John Gribben:
So hello, I’m John Gribben, and welcome to this VJHem, where we’re here to talk about the recent findings from the American Society of Hematology. I’m joined by my colleagues, Meghan Thompson, Alessandra Tedeschi, and Matt Davids. So welcome too, all of you.

John Gribben:
I think this was one of those years where nothing, although we’ll talk about it in detail, nothing hugely new, but a lot more consolidation. Although certainly a few things that we’d like to kind of commit and talk about. But let me, first of all, just go around and ask you all, what do you take away as your highlights from the CLL sessions at ASH this year? So Meghan, why don’t we start with you?

Meghan Thompson:
Yeah, thanks so much. So I agree there was a lot of long-term follow-up, not a lot of maybe new practice-changing data yet. One of the exciting things to see was longer follow-up at the Phase 1/2 BRUIN trial looking at LOXO-305, which is one of the highly selective non-covalent BTK inhibitors. And it was nice to see this data presented.

Meghan Thompson:
There were 94 CLL patients, and just about over 80% of them had had a prior BTK, now a standard of care for us. And a lot of those patients had C481 or known resistance mutation, but a lot of them were clinically resistant and also did not. And overall, the drug was found to be very safe. And then, while it’s a Phase 1, early Phase 2 results in terms of efficacy, the efficacy looks good in both the BTK wild type and mutated patients. So I think that this is an exciting drug and certainly looking forward to longer-term follow-up.

John Gribben:
Yeah, I agree with you. I was actually particularly struck by the safety profile. It really looked like with larger numbers of patients. I mean, we’ve seen this in some of these early phases before; it looks very safe at the beginning. But it really had a very impressive safety profile considering that many of these patients had already had either problems or became intolerant to other BTK inhibitors. Alessandra, what about you? What do you take away as your highlights from virtual San Diego this year?

Alessandra Tedeschi:
I totally agree. I would say with the LOXO data are very impressive. And now, we have another BTK inhibitor, which is important for our clinical practice. And of course, it’s impressive, the data on BTK particular patients, even on those are relapsing after BTK. Also, to outline the data on the MURANO study, at least we have the five-year follow-up with a median progression-free survival of the MURANO study for venetoclax–rituximab reached 53 months.

Alessandra Tedeschi:
And a lot of data on the deepness of responses, I think in this year, even in the CLL14 study, in the MURANO study, in the CLARITY study, a lot of logarithms we saw on the dynamic of the responses and how it’s important for each MRD response. And the dynamics of the response is also important.

Alessandra Tedeschi:
But I would also outline the follow-up of the MURANO study. Because we never look at the progression-free survival two of the study. We always focus on the progression-free survival one while there was a poster on the progression-free survival two after MURANO, and venetoclax–rituximab did not compromise the progression-free survival at all. And this is important, there was not reached for patients that were treated with venetoclax-rituximab. And they were re-treated safely again with venetoclax-rituximab and then with the BTK inhibitor. So we are starting also to see sequencing of our treatments and not only the photograph of the first treatment we have. And I think this is very important for our clinical practice.

John Gribben:
Hold that thought, because I’m going to come back to that with all of you. And Matt, what was the highlight for you?

Matthew Davids:
Yeah. I mean, I certainly agree with my colleagues on the abstracts they mentioned. I can add maybe to say something a little different that I really did enjoy your presentation, John, on the UNITY-CLL study. Actually, this is an important Phase 3 trial. It’s one that we’ve been waiting for the results on for some years now. As a reminder, this is the newer PI3-kinase delta inhibitor, umbralisib, given with a CD20 antibody, ublituximab, or so-called U2 regimen compared to obinutuzumab and chlorambucil. This is a large Phase 3 data set, over 600 patients initially enrolled in the study. And it was great to see the efficacy and safety data, the efficacy data in the frontline setting, median progression-free survival of around 38 months or so, a little less in the relapsed/refractory setting.

Matthew Davids:
I think you’re seeing, as we saw in the early phase studies of umbralisib, that the safety profile of this drug does seem to be a bit better than the approved PI3-kinase delta inhibitors, particularly in the frontline setting where those toxicities have really been prohibitive for those other agents. So I think this could be a feasible regimen now for frontline use the U2 regimen, potentially a nice alternative to BTK inhibitors or venetoclax based therapy for patients where perhaps those are contra-indicated.

