of debates and discussions about how to look at all of that.

Then I think what often made the whole study quite complicated is the primary endpoint was a modified progression-free survival rather than just a standard progression-free survival. And part of it was trying to just make sure that if doctors felt a little bit concerned that things weren’t as good as what they wanted, and they added additional therapy, that would be counted in the modified progression-free survival, compared to documenting disease progression.

So when the data came out showing an advantage in the primary endpoint which was modified progression-free survival people were a little bit skeptical about what exactly that meant, and early on in the study there was no evidence for overall survival advantage. However, as time has gone by the typical progression-free survival has also shown the same advantage, and now the report that came out most recently shows an overall survival advantage.

And I think, to be frank, the reason the overall survival advantage is really interesting is it really questions our whole premise that you can salvage people, like we thought in the past, with an autologous transplant and lose nothing because when one looks at these 2 cohorts in the study how they got managed in the patients who relapsed, they were treated very similarly. Most of them got transplant. Most of them got novel agents. There was not a difference between the 2 groups, and yet you can still see an overall survival advantage, suggesting that different to what we thought before what you do in the front really matters.

Transplant strategies and outcomes for patients with relapsed/refractory HL

DR LOVE: What’s the thinking about the cure rate of transplant on relapse? What’s the working number?

DR ANSELL: Yeah. So I think that working number has bounced around a little bit, and as we showed, as you get newer agents that are being incorporated into the salvage that number may actually be going up. But I think in general kind of a ballpark number is in the 60-65% range.

DR LOVE: So in a way it does seem like there’s something going on here that is a little hard to understand. I mean maybe the statistics add up. But again, getting back to the way people saw the data — and I was very surprised because people, particularly docs in practice, all docs hate bleomycin, so the opportunity to avoid it, like the docs in practice were all over it.

But I mean I’m going to say up until 6 months ago, up until these new data, I was still hearing people say, “Well, BV+AVD in the high-risk patients.” And incidentally, I don’t know whether you still think that’s a valid thought. I never really understood it. I felt like if you have a better therapy why wouldn’t you want to use it all the way down even though maybe you don’t have the data. But what about that issue?

DR ANSELL: Yeah. So I think that’s very accurate. I think in general in private practice that was embraced because it simplified management of patients. You could give the treatment, you could put them on growth factor, you could ensure that their blood counts were good and just get them through the treatment. You didn’t have to worry about is that little cough that the patient mentioned a real bleomycin lung toxicity and could that put you at risk of missing it. So I think you’re right, many in practice just embraced it.

I will say this much to also your other point, is that it’s become increasingly difficult to say that this is not the appropriate therapy for all patients with advanced-stage disease when you have an overall survival advantage. I mean quite frankly I think if you ask patients what do you want, patients want 1 and done. They just want to be finished with treatment. They want to get their treatment, they hopefully want to get in remission, and they hope it never comes back and they can get back to general life. The whole thinking about well, we could always come back at a later point and salvage things I don’t think is a very attractive approach for patients.

DR LOVE: Well I guess the other issue is how many people don’t actually make it to transplant.

DR ANSELL: I think in general it depends a little bit on the population of patients you’re looking at. So as you well know, there are 2 cohorts of people that have Hodgkin lymphoma, young people, but then there’s a second population about 20 or 30 of your patients — 30% of patients which are elderly, and those are a lot more challenging to treat because many of them are not eligible for transplant, or as you said, don’t make it. Many of the younger patients, most of the younger patients, typically make it to transplant. They are able to tolerate the appropriate treatment, and a true refractory patient who doesn’t have a response at all is not as — is pretty uncommon.

DR LOVE: For those patients who go to transplant, who’ve had brentuximab in the up-front setting, what do you do about post-transplant maintenance? Do you still use brentuximab?

DR ANSELL: Yeah. So that’s a good question, and that’s I think what’s made a lot of treatment quite complicated. And I guess in my practice my sense is how well did the patient benefit from the brentuximab prior to transplant. So if they received it, and they had an excellent response, then I will use consolidation for kind of the remaining number of doses.

