A five-part session with experts John Gribben, Barbara Eichhorst, Susan O’Brien and Matthew Davids who debate the key updates in diagnosis and treatment of chronic lymphocytic leukemia (CLL) following the ASCO and EHA 2020 virtual meetings.

Welcome to The CLL Sessions brought to you by The Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts John Gribben, Barbara Eichhorst, Susan O’Brien and Matthew Davids who debate key updates in the diagnosis and treatment of chronic lymphocytic leukemia (CLL) from the ASCO and EHA 2020 virtual meetings.

The topics of discussion include frontline therapy, BTK inhibitors, novel combination therapy, measurable residual disease (MRD) negativity, treatment sequencing, transplant and resistance.

Frontline therapy & high-risk CLL

“Patients were randomized between venetoclax plus obinutuzumab for 12 months total or chlorambucil plus obinutuzumab. And now the update after 14 months showed as expected, the progression-free survival has continued to be superior with the venetoclax plus obinutuzumab arm. But the new finding is that we see for patients separated according to the IGVH status, not only the PFS is significantly better in those patients with an unmutated IGVH status, but also now the curves are separating for the group of patients with mutated IGVH status.”
Barbara Eichhorst

BTK inhibitors in CLL

“We saw recently the five-year update from the RESONATE-2 trial, which was ibrutinib versus chlorambucil. That was the trial that gave the frontline label to ibrutinib. That the update from that trial shows that at five years, 70% of people are still in remission. Which is phenomenal, it’s just great.”
Susan O’Brien

 

Novel combinations

“Probably the more popular studies have been the ones combining novel agents only and trying to get rid of chemo-immunotherapy, there’s certainly a lot of enthusiasm in the field for that approach. And we saw an update of the CAPTIVATE study at this EHA meeting, a reminder, this is the combination of ibrutinib plus venetoclax in the frontline setting with an ibrutinib lead-in to help cytoreduce. And they confirmed again that this does reduce the risk of tumor lysis syndrome from the venetoclax.”
Matthew Davids

MRD negativity in CLL

” I think MRD attainment is crucial, because you want to get the deepest possible remission. Because you know once you’re off-therapy, that the disease may start to come back. And so the deeper the remission, the longer it’s going to take for the disease to come back.”
Matthew Davids

Treatment sequencing, transplant & resistance

“We have data to support that, MCL1 may play an important role in venetoclax resistance in CLL. So, there’s a number of direct MCL1 inhibitors that are in the clinic in various stages, early phase clinical trials where we have not seen data yet. There are some concerns around the possibility for cytopenias and cardiovascular toxicities based on some of the preclinical models. So, I think a careful exploration of these drugs in the Phase I setting is certainly important.”
Matthew Davids

Full Transcript
John Gribben:
Welcome, everybody, to the first of the CLL sessions on VJHemOnc. I'm John Gribben from Barts Cancer Center in London. Today I'm joined by my very good friends and colleagues, Susan O'Brien from University of California Irvine, USA, Barbara Eichhorst from University of Cologne and the German CLL Study Group in Germany, and Matt Davids from Dana-Farber Cancer Institute, Harvard Medical School in Boston, USA. Today we're going to look at some key news and topics in a very active time in the research and treatment of CLL, with a lot of data and insight coming from a very exciting virtual EHA which came hot on the heels of a virtual ASCO. So, we're all getting used to virtual meetings.

John Gribben:
So let's just get straight in, because I think we've got a lot of things to talk about. And let's start with what we saw in terms of frontline therapy for CLL. So Barbara, we saw updates from CLL 14 study. You're the German CLL Study Group, obviously you led this study. Obviously you've had a great deal of time to think about this approach, so what did you take away from the update that we saw presented at the meetings?