Matthew Davids:
I don’t see it as displacing those two therapies for patients who are candidates, though. And then the other thing I did want to mention, which also struck me at the meeting, was the CLL14 update. We saw some very elegant MRD data, which we expected to see from the abstract, but the German group nicely snuck in some updated PFS data, which I think is really important. We found that four-year PFS for venetoclax-obinutuzumab 74%. So that means since the last data cut when it was 82%, only 8% of patients have progressed in that year from three to four off of all therapy, which to me looks very reassuring that you can get durable benefit from venetoclax-obinutuzumab, particularly for lower-risk patients who don’t have TP53 aberrant disease.

John Gribben:
Yeah. As you say, it was a nice little bonus from CLL14, because of course, it wasn’t in the abstract, and I don’t think many of us were expecting to see it. And it kept it almost till the very end of the presentation and just kind of threw it in there. I’m going to come back and talk about the stuff about the dynamics of the MRD, and Alessandra, you talked about it too. Because I think that was a recurring theme we saw in lots of the talks this year, looking not just to MRD positive or negative, but the dynamics. I want to hold that thought and come back to it. But yeah, I completely agree with you, Matt, the CLL14 data, I had been a little concerned that the PFS was dropping off, but really another year later hadn’t dropped off that much.

John Gribben:
And I was beginning to worry that one-year fixed duration venetoclax wasn’t going to be enough. And Meghan, I’m coming back to you. Alessandra already touched on the issue of PFS two and thinking about re-treatment after venetoclax; of course, your own presentation was on kind of looking at exactly this. And I’d like to just talk and get the three of you involved in thinking about the whole question of sequencing, but particularly if we’re talking about using venetoclax-based, fixed duration therapies, what’s your thoughts about the data we see emerging about, when and whom you would re-treat with venetoclax regimen, do you re-add in an anti-CD20 antibody or not? And what are we thinking about? And I completely agree with you, Alessandra, more presentations starting to think about PFS two, which is now becoming more and more important in terms of thinking what we’re seeing. So, so Meghan, you presented the data. So you’ve obviously, in terms of your own presentation, also been thinking about the other data we saw in that kind of field. So what are your thoughts in that area?

Meghan Thompson:
Yeah, so I think for the first time we saw, still a very small number of patients in the two presentations, which were different patient populations. So I was part of a project that was a collaborative effort for patients treated in the U.S. And then we used the Core CLL Database, and we identified patients who had been treated either on clinical trial or off of clinical trial with a venetoclax based regimen, both treatment-naive and relapse refractory, although this is the heavily pretreated population. And I had valuable responses on 18 patients who were re-treated with a venetoclax-based regimen. Now, most of those patients were treated with monotherapy regimens, did not have anti-CD20 added, although some of them did. And we had short follow-up but an overall response rate with 72% on 18 evaluable patients. And we were also able to take a look at some basic safety data and also just physician practice.

Meghan Thompson:
How are you re-introducing venetoclax in the second line? Did people do the standard dose escalation? And most people did, with the exception of two of those patients. So we found an overall high response rate. I think the numbers are still very small. I think also, with longer follow-up, it would be interesting to see if responses deepen. The patients that we followed who had a complete response had a longer duration than those with stable disease. So I’m looking forward to collecting a little bit more data there. But as Dr. Tedeschi mentioned, I think it was really important also to see the MURANO follow-up.

Meghan Thompson:
A little bit of a different patient population, now our kind of real-world look included 60% of those patients have been treated with a prior BTK. So a little bit different population than MURANO, they also had 18 patients, same number with evaluable responses and actually found the same overall response rate, 72% with Ven re-treatment. So you have two kind of different takes on it with similar responses. Their follow-up was a little bit longer, I believe, but still short, so it’ll be interesting to see over time, kind of how durable those responses are. And then, they also presented data for BTK after the MURANO regimen, which was also very promising. So it’s nice to see some more data, even though there’s a lot of retrospective work and real-world work about BTK after venetoclax, now it’s nice to have kind of confirmation of that with these patients who have been followed really closely.

John Gribben:
So you already talked about the MURANO re-treat, I think. Well, of course, we’re now seeing, is we’re seeing patients with, MURANO being re-treated, who had the first lock where the people who relapsed quite early and now we’re seeing people who’ve had longer durations of responses. And of course, those are the people that I think naturally we’re all going to be more comfortable going back to venetoclax re-treatment for. And it did seem as if that yes, the PFS two was longer in those whose PFS one was also longer. And I guess it’s intuitive to think that would be the case, but was that your interpretation of what you were seeing overall at the meeting also?