In contrast, if that was part of a regimen that they progressed on, then I don’t know that I think there’s any merit in adding that. I think you add neuropathy and toxicity and not benefit.

Chemoimmunotherapy options for patients with HL

DR LOVE: So one of the things that I thought was interesting also this debate was going on, and people are like a little skeptical in the beginning, and then they were just using it in high risk. I was looking over and noticing that the new trial, the control arm was BV+AVD, which told me where you thought — or where the investigators kind of thought things were heading.

And you mentioned in your talk that there’s this Phase III trial right now that’s comparing that to IO plus chemo. I guess one question is why don’t you use both.

DR ANSELL: Yeah. So I think there has been a lot of conversation, and in that trial there was also a lot of debate about whether there should be a standard ABVD arm, which would follow the RATHL kind of approach, dropping the bleomycin, but it was felt that that wasn’t useful because we really felt that brentuximab added to AVD was preferable. And then the other discussion, to your point, was to use both agents together plus AVD chemotherapy. And the only reason that that was not included was just because there actually had not yet been a study that did that, added both of those agents plus the AVD, to be able to point to the fact that it was safe to do that.

DR LOVE: Although I would assume — it seems like it would be. I guess now we have data that it is?

DR ANSELL: Absolutely. So I don’t think, again it was — one has to remember these studies are always designed probably I would guess 4 or 5 years ago, and at that time it was still really unknown.

DR LOVE: So any thoughts or predictions? I mean I’m thinking maybe that the — it’s nivo, right, the IO —

DR ANSELL: Correct.

DR LOVE: — that they’re using?

DR ANSELL: Yup. So it’s nivo + AVD versus BV + AVD.

DR LOVE: So I guess it wouldn’t be a bad wager to think about nivo having a higher response rate. I don’t know. What do you think? I mean it was seen in the relapsed setting. Any predictions here? But also maybe it’s not going to be the same in the long run. Is it going to have that same staying power that B vedotin does?

DR ANSELL: So I think that’s a key question, and I think that’s where randomized trials are so important. I mean one could make a case both ways. You could say, “Hey, there’s data from the ECHELON study suggesting that BV may actually hit a precursor cell, and that’s going to be important.” But there’s equal data you can go that nivolumab does all kinds of immunologically important things —

DR LOVE: Right.

DR ANSELL: — and that’s going to be important. And if you look at the results in at least overall response rate they both look excellent. But I think when it comes to Hodgkin lymphoma durability of benefit is the key. How long are patients going to remain in remission and how many are going to be cured? And that, I think, is a difficult question to answer, and it would be a pure guess or wager as you say.

DR LOVE: Although in terms of in the relapsed setting I think it was observed early on that BV, particularly if you have a clinical CR, can have very long durability, maybe cure I’ve heard. So I don’t know what’s going on there. I guess it’s chemo, I guess, right?

DR ANSELL: Well, remember chemotherapy, even very old chemotherapy —

DR LOVE: Right.

DR ANSELL: — has been highly effective in Hodgkin lymphoma, and you’re quite right, in the pivotal trial of brentuximab vedotin about a third, 20% or so of patients had this very long tail. And even though they had failed everything and a transplant they had patients who were cured potentially, so probably are. So I think to your point that we don’t really know exactly what the subset of patients are that are going to be cured with these regimens.

Current and future management of limited-stage disease

DR LOVE: So I want to ask you a little bit about limited-stage disease. You showed a whole bunch of encouraging studies of new strategies and new approaches but coming out of there it wasn’t exactly clear like exactly what the current state of the art is and even how it relates to approvals.

I also see you have this paper in Blood Advances, “Real-World Study of Combined Modality Therapy for Early-Stage Hodgkin lymphoma”, so I’m curious too what you’re take is about what’s going on in the community right now in terms of how these people are being managed and how that compares to the way you manage patients. So can you kind of summarize that whole area, of course particularly the issue of whether ECHELON-1 or BV+AVD has a role there?

DR ANSELL: So I think that’s where this has become quite complicated, but I guess to simplify it for myself I would say that the standard for multiple years has been in early-stage patients with limited disease and favorable factors, so that really is very favorable patients, they can get away with very modest chemotherapy, 2 cycles, for example, of ABVD chemotherapy and 20 Gy of involved-field radiation treatment, and their outcomes are excellent.

