A session with experts leading experts Gilles Salles, Nirav Shah, Ulrich Jäger and Stephen Ansell, who debate key updates in lymphoma from the 2021 EHA and ICML meetings.

Welcome to The Lymphoma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Gilles Salles, Nirav Shah, Ulrich Jäger and Stephen Ansell, who debate key updates in lymphoma from the 2021 EHA and ICML meetings.

Antibody therapies

“We’re actually seeing very high and very encouraging response rates in very refractory patients. And I think that to me is really the take home message.”

– Stephen Ansell

“I think we really need to optimize the dosing schedule and a means of administration and I’m excited to see that subcutaneous might be an option for our patients, especially to be able to give these drugs outpatient in a friendly way to the people who need it the most.”

– Nirav Shah

Current data and advances in cellular therapy

“But I don’t think we fully understand the mechanisms of relapse with CAR T-cell therapy. And I think it’s quite complex, but I think that the field is going to evolve. The number of allo CARs being produced is incredible.”

– Nirav Shah

Novel therapies

“New drugs are going to change our algorithm and I think that to me is the biggest question moving forward is where do we place these different drugs and the different histologies and what is the appropriate sequencing?”

– Nirav Shah

“One thing that may come up and that’s interesting in the field were the mouse in animal data on the degrading agents. That’s a new technology that may serve as an interesting tool in the future. Let’s say not target pathway but indirectly by degrading some of the proteins. I thought that was quite exciting also.”

– Ulrich Jäger

Watch the full session
Full Transcript

Gilles Salles:

Hello. My name is Gilles Salles. I’m a physician at Memorial Sloan Kettering in New York, where I chair the lymphoma service. Today, we are going to discuss the presentations and update from the recent spring meetings, ASCO, EHA and ICML. And in order to have this discussion, we have a very distinguished faculty panel with us, with Dr. Steve Ansell from Mayo Clinic, Dr. Ulrich Jäger from Vienna in Austria and Dr. Nirav Shah from Wisconsin College in Milwaukee. Welcome to all of you. And I think we had a fantastic update on many topics. Actually, it was quite interesting that despite what happened in the last few months or the last 12 months with the COVID pandemic, there were still many advances in the field of lymphoma.

Gilles Salles:

Maybe to start with the update that we heard, let’s focus on immune therapies and more specifically on antibody based therapies. And I think we had several updates on the field of bispecific antibodies, which seems to be promising drugs in different histologies. Maybe we can start with you, Steve, if you agree, what were your key message that you have get from the data that we heard during this meeting regarding the use of these new drugs?

Stephen Ansell:

Yeah, thanks Gilles. I would say that I think bispecific antibodies are coming into their own. I think that the key message for me around all of these meetings was we’re working out how to give this in a safe fashion. We’re working out how to give bispecific antibodies and the schedule and the doses and even whether you can administer these subcutaneously, which all of which are proving to be promising. Furthermore, I think the thing that’s proving to be promising, we’re working out how to manage toxicities because as we’re getting to what I think are optimal doses, we’re starting to really see some of the immune mediated effects, the cytokine release type of syndromes and the like and as we’re doing that, I think how to schedule, how to administer and how to manage those issues, I think are being achieved in a very efficient fashion.

Stephen Ansell:

I think what is equally interesting and equally promising is the fact that we’re actually seeing very high and very encouraging response rates in very refractory patients. And I think that to me is really the take home message. Is that in patients, particularly those with large cell lymphoma, particularly those failing transplants and even failing CAR T-cell therapy, bispecific antibodies are proving that you can still reinvigorate the immune system or bring the CAR T-cells into the mix in a way that’s really promising. And I think data that we’re seeing shows that somewhere between 25, even to 30% of post CAR T-cell failure patients are patients who respond to this treatment. All told, I think bispecific antibodies are really kind of coming into their own at this point.

Gilles Salles:

Thank you. Dr. Shah, any further insight regarding this class of agents?

Nirav Shah:

Yeah. I want a mirror what Steve said. I think we really need to optimize the dosing schedule and a means of administration and excited to see that subcutaneous might be an option for our patients, especially to be able to give these drugs outpatient in a friendly way to the people who need it the most. I think the most exciting thing about these drugs is the efficacy signal we’re seeing in this highly refractory population. And what I’m interested and excited to see is where do these drugs place themselves? Are they truly going to be in a CAR refractory population? Or are these drugs that potentially could compete with CARs as a drug off the shelf, without the manufacturing needs, without the high expense associated with CARs that we can get prior to CAR T-cell therapy and will lead to durable responses?