Alessandra Tedeschi:
Yes, yes. I would say yes, of course, we also see for the first time, I would say, in the MURANO study what impacts on MRD doubling time because as for now, we didn’t have many predictive factors of patients treated with the venetoclax-rituximab and what we saw again, that patients with 17P deletion, complex karyotype, but then they didn’t have a MRD doubling time spectrum compared to the others. So again, we are seeing that there is a high-risk population, of course, but seems that this is patients that are relapsing this moment, then going to receive a second-line treatment. So these patients do also were with the second salvage, I would say, so this is important.

John Gribben:
Actually, off course, this is a good time as any to talk about. For me, as I said already, one of the themes of this meeting was looking at the dynamics of MRD. And I thought we saw a number of very eloquent approaches, lots of different modeling going on. And for the people that are probably not CLL aficionados. A lot of it quite arcane and quite complex in terms of how it’s all being done. But a general theme coming out of several of the studies was that people who receive the novel agents. The dynamic of relapsing looks a little different than the arm who received the chemotherapy. Now I know you and I have talked in the past about how potentially chemotherapy might be able to induce some kind of genetic changes in the cells as one potential mechanism. But what are you making out of how it might be getting treated with venetoclax before would change the doubling time of the CLL at relapse?

Matthew Davids:
Yeah, I think that’s a really tough question. And the hypothesis that you mentioned is…

John Gribben:
That’s why I kept it for you.

Matthew Davids:
Yeah, that was going to be my answer, I think there probably is some genetic toxic damage from chemo and immunotherapy that enriches for faster growth rate based on a variety of different mutations that are induced. And, we don’t know too much about resistance to venetoclax in the frontline setting yet. CLL14 has not had too many progressors. Certainly, those progressors seem to have TP53 dysfunction, more likely. But the German group did a very nice, and as you said, elegant analysis of growth rates in the Ven-Obin treated patients in CLL14, and certainly, patients who have high-risk markers had faster growth rates.

Matthew Davids:
But I did also, as you said, I was struck by that faster growth rate in the chlorambucil-obinutuzumab arm. Even sort of matching for different risk factors and the genomics of the disease. So it does seem like there’s something about the chemo-immunotherapy that’s leading to faster regrowth. And this is even looking at a 10 to the minus six deaths. So it’s not just that you’re getting deeper remissions with the venetoclax, it’s all things being equal, you can get to 10 to the minus six, even in some cases with chlorambucil-obinutuzumab, but those clones are going to grow back faster. And I think that’s a puzzle that we need to continue that unravel.

John Gribben:
I thought perhaps particularly with the MURANO data, no offense to Arnon. But I think perhaps he was overinterpreting the data to see a plateau in that curve that I wasn’t seeing yet. But I see Ms are flattening it out, but I thought plateau is perhaps an overstatement. What do you think all this means, Meghan, in terms of people in practice about how confident they’re going to be re-treating with venetoclax rather than immediately changing over to a BTK inhibitor or potentially moving on to a third-line therapy if it becomes available to something like umbralisib?

Meghan Thompson:
Yeah. So I think there’s not enough data yet to say that re-treatment after fixed duration is really a standard approach, especially when there are a lot of other great options for patients. I think we need more data, particularly in the frontline setting. There’s almost no data now. So I think if someone’s being treated upfront with fixed duration, patients that maybe this approach would be considered in are later-stage patients who have fewer options maybe were treated with venetoclax-rituximab fixed-duration in the relapse setting years ago have been through some other therapies and had a good initial response to venetoclax and then a duration of treatment-free for a while. Maybe those are the patients, but there are a lot of other good options right now. So I think before this is a standard approach, we definitely need more data.

Meghan Thompson:
And then of course, there’re those patients who really would not be in this very small group. And patients who have had resistance or had just progressed after six months. So I think, I think a lot more needs to be done, but I think it is good. And I think, take away from this meeting is a lot of the frontline treatment options were fixed duration combination therapies that do include both BTK and BCL2.

Meghan Thompson:
And so when you have patients who this is still on in the clinical trials setting, what will you do once you do a fixed duration, anti-CD20, BCL2, BTK, or even an MRD driven approach, what you get is only in the clinical trial setting. If these do become standard approaches, at some point, I do think that this will be a very relevant question for people. Can they be rechallenged with a BCL2 inhibitor? So I think it’s still forthcoming. And I think it’ll be very important, especially once we see longer-term follow-up from these combinations in the frontline setting to see if patients can be re-treated, but I don’t think it’s by any means ready for a standard of care yet.

John Gribben:
So, of course, all three of you mentioned the LOXO trial, can any of you potentially see that non-covalent BTK inhibitors can displace covalent binders as a class of drug going forward? Anyone thinks so?