In contrast, if you have advanced — early-stage patients that have unfavorable characteristics those patients need a little more chemotherapy, so typically they have received 4 cycles of ABVD chemotherapy plus involved-field radiation treatment and typically received 30 Gy of radiation treatment. Now a lot of people are anxious about radiation treatment, so that’s where all of this data comes from, the studies that I was showing, and that is to say could you just skip the radiation. And so trials have looked at, like the RAPID trial, simply just giving chemotherapy, and if you were PET negative omitting the radiation.

Quite frankly, if you look at at least 3 studies that looked at that the answer is you can do that but you do lose some of your progression-free survival, and more patients will relapse, about 5-8% more people. So you have to be good with the risks that you now are avoiding, but obviously the risk that you now potentially are putting more patients at the likelihood of needing salvage treatment because they relapsed.

So that’s where the data that you see that we published came from. We went back and looked — before this RAPID trial came out we standardly gave everybody combined modality treatment. When the RAPID trial data came out and said you could probably skip it we started to leave out radiation treatment. And we actually looked at our data, and our data was a little — well quite a lot worse than we expected. In other words more patients relapsed if radiation treatment was omitted. And as we looked at why that was it was because the criteria for who got that approach was liberalized because we kind of went well, the study looked at very limited patients, not a lot of bulky disease, we kind of did the same thing with patients that had more bulky disease.

So the takeaway for me is that if you’re going to be able to quote clinical trial results you need to follow clinical trial data, and when you get a little more kind of loosey goosey about it that actually may cost you. So I think when all is said and done I still think that combined modality treatment remains the standard treatment for early-stage limited patients because of the fact that the results are excellent.

DR LOVE: Can you comment on the — you had the 27-year-old man that you presented as one of your cases with Stage IIA disease, got 3 cycles of ABVD, had a CR, but then recurred. So how does that case fit into what you were just talking about?

DR ANSELL: Yeah. So that’s exactly the patient that we kind of became a little more cautious after seeing those kind of events happen to patients. So we followed the RAPID approach here. The patient received 3 cycles of treatment, had a negative PET scan, and we omitted radiation therapy. That patient then subsequently had disease recurrence. So again, the idea is well you can go ahead and get the patient back in remission with subsequent treatment, and that is true in the majority of patients, but that’s a devastating event for patients. So again it just to me speaks to the caution that one has to take when you’re thinking about omitting treatments that have been shown to be effective if it turns out that that actually may compromise outcome.

Overview of classical HL and strategies targeting Reed-Sternberg cells

DR LOVE: So I want to talk a little bit about relapsed disease and new strategies, but also I want to give you the opportunity to — because you’re so great at kind of explaining translational medicine or oncology, and it’s just Hodgkin is such a fascinating disease, and I’m looking at this incredible bispecific plus preloaded NK cells. I love that one. We’ll get to that later. I want you to explain that thing, how that works.

DR ANSELL: Right.

DR LOVE: But let’s just start — let’s just start with something simple, which is I mean some of the data you were showing with checkpoint inhibitors was just such a reminder how potent they are in this disease. Can you talk about the biology of Hodgkin lymphoma and why with this amplification, for example, that you see so much response and the whole thing about how that ties into the classic vision of what Hodgkin lymphoma is and what Reed-Sternberg cells are?

DR ANSELL: Yeah. So as you well know, Reed-Sternberg cells are CD30-positive cells that are what we call a crippled B cell. So although it doesn’t look very much like a B cell and doesn’t have any of the traditional markers it turns out it does have genetic evidence that that’s what it is. But with all the genetic changes that have happened we found that this amplification of chromosome 9p24.1 results in very high expression of PD-1 — PD-L1 on the outside of the cell surface. And that along with CD30 helps to really define those Reed-Sternberg cells.

Interestingly, the Reed-Sternberg cell is really a minority of the cells in the microenvironment, and that’s because those Reed-Sternberg cells secrete a lot of cytokines that recruit a very robust immune environment. But what’s interesting is that immune environment often is facilitating the success of the tumor cell rather than really being the immune system trying to control the tumor cell.