Nirav Shah:

I think that’s a big question mark here is that durability. A lot of these patients have been treated on clinical trials. There’s eligibility criteria, there’s a selection bias in that setting. And so I think it’ll be interesting as more and more of these studies mature if we get a sense of are these curative? And I think that’s a big question for me.

Gilles Salles:

Thank you. Uli, may you come onto a little bit regarding some of the potential combinations of these antibodies, but also the limitations that were addressed by Nirav and Steve.

Ulrich Jäger,:

And that’s exactly what I wanted to get at. Thank you for the question. We did see of course mainly data for monotherapy, but particularly for the aggressive lymphomas, it’s probably important to combine them. What we’ve seen is a combination of for instance, mosunetuzumab with polatuzumab, that did induce higher response rates, even in post CAR T-cell patients with T-cell activation that was observed. I found that quite interesting. And it seems that the combination with chemotherapy where we also saw one of the other abstract seems to be quite toxic. I think the key issue will probably be really be applicable to everybody, let’s say a bispecific CD20 antibody, together with CHOP or R-CHOP. Or let’s say together with CHOP. I’m not so sure so I think that’s where we have to optimize things. Maybe combine them with other new drugs, et cetera. And I’d like to make a comment also to what Nirav said, particularly in first line, the bispecifics may be better than CARs because we have them ready. And so I think we may see a revolution in the first line treatment.

Gilles Salles:

Steve, you wanted to make some comments regarding potential combinations, I understand.

Stephen Ansell:

No, I actually would say, just want to pick up on something that Nirav said, which I think is very important because as we’re thinking about how to place these agents, I do think it’s going to be important to see the durability of benefit. And as we look at the combinations, we’re really going to need to see that this brings additional cures. Again, that’s something we really want to see but we are seeing tails on some of the immunotherapy cellular approaches where we’re seeing a subset of patients where we truly believe those people may be durably in remission, maybe cured. But I think we haven’t quite seen the same just yet from the bispecifics. And so I think we need to watch the space. I think it could be there, but I don’t know that we actually have the evidence to that.

Stephen Ansell:

And I do think Uli’s point about toxicity is also the other thing to watch is that I think combinations are encouraging but these are agents that have quite substantial toxicity. And I think when we use them earlier in the immune response might actually be more robust, we may actually see more problems than when we see when we use them later.

Gilles Salles:

Is any one of you willing to provide to our audience some more specific insight regarding the management of the infusions reactions, the associated CRS, the need for hospitalization of patients during the step of dosing. I think probably the three of you have had experience with some of these antibody. I don’t know who wants to start with that. Uli?

Ulrich Jäger,:

Yeah, we have some experience with both with a first line chemo combination. We had some spectacular responses, but we also had, for instance, one elderly patient who is really suffering from this treatment. Is in response, but did not recover after the third cycle. Very active, but so this patient had to be admitted, particularly for some kidney problems, et cetera, not only CRS. And then we’ve seen one post CAR-T-cell patient receiving glofitamab, also spectacular response but after the first infusion neurotoxicity quite heavy. I think those are weapons and we really have to learn how to use them.

Gilles Salles:

Nirav, any insight regarding the current step of dosing and the potential need for hospitalization with some of these patients. Do you see this as an obstacle for the pickup of these drugs in the community? Do you think this is more or less predictable from your experience? How do you forecast the use of these drugs?

Nirav Shah:

Right now a lot of it is protocol driven and so patients are hospitalized. I think going forward for this to be a clinically meaningful therapy that can be given in the community by doctors who are treating, not just lymphoma like us here but multiple histologies of cancers, they’re going to have to really tease out the toxicity and safety management and have nice algorithms in place. All of us work at tertiary referral centers where we can easily admit a patient and have inpatient services that can monitor for CRS. Like Uli, I have used this actually in combination frontline and gave it to a very fit gentleman in his fifties. He had an incredibly difficult time with this regimen. He got cytokine release syndrome, required tocilizumab, developed PEs, was hospitalized three times, he’s in CR and I think he’s going to get through this now. He just got his last cycle but I thought to myself, this guy was even 10 years older, this therapy might have crushed him compared to standard R-CHOP which we can give in the community up to 80-85 without even thinking much about it with growth factor support.