Barbara Eichhorst:
So the update of the CLL14 trial, just for remembering, that's a Phase III trial in unfit patients. So there was no age cutoff, but patients with a certain co-morbidity were included and then were randomized between venetoclax plus obinutuzumab for 12 months total or chlorambucil plus obinutuzumab. And now the update after on 14 months showed as expected, the progression-free survival has continued to be superior with the venetoclax plus obinutuzumab arm. But the new finding is that we see for patients separated according to the IGVH status, not only the PFS is significantly better in those patients with an unmutated IGVH status, but also now the curves are separating for the group of patients with mutated IGVH status.

Barbara Eichhorst:
This is also for clinical practice, as in this is very relevant. Because so far, we still have the paradigm that chemo- immunotherapy is still an option in those patients with favorable cytogenetics. However, this trial shows now that after a relatively short observation time, that there is also benefit. The other news which we have seen already from last year, which is not so good, is that we see again in the very high-risk patient population of patients with TP53 mutation or the lesion that also here, the novel combination. PFS is significantly worse in those patients, so, of course it's better than with chemo-immunotherapy.

John Gribben:
For Matt and Susan in the USA, do you see there being a place for a one- year fixed-duration therapy in this approach? Do you think it is something that will be attractive to patients in the US?

Matthew Davids:
Yeah, I certainly think so. I mean we've had this now for over a year, approved and paid for in the US. So, it's a popular choice amongst my patients. They like the idea of the time-limited therapy. And I think particularly for the mutated IGHV patients, we're going to see a very long PFS from that one year of therapy. I guess one of the questions I had for Barbara is it seems like the unmutated IGHV patients, you've got the venetoclax-obinutuzumab maybe starting to progress a bit more? I don't think there's a statistically significant difference yet, but how do you view that population?

Barbara Eichhorst:
Yeah, I agree with your Matt. So as a matter of concern, we know that these are, the residual CLL says that they will proliferate faster than amongst those patients, the mutated IGVH stages. So therefore, it's a question of how deep the remission will be. We have seen our data on the minimal residual disease measured by a newer method, so-called next generation sequencing. We see very deep remissions, and probably there are also unmutated patients among those. And probably also here, progression-free survival will be very long. But the less deep the response to this combination therapy is the faster we, I expect to see also here again, the relapse. So, the curve looks very good for patients with mutated IGVH status. For the unmutated, this is obviously not a curative treatment.

John Gribben:
I'd imagine that in California, the idea of novel therapies and fixed-duration and chemo-free would be something very attractive. But are you ... particularly for that higher group of patients, do you think one year of therapy is enough in that setting? We didn't see the mutated and unmutated split that same way in the MURANO data, did we?

Susan O'Brien:
No, we didn't, and it is an interesting question. I think this question has actually come up before, in particular when we saw the update on the MURANO data in the relapse setting, the trial of BR versus venetoclax-rituximab. We saw that the majority of patients who progressed very soon after stopping treatment, and remembering that in that relapse trial, treatment was for two years rather than one. But what we saw is that the early relapsers were clearly very much enriched for 17p-deleted or p53-mutated. And I've heard many discussions amongst CLL physicians about whether they in the relapse setting, would actually stop therapy on their patients with high risk disease. And I think the fact that, as Barbara said, we're beginning to see the curve separating in the frontline, probably that same discussion would be relevant to the frontline.

Susan O'Brien:
Albeit, I think it's important to point out that at three years, there was still no median PFS in that high-risk group. So they're still doing quite well in maintaining remission for a number of years off of therapy, which is still a pretty attractive concept for those patients. But I think it really raises the question of, in that group, would you stop or would you keep going? I remember that when John Seymour was asked on the MURANO trial ... "Well, maybe you should have continued and waited until those patients became MRD undetectable?" He raised the point that in most of those patients, their MRD levels either have plateaued or actually going up. So, he made the point that he didn't think that high-risk group would have become MRD undetectable. But it still doesn't answer the question, and you can answer it. Well, maybe they wouldn't have become MRD undetectable, but would their remissions have lasted longer if we continued therapy? And I think this raises the same question.
John Gribben:

I think our view about thinking about more continuous therapy is the perfect segue into talking about BTK inhibitors, in which of course we're used to giving a continuous therapy. So as always, Susan, some of this isn't new. But it's also new to see the continued updates on the ibrutinib-acalabrutinib data, it's always reassuring to see where the curves are. What did you make of what you'd seen? Particularly thinking, focusing right now on the upfront setting, of any surprises, any disappointments for you in what we saw?