So different to I think solid tumors, where the malignant cell is maybe protected to some degree, but the immune system is trying to get to the tumor cells, there’s more going on in Hodgkin lymphoma than that being simply true. So one of the things are clearly when you block PD-L1 on the surface of the Reed-Sternberg cell that then allows PD-1-positive effector cells to be able to target the tumor.

That’s part of the story. But a further part of the story is also the fact that PD-L1 being so highly expressed and driven by a genetic reason actually might be part of the mechanism that actually provides a message that grows the Reed-Sternberg cell. So when PD-1 binds to PD-L1 there is good data to say that there is reverse signaling back into the tumor that actually can further amplify the disease growth. And that’s why I think with both of those mechanisms being affected you can get such dramatic responses.

And I think that the thing that to me makes it clear that there is more than just simply activation of T cells is the picture that I showed of the patient with the huge mediastinal mass. I remember one of my first patients treated with just nivolumab alone prior to AVD chemotherapy. He had a mass that was really quite enormous, and the concern was if that got any bigger he would be in ICU in a heartbeat. And yet he was much better within a few days. It just shrunk the tumor way down, suggesting that it actually shut down a lot of this whole cytokine environment rather than activating the T cells. So I think all told it’s a little different in Hodgkin lymphoma compared to other solid tumors.

DR LOVE: What about the specific amplification that’s actually seen in Hodgkin lymphoma, rarely seen in other cancers? And I’m curious, incidentally, what we know about these other cancers. But can you talk more about what this amplification is and why it makes the cells more sensitive to PD-1 if we know that?

DR ANSELL: Yeah. So this amplification is at chromosome 9, and it’s the 9p24.1 locus. And we see either copy number gain or amplification, so multiple copies of that particular part of the gene. And when that happens it does 2 things because at that locus are 2 different genes, PD-L1 and PD-L2, but also the whole JAK-activating component.

So 2 things drive downstream of that, high expression of PD-L1 and JAK-STAT activation, which by the way also drives up PD-L1. So on the outside of the cell then there is a very high expression of PD-L1. And as you point out, that’s true in Hodgkin lymphoma but it’s also true in mediastinal large B-cell lymphoma and certain other — diffuse large B-cell lymphoma, some of the unusual types, some of the CNS lymphomas, and most of those are patients that have really good responses to the PD-1 blockade. In contrast to other patients with lymphomas, who don’t have those genetic amplifications, where the response rates are quite dismal.

DR LOVE: I don’t know if you happen to know. We had a patient presented to me that had breast cancer who had that amplification. I don’t know whatever happened with that patient, but do you know whether or not people respond better, or they respond when they have solid tumors with this amplification?

DR ANSELL: I think as you point out that data’s quite limited, but certainly anecdotally if the — that’s a targetable lesion, so if you actually see that degree of amplification those patients tend to benefit. And it seems to me that the tumor cell, whenever something happens genetically in a tumor cell, it gives that cell a growth advantage. That’s why that cell expands and becomes a dominant player within the tumor environment.

So it’s got to do something beneficial. So when you then take away that potential beneficial effect by blocking the signaling coming through that PD-L1 expression, that’s where patients end up having a good result.

Addition of antibody-drug conjugates to HL treatment strategies

DR LOVE: So another translational issue I wanted to ask you about, and certainly there are a lot of clinical trials trying to assess the value or the role of checkpoint inhibitors, but one of the things you see a lot in oncology is chemotherapy or antibody-drug conjugates with chemotherapy plus IO. In bladder cancer they’re all excited about it. In lung cancer it’s standard of care first line. They’re seeing 5-year responses — or survival in some patients. Any thoughts about what’s going on when you add in an IO to chemotherapy, and is there any kind of magic or synthesis going on there?

DR ANSELL: Yeah. Again a great question. And so I think the concern had been in the past that when you add in a chemotherapy at the same time as trying to optimize an immunotherapy the chemotherapy’s going to kill the cells you’re really trying to get to do the work. It turns out that’s not as clear as what we thought.