Nirav Shah:

I think this is a new evolution in the lymphoma space and obviously these drugs, the community doctors will want to use them but I think it’s going to be important for us to really define how to give them, what combinations are safe? And really have a set-up. I think that these community centers are going to have to have sort of either admitting abilities or 24 hour sort of around the clock services like we all do, so that when they have that fever, they can be admitted and be given things like tocilizumab quickly.

Stephen Ansell:

In our practice we’ve actually positioned our bispecific antibodies kind of right with our CAR T-cell program and so use them kind of in combination. I think the points that are being made are important because you need the access, you need the folks familiar with the side effects and toxicities. I think if you move to a practice where that isn’t a usual event where those kinds of facilities are available, I think there’s going to be a greater amount of education needed and awareness to really be on top of those type of toxicities.

Gilles Salles:

Yes. I think we understand that and I think all these points are well taken and thank you all of you for sharing your experience and your organizational steps that you have taken in order to bring these new agents to more patients, knowing that right now, we are still in clinical trials and trying to better understand what is the optimal scheme of dose escalation, what are the potential combinations? And obviously we look forward to see what are the consolidated results that we can see because the follow-up is at best 12 to 18 months for some of them, but really rather in the range of six to eight months in median for the other ones so we don’t have the follow-up that we have with many other agents.

Gilles Salles:

Covering this field of immune based therapies and leaving aside the antibody drug conjugates that we will touch upon much later, any further insight regarding the use of monoclonal antibodies alone or in combination? There were some data regarding the update of obinutuzumab with atezolizumab. There were some data regarding the update of the L-MIND study combining a tafasitamab plus lenalidomide. What are you take home message from these studies, or that I haven’t mentioned? Uli, do you want to start with that?

Ulrich Jäger,:

Yes. I think for the tafasitamab, it’s pretty clear that I think that’s a good combination with lenalidomide and of course it’s a CD19 antibody so we add another dimension to the usual CD20 treatments. I’m still pretty impressed with that possibility for elderly patients, for instance. And I think that’s good. Regarding the introduction of checkpoint inhibitors, I’m not so sure where we are going yet. I think there, it’s more a question of defining the patients who will profit most from this type of treatment because not every diffuse large B-cell lymphoma for instance, will profit from it. Same goes for the lower grade lymphomas. But I think the verdict is not out for the checkpoints.

Gilles Salles:

Steve, checkpoint inhibitors has been a topic where you have invested a lot of efforts and contributed to bring these drugs to our field, especially in Hodgkin lymphoma. What are you feeling regarding the development of immune checkpoints in all the lymphoid malignancies? Do you see something really emerging as a new and really striking that we should move forward?

Stephen Ansell:

Yeah, I think it’s the points are important and that is that immune checkpoint blockade, when you simply are just taking away an inhibitory signal, because that’s in essence what we’re doing, you’re assuming that the cells are ready to go and are able to then with taking away the inhibitory signal, have an immediate activation and direct it against the tumor clone. And I think what we’re finding in T-cell and B-cell lymphomas broadly, large cell lymphoma, follicular, the T-cells are really not that ready to go. And when you just simply take away an inhibitory signal, they’re not really all focused and able to target the tumor in an effective fashion. I think, what are we going to need to see in the future is that you’re going to need to give a promoting signal and then prevent these inhibitory signals subsequently. Either a agonistic approach, a bispecific antibody, additional kind of viral therapy vaccine approaches, but something that will actually trigger the immune system and then prevent the inhibition.

Stephen Ansell:

I think that’s an area that’s only really getting started to be explored. I do agree with the Uli that I think one of the things we always need to be is really critical and rigorous in our research so when if we think this is not an effective approach, we have so many things to do. We need to set things aside and not become completely focused on always doing the same thing. But I do think that if we’re looking at lymphomas in general, most of them are going to need something agonistic at the same time as trying to inhibit the inhibitory signal to really get a good response.

Gilles Salles:

Thank you. Let’s move to cellular therapy unless Nirav, you have something to add regarding antibodies.