Matthew Davids:
I would say it’s certainly within the realm of possibility, there’s certainly a lot of hoops that would need to be jumped through first. I think what you alluded to before about the safety profile differences, maybe influential there, John. So I think if LOXO can show that it’s highly effective, both in BTK wild type and mutant patients, but with at least appearing to be a better safety profile. We heard from Dr. Mato that they are planning ahead to head study versus ibrutinib. And if they can show in that study that there’s better safety profile and at least comparable efficacy, then have an important role.

John Gribben:
Sure. Now, Meghan already alluded to there, the fact that we saw lots of data on the doublets and triplets, so Matt, you presented some your own studies triplet data, or what’s your take overall on… I guess I’m coming back to all of you. I guess the answers to doublets versus triplets is going to take the clinical trials, but how are you interpreting what you’re seeing in terms of doublets versus triplet and in terms of the therapy that we saw this year and more updates on the studies that are ongoing?

Matthew Davids:
Yeah. I mean, I would say it’s early days still, we presented an update on acalabrutinib, venetoclax, obinutuzumab, the AVO data. We saw data from the BOVen study with zanubrutinib, venetoclax, obinutuzumab as well as updates on ibrutinib, venetoclax, Obin. So the triplet data are there, but they’re all single-arm studies. We don’t have any randomizations yet. We have doublet based regimens that we’ve seen that look nice as well. We saw an update on the CAPTIVATE study for the first time, seeing the MRD cohort data for ibrutinib-venetoclax upfront. Also looks very good, but as you’re alluding to, I think questions are going to be around, do we need the CD20-antibody?

Matthew Davids:
There are studies that will help us to answer that, that are ongoing in the UK and also the 311 study of acalabrutinib, Ven, Obin versus AV versus chemo, for example. So that’s one question, but I think as Meghan was saying, do we really need to use both of our best mechanisms upfront BTK and BCL2? So we really need studies comparing that approach to, for example, Ven-Obin and then sequential use of a BTK inhibitor later in the course. And there are again, studies like that planned, so that’ll be important, but we’re not going to know the results for many years.

John Gribben:
I know. Now, of course, Alessandra, this is where your concept of PFS two becomes even more important for using all of our best class of drugs upfront. We have to know, and almost invariably, we’re going to be doing that fixed duration, or there’ll be no point in doing it that way. Almost invariably, we’re going to have to know what happens to the patients after progression, but I’m certainly not going to be around in my career to be seeing the results of many of those studies. You guys are all young enough to be potentially seeing it, but these are going to be very long studies to readout. And as always, potentially by the time we get the readouts on these studies, the whole field will have moved onto something else again. So these are going to be very long studies to do, aren’t they?

Alessandra Tedeschi:
I believe yes, but first of all, how Matt, you said we need randomized studies to understand if it’s better to add or not the monoclonal antibody because we know that more is better in hematology, but we know that it’s not always through all these things. But I think that all these Phase 2 studies in which the treatment is arbitrarily chosen, I mean, CLL14, it’s chosen on an arbitrary scheme at the end it’s 12 months, but there is not a rationale for the twelve months. So all these Phase two studies may be, and those studies with a longer, it’s very different from a one study from the other.

Alessandra Tedeschi:
Will help us to understand maybe which is the better dose and which is a rare schedule we would administer to our patient. 12 months, 24 months, it’s better MRD driven or not. Something we have learned from the CAPTIVATE study at the end of that because, after 12 months if you are MRD negative, seems for, this is free survival at one year, you don’t need anymore ibrutinib. But all these Phase two studies, we learn something about the schedule and the how long would be the treatment of these patients. Otherwise, with randomized trials, as you said, we need years and years and years to have a definitive answer to everything.

John Gribben:
It’s why I’m hoping that really the dynamic MRD studies are really going to give us a clue, about what’s happening in many of these patients and give us some anticipation. But we’re clearly going to need a lot more data than we saw just this year, in terms of correlating MRD dynamics with real-life data, I guess the more you think about using up all your drugs, the more you have to think what else is out there. We obviously saw Bill Wierda and Tanya Siddiqi update as again, on the TRANSCEND, the CAR T-cell data. So, Meghan, back to you again, what’s your take on where we are with CAR-T, and are the data looking good enough for us to be able to think that those patients who have failed our other best therapies are going to be salvaged with these approaches?