So 2 reasons I believe that is the case. One is T cells, which are the cells that we obviously are having the greatest impact on, are actually very, very quick at replicating. So even if you do have effect on the chemotherapy you can quickly replace them with additional new ones. The second thing is the ones that are already in the tumor, or in the environment in general, we know them to be very immunologically exhausted. So quite frankly they’re not all that great. So it may not be a bad thing to get rid of them and kind of like bring a whole new team on, as it were, a whole new set of cells, and those cells are much more robust and ready to work, and then you protect them by the PD-1 blockade. So I think bringing on a fresh set of legs, a fresh set of team to bring them on to do a better job is kind of what chemotherapy does by clearing out all the old and useless ones.

DR LOVE: Yeah. That’s the kind of translational discussion that makes sense to me. Anyhow, I want to go back to the ECHELON study and ask you about some of the other things that you were talking about. And one that I thought was really interesting, I’m not sure I quite — I think I got it, but I’ve never heard it before, was this issue of second cancers, and your description of why you think there’s less second cancers in the BV group, because I was really surprised. I’ve never even heard of that kind of explanation, but can you kind of go through that?

DR ANSELL: Yeah. So I think, again, because young people get Hodgkin lymphoma, and young people who are potentially cured have a very long life ahead of them. Second cancers which could come from the treatment you gave is always a substantial concern. So one of the challenges in incorporating that intensive treatment escalated BEACOPP into practice was that initial studies there, particularly if you gave 8 cycles of escalated BEACOPP, there was an increased number of second malignancies. So that was one of the reasons people shied away from that treatment and mainly focused on ABVD.

So now the concern was if you bring a new drug, and basically it’s a chemotherapy agent on an antibody delivery process, and you put that with standard chemotherapy, are you going to go back to an increased risk of second malignancy. So that’s the reason that there was a focus on that. And even with standard ABVD chemotherapy there is kind of a baseline rate of just a few percent of patients that could get second malignancies, and it’s a variety of different ones.

What was curious in this study, and I think we have to be cautious because this is kind of the only study where it’s been shown, and we need to look and see if it shows up in other trials as well, is that the number of solid tumor second malignancies between the 2 arms was identical. The number of additional hematological malignancies was greater in the ABVD arm. So it would appear that the brentuximab vedotin may have suppressed the cells that would have generated a lymphoma because predominantly second lymphomas were far fewer in the brentuximab arm.

Now that’s not a surprise because these — Hodgkin lymphoma and other lymphomas occurring in the same patient is seen from time to time, but it would appear that the CD30-directed treatment is getting rid of a cell that would generate those malignancies down the road.

DR LOVE: Really interesting. You also showed some data in terms of fertility, and I know that that wasn’t a primary endpoint, but it was looked at, and maybe you can just chat a little bit about what was seen there and again what you think the implications might be. And also just curious for an update on how you approach the issue of fertility in your patients.

DR ANSELL: Yeah. I mean I think that’s a very big issue because you want patients to be able to get back to normal life, and a young person who has their life ahead of them and has a partner that they hope to start a family with, they would love to be able to — be able to have that be successful. So we actually, in our practice, will offer cryopreservation of sperm and ova or fertilized ova as a standard part of our practice to ensure that we have that as a backup.

Now ABVD chemotherapy has only modest effects on fertility. Many patients may still be able to be pregnant even if they received that treatment, but as a backup you want to have options down the road. So now bringing another drug to the combination the concern was would you impact fertility in an unfavorable way and would it mean that there were going to be more people with problems with fertility down the road.

The reason it was not a primary endpoint is we did not do specific fertility testing. We didn’t do sperm counts and the like to really prove anything. They simply just looked at how many patients or their partners got pregnant and had a healthy child subsequently. And they showed that really there was no negative effect in the brentuximab arm. I wouldn’t say that it meant anything that there were more pregnancies in that arm, I think it’s just the numbers, but it certainly wasn’t a negative effect in any way.

Long-term management of HL

DR LOVE: Anything you want to say about how you approach the issue of transitioning patients from active treatment, often very intensive treatment, to the hopefully long-term survival issues that they have to deal with? And what are some of the preventive strategies that you bring up, particularly with the younger patients?