Nirav Shah:

No, I think Steve and Uly did a great job. Like Uli said, I think with the online data, it was just promising to see a tail on that with the long-term follow-up that they provided albeit a selected sort of patient population they worked with. Really second line therapy, not the multiply relapsed that we’re used to putting on clinical trials. But there might be a place for that regimen for select older patients that are CAR auto ineligible.

Stephen Ansell:

Well, maybe I can jump in and ask Gilles the questions, seeing he’s getting to ask all the questions today. Do you think we’re going to cure anybody’s deal with the L-MIND data and with the tafasitamab plus len. Do you think that tail is a curative tail like we’ve seen with other immune therapies?

Gilles Salles:

Yes, frankly speaking, it’s obviously difficult to decide, but when you see patients with relapsed DLBCL that had failed one or two lines of therapy and who has been in complete response after an immune intervention for more than one year, I believe that this is likely that this patient is being cured. We have had discussions regarding the maintenance phase of these trials, which I feel is too prolonged and probably unnecessary, frankly speaking. I think that the one year combination is fine. Maybe it can even be shorter in term of len exposure, but after that, when a patient has been in a complete response for six to 12 months, maintaining a CD19 pressure, although this is part of the paradigm with CAR T-cell, may be unnecessary.

Gilles Salles:

But I had patients in this trial, in my former institution, which I left one year ago and these patients were on study for three, four years and were in complete response. I believe they are cured. One of these patients may have been second line. The second was really in third line refractory to [inaudiable] so I think it’s really a chance for them. It’s a limited proportion of patient I believe but they exist.

Gilles Salles:

Let’s move to cellular therapy. During this meeting, we heard a couple of updates regarding the role of cellular therapy in follicular lymphoma, with the presentation of the final result of the ELARA study. We heard some data regarding the ZUMA-5 study in follicular, also some data regarding the use of cellular therapy in mantle cell and some updates from a real life study. Maybe I start with you Nirav, because you have been heavily invested in this field also. What’s your take home message that you will take regarding cellular therapy during this spring’s meetings?

Nirav Shah:

Yeah. It works. It continues to work and we’re only extending the histologies now. Obviously the approval was most needed in DLBCL. It’s an aggressive disease. We needed to move quick. Those approvals happened. Now we’re extending this to the other histologies and I think the question for me is going to be in diseases like follicular in particular, is there are a lot of treatments. And because there are a lot of treatments, you may not actually need to jump to CAR right away and ZUMA-5, while a very effective therapy, there was considerable toxicity. What I found differently was in the ELARA trial with it, if memory serves me correct, there really wasn’t any grade three CRS or neurotoxicity. And so that could be a game changer if that’s really the case that a 4-1BB CAR in an indolent histology can provide that long-term benefit without the side effect profile.

Nirav Shah:

Because for me in diseases like follicular, the goal of the game is not always necessarily cure, is to keep them at a high quality of life. And I treat it more like hypertension, be able to manage it, live your life and not necessarily we have to give you all the big weapons ahead of time. But I think the consistent message is that CAR T-cells are an important treatment in the entire landscape of all the lymphomas. We’re going to keep getting approvals in other histologies with newer products and the real question I think, outside of DLBCL is when is the right time to use these therapies, given the long-term risk of lifelong B-cell aplasia, which we don’t understand how that may impact people’s longterm immune health.

Nirav Shah:

And with other drugs, like bispecifics, which also look best in follicular lymphoma, is where do we place CAR? Is it a last line therapy when we’ve exhausted all the oral agents and things that can keep people at home? Or do we do it earlier? Or maybe in younger people? Those patients with 30 and 40 year olds with follicular lymphoma, do we use these earlier? But I think those to me are the main questions and I’d be interested to hearing what Steve and Uli thought as well.

Gilles Salles:

Uli, you have also been heavily invested in the field of CARs. What are your main messages that you have taken from the different presentations that we heard and maybe focusing for the time being on follicular and we’ll come to other histologies later.

Ulrich Jäger,:

In direct response to Nirav, I think one of the major questions will be where can we place the CARs in respect to the autologous stem cell transplant? Is the pOT-24 population is that the ideal population? Which I think would probably be one of the first targets, of course. And then we’ll see where it’s going. But I think what we’d really like to see is a head-to-head comparison with ASCT in the younger patients. And then, I still like the ZUMA-5 presentation by John Gribben, who showed that this SCHOLAR-5 data compared to conventional treatment really are much less impressive than the CARs. I personally think we have good tools. We’ve used only the tisa-cel for follicular lymphomas and the liso-cel and with both of them we have almost no toxicity. We don’t have experience with the axi in this respect.