Susan O'Brien:
No, I wouldn't say disappointments. I mean not at this meeting, but we saw recently that the five-year update from the RESONATE-2 trial, which was ibrutinib versus chlorambucil. That was the trial that gave the frontline label to ibrutinib. That the update from that trial shows that at five years, 70% of people are still in remission. Which is phenomenal, it's just great. But as you pointed out, that's with continuous therapy. What we did see was an update on the ELEVATE trial, which was the trial of acalabrutinib plus or minus obinutuzumab versus chlorambucil-obinutuzumab. And that also is not time-limited, just like with ibrutinib. And what that update clearly showed was that, not surprisingly as Barbara said, the either acala arm producing significantly better results than chlorambucil-obinutuzumab.

Susan O'Brien:
And again, I don't think that that was very surprising. It was interesting that the acala-obinutuzumab curve was a little bit higher, the PFS curve than the acalabrutinib single-agent. But it's important to note that those differences so far at least, are not statistically significant. That has been approved as a frontline regimen in the US. And interestingly, the label is sort of interesting. Because what the label says here is it can be given either way, so they really leave it up to the physician as to whether they want to give the antibody with it. But nevertheless, the PFS curve looked great, above 80% at two years. So, these are clearly going to be very durable remissions. One of the potential advantages of using in acalabrutinib is that the cardiovascular side effects have seemed to be decreased. So, there does appear to be less atrial fibrillation and less hypertension.

Susan O'Brien:
I will point out that it's important if we're going to compare across drugs without a head-to-head comparison, which we don't have yet. That we know from ibrutinib that the hypertension can occur any each year of onset. It can occur late. So we can have a patient on drug for five years, and they can start to develop hypertension. So it's going to be important when we're comparing those hypertension rates across drugs that we compare at the same time point, in terms of the followup. But nevertheless, I do think the data suggests that the cardiovascular side effects are clearly reduced with acalabrutinib. So, we do have an option to use that here in the States.

John Gribben:
Now of course you raised the issue that I was going to raise, if you hadn't already raised it, of the interesting finding on ELEVATE. That the addition of the anti-CD20 antibody, obinutuzumab here did appear to do a little bit better. We thought that issue had been put to bed with the results from the ALLIANCE trial, that showed no impact from the addition of rituximab. And of course we'd seen the iLLUMINATE data where the addition of obinutuzumab to ibrutinib showed good results, but of course there was no ibrutinib-only arm in that study. But I think most of us interpreted, think that the obinutuzumab didn't look like it was adding a huge amount to what we'd seen from the RESONATE-2 trial alone. So, the question is out there. But do you think the results of that data as shown, are going to make physicians add obinutuzumab into acalabrutinib in the frontline?

Susan O'Brien:
I doubt it without more followup, particularly because physicians who are used to prescribing BTK inhibitors are used to starting the patient on the drug and not having to start anything IV. So, I don't think that data will compel people to use it. But it will be very interesting if with longer followup, those curves continue to separate. And then of course, it will raise the issue that maybe we can assume it's a class effect, rather it's an antibody effect. That maybe with a more potent antibody, there will be a difference. But you're right, I think, to me, I was actually a little bit surprised when I first saw that data. Because we did know that at least with rituximab, there has been two randomized trials now, clearly showing no benefit in terms of PFS with the addition of rituximab to ibrutinib. So we'll have to see with a newer antibody, maybe it'll be different.

John Gribben:
Okay.

Matthew Davids:
I think it does speak to the fact that not all BTK inhibitors or CD20 antibodies are alike. And I think we could have potentially predicted the results with ibrutinib and rituximab, based on some of the antagonism that's been seen in preclinical models there. So perhaps by using the more specific BTK inhibitor and a more potent CD20 antibody, that you really can have some synergy there. But I think as Susan says, time will tell, based on whether that PFS curve stays up.