Meghan Thompson:
Yeah, so I think even tying into using, a triplet combination upfront that patient selection is a really important part of this conversation too. Looking at what studies are in art enrich for these high-risk patients del(17p), TP53 mutation, and then some of the other emerging as genetic characteristics, we’re seeing. I think that it’s certainly both the 24-month follow-up from the liso-cel monotherapy, as well as the BTK in combination with liso-cel data are really promising. I think the question becomes which patients are appropriate for this time-intensive, costly, and really aggressive approach, when other treatment options exist. It was nice to see that there were a lot of P53 aberrant patients in the TRANSCEND 24-month follow-up. Some of whom had durable responses. So I think it’s good to have this approach, in the back pocket, again certainly in the trial setting, but especially for those patients who, with genetic characteristics that the novel combinations haven’t yet quite overcome.

John Gribben:
I guess as well, Alessandra, there’s a changing dynamic of who are the patients who are going to be coming to this type of therapy as more and more of these new and novel combinations of therapy come along. And I’m kind of aware of thinking already what happened in the lymphoma field, where you got better upfront therapy, you got worse relapses. So, it may be harder to salvage these people back in the future. So you already alluded to the issues Alessandra that in Europe, of course, the CAR T-cell field has a little bit lag behind where things are in the U.S. And certainly in Europe, we haven’t had as much exposure to the liso-cel clinical trials that have largely occurred in the U.S.

John Gribben:
But certainly, in Europe now CAR-T and lymphoma fully established as being a treatment approach. And one would imagine that if when liso-cel becomes approved in CLL, the same kind of approach will open. So there will be doors open for some of our patients to be treated in this way. I guess, starting in that very end-stage population. It’s a question of how do you decide in which group of patients you’re able to try to move it forward? Any thoughts on that?

Alessandra Tedeschi:
Not many thoughts on that from this moment, of course, we are doing a lot of CAR-T in high-grade lymphomas and acute lymphoblastic leukemias but not in CLL, as you said. From the studies, I have seen the population was a very high-risk population in progressive disease after BTK inhibitors. So the venetoclax, and of course there were also a lot of Richter’s transformations in the Tanya Siddiqi’s study. So maybe for sure, we have to select the high-risk population but treat with the best kind of cellular therapy, because they have been submitted to so many treatments because otherwise, we won’t have a nice [inaudible] cell there. And so the selection should be made before we perform a lot of other drugs. I believe.

John Gribben:
I know you’ve got some regular studies ongoing. I see a huge amount on Richter’s at this meeting. Anything kind of catch your eye in the Richter’s field, any hope there for a Richter’s patients, other than the just the CAR T-cell data we already saw?

Matthew Davids:
Yeah. Not too much new at this meeting beyond that, at least in the clinic. I think there have been some interesting insights on the more basic side, trying to look for different pathways that may be involved trying to dissect the NOTCH pathway a little further and how that might influence Richter’s pathobiology. I think on the clinical side, we presented some data earlier in the year at ASCO on the venetoclax R-EPOCH combination, sort of a chemosensitization strategy, which I think looks promising.

Matthew Davids:
And then, I think some of the checkpoint approaches, it doesn’t seem like checkpoint blockade on its own is going to be enough in Richter’s. But perhaps finding the right combination partners. MD Anderson has presented some data on BTK inhibitors with pembrolizumab or nivolumab, for example, in the past. So I think those are promising angles, but as you well know, John, CLL is a challenging disease for immunotherapy. I think the same issue exists with the CAR T-cells and CLL. You’re relying on autologous T-cells that are dysfunctional from CLL patients. And you still have often a burden of disease there that’s contributing to the immune suppression. So I think looking at novel combination partners to enhance the activity of cellular-based therapies is really going to be crucial in CLL.

John Gribben:
Yeah. And of course, we saw that from Tanya and Bill presenting the data, looking at using ibrutinib not in terms of its CLL act and activity, although I’m sure that’s a part of it, but some of those patients are already ibrutinib resistant. So really using it for its immunomodulatory effects. And I think we probably need to do a lot more to really understand how the CLL impacts on it. Well, believe it or not, guys, although we said there was not much we’ve managed to use up the entire time already.

John Gribben:
So all that remains for me is to say that you can hear that, although we all started off by seeing not a huge amount of brand new Phase 3 data in CLL, plenty of data for the four of us to be quite enthused and to talk about. And a lot of incremental data, that’s going to be very useful. And a lot of modeling that I think is going to be extremely useful for planning for clinical trials in the future. So with that, I’d like to thank you all for your attention, thanks to Meghan, Alessandra and Matt for their incredibly insightful comments on what we saw at this meeting. And thanks to VJHem for giving us this platform to share our views with you. So see you all at the next meeting and look forward to it then. Thank you very much.

Alessandra Tedeschi:
Thank you.

Matthew Davids:
Thanks.

Meghan Thompson:
Thank you.

Alessandra Tedeschi:
Thanks, bye.