Gilles Salles:

Steve, do you foresee that potentially in follicular lymphoma, this would be a one time treatment with some of these CAR T-cell that will be delivered to patients which are not heavily symptomatic? You may not need bridging, it could be potentially ambulatory in some patients and after the immediate follow-up periods, they will be well? Or do you foresee obstacles to the development of this therapy in those patients?

Stephen Ansell:

Well, I think first thing I would say is that over time, as we get used to using agents, we get better at doing it. And if you think of initial CAR T-cell studies and the toxicities in subsequent CAR T-cell studies, we get better and better at knowing how to anticipate, how to manage and how to kind of really get people through the treatment in the best and most effective fashion. My personal view is that I think CAR T-cell therapy may be a game changer completely in follicular lymphoma.

Stephen Ansell:

And the reason is if we see a tail like we’re seeing in large cell lymphoma, where potentially patients with follicular lymphoma are in fact cured with CAR T-cell therapy, that may change exact completely how we think about CAR T-cells. And we may instead try and work out how to give it to people with a view of curing them of their cancer and having it stay gone. And obviously as Nirav said, we have to kind of be cognizant of toxicities and the price we may pay. But I would anticipate that over time we’ll work out how to do it better and safer. And if that’s the case, I see this completely changing how we manage follicular lymphoma and possibly mantle cell lymphoma as well.

Gilles Salles:

Yes, I share your prospects. And I was fairly impressed. We treated a lot of patients, not a lot, but many patients, I will say before I left France and we started also to use those in follicular lymphoma. It goes quite well, as long as you don’t have patient with a huge tumor bulk probably transformed or with occult transformation. And some patients went really uneventful treatment and I found this will really change the way we see patients. There were some also interesting results regarding treatment of patient in the ZUMA-5 trial. There were certain patients with relapsed, 11 of them were follicular. All of them have a maintained CD19 expression. And I think nine of these 11 patients reached the second CR, which I feel is impressive. Obviously we don’t have the follow-up for these patients, but the expansion of CAR were found to be identical almost to the first expansion. And even if you have to repeat it, it’s quite impressive. I know one of these patients and it was fairly amazing to see the response with a smaller tumor volume, which probably explains the lack of toxicity. We are seeing…

Ulrich Jäger,:

Gilles, can I make a comment regarding the transformation because I think that’s also an interesting point because even in the aggressive lymphomas, the transformed folliculars do very well compared to the others. The question’s really, if you use it early, can we even avoid transformation in some of these patients?

Gilles Salles:

That’s an interesting topic. I was going a little bit to the field of new CARs and Nirav, I know you survey this field very closely. We were all expecting to see bispecific CARs coming or improved CARs coming. What have you seen during these meetings regarding these advances that we are looking forward? And you may further extend and we may further discuss early result with allogenic CAR also. What are your take home messages from these meetings?

Nirav Shah:

Yeah. I think that the CAR technology, just like everything else is going to advance. We have these first three CARs, which are incredible advances in the field, but I think there’s room to be improved. We’ve seen data over the years coming for a variety of bispecific CARs. CARs targeting 19 and 22 combination, they’re using that CAR in combination with a PD-1 inhibitor. We’ve seen data on 2019 CARs, which seem very reasonable and in the NHL spectrum. And most recently we’re seeing the allogeneic CARs, which are anti-CD19 off-the-shelf product. And again, early data, limited follow-up. I think my biggest question within an allo product is durability. Because one would imagine that these allo CARs are less likely to persist for the patient’s lifetime.

Nirav Shah:

Although the whole question of persistence does seem to depend on the histology that you’re treating. Maybe more meaningful in diseases like ALL, less so in our aggressive non-Hodgkin lymphomas. I think the question is though, is dual-targeting going to be better than single targeting? And there are large trials undergoing. I think you’re aware of Gilles, that I believe you guys are participating in with us. And I think we’ll start to see those questions being answered. We know from tumor biopsies that about a third of patients do lose CD19, at least in aggressive non-Hodgkin lymphoma. But I don’t think we fully understand the mechanisms of relapse with CAR T-cell therapy. And I think it’s quite complex, but I think that the field is going to evolve. The number of allo CARs being produced is incredible. And the one advantage is no manufacturing. And I’ve had over the years now, several manufacturing failures, even with the commercial products. And so having a drug available off-the-shelf, if they can prove durability and similar efficacy, I think could be a game changer as well.