John Gribben:
Well, Matt, thinking of synergy and thinking of combinations, that gives us ... nicely into the next things I wanted to talk about. Because of course we saw lots of presentations on a whole variety of doublet, triplet type therapies of combining BTK inhibitors venetoclax plus or minus antibodies. So lots of trial data, we could spend the whole night talking about just the trials that we saw presented, but anything that you took away from the meeting specifically and wanted to focus on?

Matthew Davids:
Sure. So when I think of combination approaches with novel agents, I kind of think of three main categories. So one would be as you're alluding to, the sort of novel, novel combinations, ibrutinib and venetoclax. A second would be adding in a CD20 antibody. And we heard great data from Barbara on CLL14 with venetoclax and the CD20, but thinking of adding CD20 plus ibrutinib and venetoclax. And then we shouldn't forget about our old friend, chemo-immunotherapy in combination with novel agents.

John Gribben:
Yeah, yeah, I was going to come back to that thought. We ... or I thought it was dead, and it seems to be trying to rise from the grave here.

Matthew Davids:
Well, why don't we start with that? So we had published our study on ibrutinib plus FCR last year, and we reported very high rates of undetectable MRD in the bone marrow. The French group also published their FILO CLL7 study shortly thereafter, and presented an update at this EHA meeting of their dataset, which continues to look very compelling. Their approach is using ibrutinib and obinutuzumab for a lead-in period. And then if patients don't achieve a CR and undetectable MRD, then they do the combination of ibrutinib with FC and obinutuzumab. And they've really shown some outstanding results in terms of depth of response, also about an 80% rate of undetectable MRD in the bone marrow. At this update, they showed some three-year progression-free survival data with very few progression events. They also showed some interesting MRD data, suggesting that those patients who achieved undetectable MRD were able to maintain that off-therapy for a few years now.

Matthew Davids:
So, I think that it's a fairly small group of young fit CLL patients who are still eligible for this type of intensive approach. But if you had a patient in their 50s who wanted a very high rate of undetectable MRD and the potential for this functional cure that we've seen previously with FCR or even on its own ... I think this is becoming a reasonable option to consider. But certainly needs to be compared also in Phase III studies. Probably the more popular studies have been the ones combining novel agents only and trying to get rid of chemo-immunotherapy, there's certainly a lot of enthusiasm in the field for that approach. And we saw an update of the CAPTIVATE study at this EHA meeting, a reminder, this is the combination of ibrutinib plus venetoclax in the frontline setting with an ibrutinib lead-in to help cytoreduce. And they confirmed again that this does reduce the risk of tumor lysis syndrome from the venetoclax.

Matthew Davids:
And then they do a combination period of ibrutinib plus venetoclax, and again showed very nice undetectable MRD rates with reasonably good tolerability. They do see some neutropenia and infections with this combination. You see some of the typical ibrutinib-related toxicities, but nothing that really seems untoward in terms of the combination. So, I think it's a very appealing regimen being all oral and fairly straightforward to administer. And it's still a bit early in that study, in the sense that we're very curious how the patients will do in this MRD randomization. That comes later on, so we'll eagerly await those results in the future.

Matthew Davids:
And then the last one that I just wanted to mention briefly in that third category is the GIVe study, which we were seeing for the first time at the EHA meeting. This is a really crucial study, because it's looking at the TP53-aberrant patients, either with deletion 17p or mutation in TP53. These are our highest risk CLL patients with the greatest unmet need, and this study exclusively looked at about 40 of those patients with the triplet of ibrutinib, venetoclax and obinutuzumab. And again, saw very deep remissions in this population. The followup is short at this point. But given the high rates of undetectable MRD, it looks promising that this could even be a feasible regimen as a time-limited regimen, even for these high risk patients. But of course as a single-arm study, we're going to need comparisons. And we have studies underway now to look at IVO in the US, as well as in the UK and elsewhere.