DR ANSELL: Yeah. I think that’s such an important question and issue, and I think it’s very important to share with your patients that unfortunately the treatments we give are not entirely innocuous and don’t have long-term toxicities, and that’s again why all the concern about how much chemotherapy you give and whether you give radiation or not, because all of that may down the road make a difference.

So I think having a survivorship plan for patients is really highly relevant and very important, and the main things that we tend to watch for are potential for cardiovascular problems, so heart disease, stroke-like symptoms, that kind of thing, and also the second malignancies, particularly breast cancers and others in women that received mediastinal radiation therapy. So it just means you start with screening earlier, and it means that you’re highly vigilant and investigate symptoms that are unusual that come up. And we typically, as I say, have our survivorship clinic see the patients, putting in place a kind of survivorship plan for down the road.

DR LOVE: You were alluding to the issue of radiation therapy with limited-stage disease. Any current numbers in terms of what that risk poses, particularly women versus men?

DR ANSELL: Yeah. That actually has proved to be quite complicated, and the reason it’s complicated is time needs to elapse to really know about risk. But unfortunately, well fortunately I guess, therapies have evolved over time. So when we’re looking now at the likelihood of getting a second malignancy, for example, we’re looking at treatments that were given 20 years ago that aren’t actually used now. Now the fields and the imaging are much improved. Now protons are being used more standardly. A lot of these things clearly are going to impact the likelihood of that, and so the numbers we would quote are probably not correct or accurate at all.

So I think when all is said and done it’s a little difficult to know exactly what that risk is. I would say though we’ve got to balance what that potential risk is with the potential of the disease coming back. So we don’t want to sell patients short on treatment based on a risk that may not even necessarily be quite as significant as we think.

DR LOVE: So how does that translate into what you say to an educated patient? I mean you probably have had patients who are physicians, for that matter. If they ask you for your best estimate of a number, again, man and woman, what kind of number — or how would you respond?

DR ANSELL: So in general my response to patients is just that that risk is really low. It’s not zero, but it’s just probably in the single-digit likelihood, but it’s something that we need to watch for. And that’s why we would keep them in our practice for the long-term, to be monitoring that.

I also would then stress to them that if we consider omitting components of the treatment to avoid those toxicities I want them to clearly understand what that may do to their outcome from the disease itself. So if we drop drugs or if we drop radiation treatment how much of an impact or how much of a risk are they taking that they may have to then come back and receive much more toxic treatment in the way of salvage therapy and a transplant.

DR LOVE: So I want to ask you about some of these new drugs and new strategies, but one more question just more clinical, and that is I’m just kind of curious after having seen so many people, particularly young people who often are very active lifestyle, very, very far away from medicine, and all of a sudden are dropped in the middle of this, getting intensive chemo, go through the whole thing, and then come out the other end cured. I’m just kind of curious — and then you get the opportunity to see these people. I’m sure you know people who went through this a long time ago, as a lot of people in practice have. I’m just kind of curious what you’ve observed about how that affects them.

DR ANSELL: Yeah. So I think it actually affects them quite substantially. And it doesn’t just affect them, it affects the whole family because obviously caregivers and others that are around have to deal with things. Many people, obviously, are putting their lives on hold while they go through things. I think particularly in young people this is right at a time when they’re in college or something that’s really shaping the direction of their lives and their careers. So it is pretty devastating to deal with this.

I think also there are toxicities and side effects that take a while to recover afterwards, and so it isn’t a case of just completing your treatment and then absolutely having nothing after that. Fatigue and other things take a while to get better. Peripheral neuropathy may take a while. So all of those things I think substantially impact the quality of life and just the outlook and mood of a patient. So I think providers need to really be cognizant of that and vigilant and engage with the patients and also utilize many of the partners that we have in health care to help folks deal with all of those challenges, and the challenges are not for the patient only, but sometimes more broadly for the family.