Gilles Salles:

Steve, your insight regarding CAR T-cell therapy and how we see field are moving. And I just see that during the time we speak there are some again, public announcement of a second randomized trial in the setting of relapsed DLBCL being positive. But Steve, your insight from what we have got during these meetings?

Stephen Ansell:

Yes. I think some of the points that were made are really important. One is the actual cell that you’re going to use in CAR T-cells. Whether it be a T-cell and NK-cell and the merits thereof. Whether it’s your own cells or somebody else’s so that it can come off-the-shelf. I think that obviously is really relevant. And then how many targets and how protected your T-cell is. What’s it going to bind to? And how quickly could the CAR T so be switched off? All of those, I think are critical factors. There’s a part of me that in my head kind of wonders how important is the persistence issue? Because in some respects you only have to cure people once. In other words, if you got rid of every single cancer cell, it doesn’t need to persist thereafter.

Stephen Ansell:

The problem is, unfortunately, all you’re doing with the CAR T-cells is kind of corralling and controlling then obviously you need to maintain cells. I think as we come to understand those concepts better, that will really help us know how to best optimize the therapy, because it may be different for each of the different histologies kind of as we move forward. We may want to go full out, take a lot of risk in some diseases and then be much more modest and careful in others. I think, as we just said, there’s so many different studies ongoing at this point, this is going to be a field that is really only in its infancy right now. We’re going to see new data probably with every single meeting for the next many years.

Gilles Salles:

Steve, another comments regarding mantle cell lymphoma in particular, do you have any insight on the update of ZUMA-2 studies and the comparison with real-life data that were presented during these meetings?

Stephen Ansell:

I must say I was really interested and excited in the data in mantle cell because commonly when we use or think about using CAR T-cells are in a disease where really you have limited options. In our practice, we tend to use a pretty aggressive approach in the beginning and autologous transplants. And then when people relapse after that, the tools that remain particularly when we start to see more P53 mutant types and more kind of a blastoid variant it’s proving to be a very difficult population. When you see efficacy, even if your efficacy ends up being tempered a little bit, as you move toward the kind of real-world scenario, I think if you can get those people in durable remissions, that is a huge advance. I remain a big fan of utilizing CAR T-cells in the appropriate population in mantle cell.

Gilles Salles:

Ul-, there were a couple of real life data coming up during these meetings. Any of these study really striking for you or providing new results regarding the management of patient and the outcome of patients that were treated with CAR T-cell outside of clinical trials?

Ulrich Jäger,:

Actually, yes. My favorite abstract at EHA was the French DESCAR study to be very honest. Steven Le Gouill presented that and the number is impressive. 550 patients received CARs with the two commercially available products. And what I really liked there is the high end response rates and durable responses. You probably know better than I do, but I think there is some selection involved in how the French colleagues treat these patients. And to my mind, that’s probably the way to go because then we are using the product resourceful. And so I really liked it. The downside that Steve also mentioned is that if you select too much, then you may miss those few patients who are rapidly progressing and in a terrible lymphoma state, so to speak when they come to the CARs, but still one third or 25% of those will have long-term responses. I think that’s what I liked most about this presentation. Let’s think about careful selection.

Gilles Salles:

I think that’s obviously an important question with CARs. The best patient responds better with low tumor volume, with normal LDH and they benefit well of CAR, they might eventually benefit of other kinds of therapy and the worst patient with ultra performance stages, rapidly growing disease or high LDH have less benefit, but some of them may have a benefit still. I think it’s a balance of selection and is not always an easy choice. And we are probably having many discussions. Our institutions know that these products are routinely available for each patient that doesn’t fit in the ideal category, whether we should pursue a CAR or whether we should leave them aside.

Gilles Salles:

I think we have been through cellular therapies but besides these bispecific and cellular therapies, a few new agents are coming in the field or a few new pathway have been identified. And we may have heard results here and there regarding new ADCs or the optimal use of ADCs targeted to B and T-cell lymphoma that represented also in Lugano or other meetings and maybe other drugs that I may have missed or other combinations. Nirav, do you have one of these presentations that really particularly was interesting for you, one that you would like to underline?