John Gribben:
Just let me come to you on that, so combinations of chemotherapy with novel agents, step forward or a step back? What's your view on that kind of use of combinations, or do you think we should be moving towards really looking at novel targeted therapies?

Susan O'Brien:
Yeah, I do. I think the combinations look really potent. And let's get to the point. What we would really like to do is cure this disease, right? And so MRD undetectability is not the same as cure, but I would say it's necessary for cure. It's a first step. So anything that we can do to get that rate up and then have more durable remissions, I think is going along the way towards trying to get a cure for everybody. That being said, there is also ... and it is an assumption right now, I have to say. Sorry, the assumption that if we have these time-limited combinations with very high MRD undetectability, that if patients do relapse down the line, they will still be sensitive to the drugs that we gave them. And so we're not kind of using up two drugs at the same time, which I think has been a concern.

Susan O'Brien:
I actually put a fair number of patients on the CAPTIVATE trial. And many of the patients said to me, "Well, wait a minute. If you're going to use both those drugs, what are you going to do then when my disease gets back?" So, even patients where we're wondering that. So as I said, it's an assumption. We don't have very many relapses off of these combo trials, because they're so new. And hopefully it's an assumption that will be correct, I think there's a good rationale to assume it. But that makes me not so worried about, "Oh, well, if I use two drugs upfront and then what am I going to do if the patient is not put into a real long lasting remission from this regimen?"

John Gribben:
Yeah. And Barbara, the one area in which of course chemotherapy might still have a role and one that the German CLL study group has looked at, is a debulking strategy. Particularly if you're thinking about using venetoclax to try to take those high risk TLS patients to debulks. What's your view? I mean I know you've been involved with some of those clinical trials, but what's your view on that as an approach? When I kind of talked to some of my patients about it, they're like, "Oh, but I thought the whole point of this was to avoid chemotherapy," yeah?

Barbara Eichhorst:
Yeah, you're completely right, John. I think it depends on the patients. I would hesitate to expose our patients with a already known TP53 mutation aberration. I mean, those patients usually respond also for a short period of time. But the risk is very high that in most cases, you just decrease CLL cell number which do not carry TP53 mutation aberration, but the good risk CLL cells. But on the other hand, if you have patients with a really high tumor burden and you give those one or two courses of bendamustine alone, you're starting with a really low tumor burden on those patients. And from our trials, the observation for example for combination with obinutuzumab, was that obinutuzumab was much better tolerated with respect also to tumor lysis syndrome or also to infusion-associated reactions. With respect to the overall response rate, my colleague Paula Cramer made here a meta-analysis from those different trials. And it seems that as expected, that these one to two cycles of the debulking treatment do not add something on deepening their response or to the overall response rate.

Barbara Eichhorst:
But however, I think that particularly when physician is not so used to using venetoclax or obinutuzumab, where tumor lysis syndrome may occur, this could be a step forward in order to reduce lymph node burden. And therefore, to have a safer start of the combination therapy. But as you said before, patients who are really aiming for a chemotherapy-free regimen, they probably would like to avoid. So I think with respect to toxicity, this one or two cycles do not add so much toxicity.

John Gribben:
We've spent a lot of time talking about MRD and its potential importance now. Lots of the clinical trials, particularly with venetoclax, have looked at fixed-duration therapies. But lots of the academic trials have been driving towards MRD negativity as an endpoint. Clearly I think all four of us believe that having a patient in a deep MRD-negative state does act as a surrogate for a long progression-free survival. And Susan, you've already said it, we're all aiming eventually for cure and that's going to be a necessary step to get there. So, what are your views? Let's start with you, Matt. So, how important is it to get a patient into a MRD-negative state?