Future management of HL — novel agents and strategies

DR LOVE: So let’s talk about some of the new strategies out there. And like I said, I’ve got to start out with this bispecific plus preloaded NK cells. So first can you explain? Of course bispecifics we’re really hearing a lot about that now, even in solid tumors we’re starting to see it. But can you explain what this bispecific is, AFM13? I don’t know, there’s probably a whole bunch of them I would guess. And then what this thing is where they’re preloading NK cells, how that works.

DR ANSELL: Right. So again, as you well know, the principle of a bispecific antibody is on the one — it binds to 2 things. On the side it’s going to bind to the tumor, and on the other side it’s going to bind to an immune cell. And the idea is you’re going to bring those 2 into close proximity. That’s going to make the immune system really grumpy and cause that immune system — that immune cell to target that particular tumor.

So in this case it’s utilizing CD30 and CD16. So CD30 is highly expressed on Reed-Sternberg cells, so the antibody will bind to Reed-Sternberg cells. But on the other hand it will bind to CD16, which can be on NK cells or on monocytes or macrophages. So what you’re doing is you’re bringing let’s say an NK cell (natural killer cell) up close against the Reed-Sternberg cell and encouraging it to actually bite the tumor.

But as we spoke about earlier, one of the challenges is just there is a really small number of Reed-Sternberg cells, and so it could actually be quite difficult for this bispecific antibody to grab an NK cell and find a Reed-Sternberg cell. So one of the ways to try and enrich and make sure that it’s more likely that the NK cell will really get to the tumor is to preload the NK cells. So in this case they took from cord blood NK cells which basically, because of the plasticity of cord blood, could be infused into pretty much anybody, and they added the antibody, the bispecific antibody, first.

So when they added it the bispecific antibody sticks to the CD16. So now effectively you’ve got an NK cell with a CD30 antibody on it waiting to find a Reed-Sternberg cell, and the moment it finds that Reed-Sternberg cell and attaches, now you’ve got the NK cell right there.

DR LOVE: Okay, well that makes sense. What about CAR T? What is the target there? And you showed a little data that looked kind of encouraging. Have you had any patients get CAR T?

DR ANSELL: Yeah. So again, the target again is CD30. So CD30 is again the same target at brentuximab vedotin, so it’s a proven target, now utilizing a CAR T cell to go after those CD30-expressing cells. And in general it’s the same principle that’s being used in B-cell lymphomas, but in just this case a different construct going after CD30.

And by the way, certain T-cell lymphomas also express CD30, and so trials are also looking at the same CAR in T-cell lymphomas.

The results in Hodgkin lymphoma look quite promising. The whole process is still a bit behind the B-cell diseases, but I think the results look really encouraging in general.

I think one of the challenges that makes Hodgkin lymphoma a little different is this environment of lots of cytokines which can kind of poison the whole system. So that’s a little bit why we still have to understand how well these NK — these CAR T cells are going to work. Are they going to run into a whole cytokine environment that’s going to make them very suppressed? That we’re still going to have to see if that’s going to allow for durable remissions or not.

DR LOVE: Do these patients get cytokine release syndrome when you give them the CAR T? And do they get neurologic issues also?

DR ANSELL: Potentially, although to be frank, in the data so far it’s actually been better tolerated and actually less in the way of those effects. Now I will say this much, part of it is because we learned a lot from B-cell lymphomas, and we actually have strategies and approaches now to try and avoid and anticipate those problems. So that’s also probably why the numbers are lower.

DR LOVE: So you also mentioned a couple of strategies that were looked at in the post-transplant setting, vorinostat and ruxolitinib, 2 drugs that you don’t hear too much about with Hodgkin, but can you talk a little bit about the thinking behind this and where you think it’s heading?

DR ANSELL: Yeah. So the thinking behind it is to try and build on the biology of what we know. So HDAC inhibitors can change the expression of PD-1 and PD-L1, so obviously using vorinostat may actually favorably kind of augment the results of PD-1 blockade. So that’s what the thinking is there. As we discussed a few minutes ago, the whole overexpression or amplification at chromosome 9p21 — 24.1 generates this JAK-STAT activation, so targeting JAK-STAT would obviously make sense too. So it’s trying to further build on other parts that we’ve learned about biology and optimizing that in combination with a PD-1-blocking strategy.