Nirav Shah:

Sure. We have worked with the new BTK inhibitor picture, pirtobrutinib, LOXO-305 and it’s different than the irreversible BTK inhibitors that we’re familiar with being acal and zan and ibrutinib, which obviously you have different levels of selectivity but mechanistically worked the same and from a resistance pattern, have a similar resistance pattern within them. And so this is a novel BTK inhibitor, it’s non-covalent and it is very selective for the BTK kinome. And we have treated a lot of people at our center with this agent and been involved with its development and really has a potential to be a game changer I think in the BTK field.

Nirav Shah:

Reason why it was efficacious in those that failed irreversible BTK inhibitors, something we wouldn’t really see. If you fail ibrutinib, we don’t think acal or zan. And two, the toxicity profile that we’re always used to hearing about. Really no AFib, no bleeding and the discontinuation rate in a very large study was actually quite low. There are several trials they have now positioned themselves to go actually head to head against both chemotherapy and the earlier generations of BTK inhibitors. But it goes to show that there’s still advances to be made in the field. And I think this is going to be a very exciting drug that will work across histologies, mostly CLL and mantle cell.

Gilles Salles:

Yeah. Thank you. That’s really an exciting field. And we see that even if the first BTK inhibitors were here, probably now six, seven years ago, we are continuing to make progress and this is interesting. Steve, any new agents that really focused your attention during this meeting and that you would like to comment for us?

Stephen Ansell:

For me, I’m always kind of keeping my eyes open for things that work in T-cell lymphomas, because that’s always kind of a bit of a wasteland and we got all this exciting data that we just spoke about in B-cell lymphomas, but in T-cell lymphomas, it’s kind of not that great. Quite frankly, I don’t think there were that many new things, but combination approaches, looking at different PI 3-kinase, other immune modulatory agents. I think some interesting data there, some JAK specific therapies with some promise. And then I think RAW1 is another target that may be very interesting in T-cell lymphomas. I think these are the things that I’m watching. I think the data is sort of still coming along, but we desperately need agents that are going to make an impact in T-cell lymphoma, like we’re appreciating and B-cell lymphomas. I think at this point we’re still kind of optimistically keeping an eye on the field, but nothing dramatic I would say at this point.

Gilles Salles:

I don’t know if Uli would like to comment on valemetostat or if I should pursue on that. But I think this was an agent that was presented in the overall session in Lugano, which is a dual inhibitor of EZH1 and EZH2 that was developed in Japan, but also with several centers in the US including here, my colleague, Steve Horwitz and is being developed also in combination in other places. I think the response rates that were seen in patients with different subtypes of T-cell lymphoma, including some patient with ATL, some patients with a TLL and others was fairly impressive. I think we were in the range of 50%, which is a little bit higher than what we used to see with novel agent. And I think the patients that achieved a response, had a duration of response that was in the range of 50 weeks.

Gilles Salles:

It seems like we have here an agent that maybe focused on some T-cell entities and may have a meaningful efficacy. Obviously we need to see more data on the safety, there were some concern or side effect, including thrombocytopenia of grade three or more that eventually led to treatment discontinuation or interruptions. But I think this is an interesting agent, probably difficult to combine given this hemetoxicity profile, but really an attractive agent. Uli, what was you take home message in term of new agents or new pathways that we have got from this meeting?

Ulrich Jäger,:

You are the EZH1/EZH2 expert, you’ve done trials with this agent. I don’t want to comment on this one but maybe it was not only the new drugs, but the EZH2 inhibitor also appeared in an abstract that tried to personalize treatment, according to the genetic subtypes or molecular subtypes. R-CHOP plus X and one of the X’s was the EZH2 inhibitor together with a BTK inhibitor, et cetera. I found that the approach interesting that we can try to tailor treatment according to the molecular data. And there were actually two abstracts in this respect and I found that possibility of using even agents that are let’s say not licensed for a certain indication quite interesting if you can combine that in a more personalized approach. That were actually some of my favorites in these two meetings.

Gilles Salles:

Thank you for that. I think we are close for the time to close this session regarding the feedback of these different meetings. Maybe I give you one minute to each of you, if you have any other further comments regarding what we heard or what you have seen, maybe through [inaudiable], maybe diagnosis, maybe a biological study or new insights regarding how we manage patients with lymphoma. Nirav, any particular topics that you would like to take and bring forward?