Matthew Davids:
So I do think it really depends both on the patient and the specific treatment, and the paradigm that you're using. So I mean, we're talking recently in the last few minutes about these time-limited regimens. And there, I think MRD attainment is crucial, because you want to get the deepest possible remission. Because you know once you're off-therapy, that the disease may start to come back. And so the deeper the remission, the longer it's going to take for the disease to come back. But in contrast if you're using a continuous therapy like a BTK inhibitor, then it's not really important at all to get to undetectable MRD. Patients we know can do very well on a partial remission, with plenty of detectable MRD for many years. But they probably wouldn't be able to stop that therapy for a long period of time.

Matthew Davids:
So I think if you're thinking about an old patient who maybe goes on a BTK inhibitor for several years, that that might be a very nice palliative therapy for them. But if you're talking about a young fitter patient, particularly if they have higher risk disease markers, there I think targeting undetectable MRD with a time-limited regimen is a good goal.

John Gribben:
Now Susan, you already alluded to the issue about what you might do in a patient who's been on a fixed-duration therapy, you measure minimal residual disease. Which probably lots of us are in a position to do, but lots of physicians in the community probably don't do at all. So, you've got groups of patients who are going to be stopped with no idea what the MRD level is. And then, but if you're working in an academic center, you've probably got access to it. What do you ... what is your approach to thinking about a patient who remains MRD-positive at the end of therapy? Would you look to continue venetoclax afterwards? Or if you were on, for instance, the MURANO approach? Or how do you think you and how do you think that might differ from clinicians that refer patients and talk to you about how to manage their patients?

Susan O'Brien:
It's an interesting question. And I think if I was going to go that route, what I probably ... what I mean by that route is trying to make a decision. Say I was going to use venetoclax-obinutuzumab upfront and I'm thinking, "Well, maybe if the patients has detectable MRD, I don't want to stop at 12 months." I think it would be hard to make a decision with only having the 12 month time point. So what I'm getting at is that maybe I would do it on peripheral blood, not on bone marrow, at six months or nine months. Maybe go by the trajectory, I'm a little bit thinking out loud here. Because as I said, I actually haven't had to do this. I have just recently started a couple of people on venetoclax-obinutuzumab, but within the past month.

Susan O'Brien:
So if I was going to do it, maybe I would get a MRD assay on peripheral blood, which is not too difficult to do, at six months or nine months. And if the trajectory was going down, that might tempt me to treat a bit longer and see if I could get them completely negative. And then if the trajectory was kind of flat, maybe I'd say, "Well, this is the best I'm going to get." Again, this is ... let me clarify. I'm not talking about 17p or P53-deleted patient. I'm talking about somebody that a priori, we don't necessarily assess as high-risk. Maybe I would do it that way. But again, I'm really just thinking out loud. I wonder if anybody in this group has actually gotten somebody off-protocol, let's say to 12 months, and then had to decide what to do? That hasn't happened to me yet.

John Gribben:
A lot of the ongoing German study groups are using really, triple combination therapies right upfront. And Susan's already alluded to the fact that some patients are already talking about, "Gosh, what do we do if it relapses?" But of course the whole goal here is to hopefully drive people to very deep remissions, and have them hopefully off-therapy for a long period of time. And then of course our hope is that those patients will then respond in the future. How has the study group, kind of talking about the very large number of clinicians around in very different settings that take part in your study group, how has your group thought about using all of these agents upfront in combination?

Barbara Eichhorst:
Yeah, as you said, John and also Susan, there is a big concern of when I use already the best available drugs in frontline. As with VEGF regimen, what options does the patient have in the relapse setting? And we have a few data from the MURANO trial, we have a few data from the CLL14 trial that probably re-exposure for example, with venetoclax. And of course, we have also data from the Australian Group that re-exposure was venetoclax obviously works. That at least patients respond again a second time. What I think we will have to evaluate now in the near future is the so-called PFS2. So we will have to look at the response duration then to the second set ... and second line treatment, particularly if you use a novel novel combination in the frontline therapy. I think this will be one of the key questions in the future, with respect to sequencing treatment in CLL optimally, in order to gain decades of life for the patients then.