Nirav Shah:

Well I think, just to summarize, everything that we talked about today, that number one, lots of excitement in the field. New drugs are going to change our algorithm and I think that to me is the biggest question moving forward is where do we place these different drugs and the different histologies and what is the appropriate sequencing? Something that I think we need to talk about more is what is the appropriate combinations? And what therapy should we be using when? I find that really, if you go across the country, we’re center specific and we all do things very, very differently. And so I look forward to getting a better understanding of how to use these agents going forward.

Nirav Shah:

Going back to the bispecifics, I think the one data set that we didn’t really talk about with the single agent frontline efficacy in older patients. Which I thought looked very promising, as a single immune therapy to give to patients that potentially again, that durability question remains in question, that’s unanswered at this time, but potentially something that could change how we treat that patient population. But I think we’re getting better at developing drugs with less toxicity and more efficacy. I think we have to just figure out what is the right sequence and when to these therapies efficaciously, to get the best outcomes for our patients.

Gilles Salles:

Thank you. Steve, your take home message.

Ulrich Jäger,:

What I think for me is really important, we’ve got all these really exciting tools but as you can tell, none of them work a 100% of the time. It really would be nice to know who’s benefiting and who’s not. And so the plenary session at ICML, I thought Brian Sworder’s presentation on cell-free DNA approaches to monitor CAR T-cell responses, I think, are really going to be a useful tool that strategy of working out who’s benefiting from therapy as we move along. I think obviously even being able to use ways in which we can identify people who are likely to benefit more than others in a more kind of a biological way, I think is where I am excited about the field going. I think right in parallel with all these exciting novel strategies for treatment, ways in which we can really monitor benefit and anticipating who’s going to do best with what treatment. That’s going to help us use the treatment in an intelligent way.

Gilles Salles:

ctDNA and really as a tool to monitor patients in the future. Uli, any other comments before we conclude?

Ulrich Jäger,:

Yeah. You guys have said it almost all so I can only agree. One thing that may come up and that’s interesting in the field were the mouse in animal data on the degrading agents. That’s a new technology that may serve as an interesting tool in the future. Let’s say not target pathway but indirectly by degrading some of the proteins. I thought that was quite exciting also.

Gilles Salles:

Yes. I think we see a couple of preclinical data suggesting that the level of inhibition of some kinases looks more potent using degraders that pull down the protein rather than kinase inhibitor and eventually avoid some reactions. But these drugs, which are often actually macromolecules are coming slowly into the clinics. They came already in solid tumors but they will come very soon in our field. Yes, I think there were many other topics that we didn’t have time to cover today. I found also at ICML sessions regarding what artificial intelligence can bring us in term of analyzing pathology, in term of using some genomic data or building synthetic arms for some studies, quite interesting and a fascinating field to try to catch up for us for the progress that can help us to better personalize treatment.

Gilles Salles:

I would like to thank you all for your comments regarding these three meetings. We had really a nice overview of this very rapidly moving and fascinating field. I think many of these programs will reach patients pretty soon and we’ll continue, we’ll make progress. As I said, sequencing these agent will be a real challenge and we need better tool to understand that. But I think that we are aiming for. Thank you again to the three of you. Thank you for VJHemOnc for having organized this session. And I hope that in the near future, we’ll have the opportunity to see each other in person rather than virtually to comment the next upcoming hematology meetings. Thank you and wishing you all a very nice day.

Disclosures

Gilles Salles has received in the last 12 months financial compensations for participating to advisory boards or consulting from Abbvie, Beigene, BMS/Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Milteniy, Morphosys, Novartis, Rapt, Regeneron, Velosbio

Nirav Shah has consulted and served on an advisory board for LOXO oncology.

Stephen Ansell has received research funding from Bristol Myers Squibb, Seattle Genetics, ADC Therapeutics, Affimed, Trillium, AI Therapeutics, Regeneron

Ulrich Jäger has received grant, personal fees, and nonfinancial support from Novartis, Bristol Myers Squibb/Celgene, Gilead, Janssen, Merck, and Roche. Grant and personal fees from Sanofi. Personal fees and nonfinancial support from AbbVie, Amgen, AOP Orphan, Miltenyi Biotec, Sandoz, and Takeda

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