Barbara Eichhorst:
With respect to the triple combination as Matthew showed or talked already about that, however we have to keep in mind that this with respect to side effects from this trial. Also a little bit from the trial from Ohio State, who evaluated also this combination in frontline therapy. The triple combination has really some toxicities. It also tends in our Phase III frontline trial, we see some more infections, and not surprisingly during the first year of treatment. So we will have to look at definitively the benefit by using this triple combination, maybe even also with the doublet combination as the CAPTIVATE trial. I think we will also have to look at longer followup with respect to toxicities as well.

John Gribben:
And the way that the drugs became available, we had ibrutinib first and then venetoclax came along. So, we had a lot more data on using venetoclax in the ibrutinib-refractory or intolerant patient population. But of course, we've seen a lot more data now about using ibrutinib after venetoclax. Is there anything that you see in terms of the sequencing of these drugs that makes you concerned about using one drug before the other, or do you think it's up to choice in terms of fixed-duration versus continuous therapy?

Susan O'Brien:
No, there's nothing that really concerns me, because most of the data that's emerged has been very good. And what I mean is you're absolutely right. When venetoclax-obinutuzumab was first approved here in the States, I was a little bit cautious about using it for exactly that reason. Because we had plenty of data that you could use venetoclax in patients failing ibrutinib, which was the only BTK inhibitor we had at the time. That those patients would go on to have good responses, and pretty durable responses. And keep in mind, in those original trials, those were very heavily pretreated patients. That had had four prior lines of chemo, before they even got to ibrutinib. And they still got, according to the published data, about a two-year PFS with venetoclax. What we were lacking, as you already alluded to, is there was almost no data about using the ibrutinib or acalabrutinib post venetoclax. Because most of the patients going on the venetoclax collects trials, both the original Phase I, the MURANO, they had not seen a BTK inhibitor.

John Gribben:
Mm-hmm.

Susan O'Brien:
But we've seen emerging data come out, probably the biggest cohort that we've seen is Anthony Mato's real world data. Where they ... he had the biggest cohort. I can't remember the exact number, maybe somebody else does. But it was, I think 40 something, and their response rate was quite good. It was, these are people who have progressed after venetoclax, but had not seen a BTK inhibitor. He had the biggest series so far, and the response rate was quite good. And it looked like those remissions are very durable. So, that's very reassuring. It's also interesting what we don't have data on. As I alluded to all of the original data from going one way to the other, is very heavily pretreated patients. If anything, I have to believe that if you have a patient who only got ibrutinib and then gets venetoclax or vice versa, they're probably going to do a lot better than the PFS numbers that we're quoting now. Because those are all, those were all done in people who were heavily pretreated with chemo.

Susan O'Brien:
So I would think, arguably, the data going either way would even be better. Sort of in this day and age, where nobody's giving somebody three rounds of chemo before they use a small molecule. But to me, the data is quite encouraging in both directions. And so I would make my frontline choice, as you just said, more based on the pros and cons for that patient of venetoclax time-limited therapy, BTK inhibitor, side effect profile, et cetera.

John Gribben:
We've talked a lot about BTK inhibitors, Bcl-2 inhibitors, which of course we think are our most effective and novel agents. But any other novel type therapies, anything coming out that's emerging, that kind of caught your attention at these meetings?

Matthew Davids:
Yeah, so I do want to kind of build off of what Barbara was saying with some of the toxicities observed with the IVO triplet. Because I think there is some emerging data now suggesting that maybe a more specific BTK inhibitor could be better tolerated, particularly as part of a triplet combination. So, we had presented some initial data at the ASH meeting on our AVO triplet with acalabrutinib. At this EHA meeting, Jake Soumerai and I presented data for the ZVO regimen. We haven't even talked about zanabrutinib yet today, but this is another specific kind of second generation BTK inhibitor that seems to be very well tolerated from a cardiovascular perspective. And I think that as you start to combine more and more drugs together, these toxicities become important.

Matthew Davids:
And so the data that Jake showed looked very good, it's 37 patients from a couple of centers primarily. So it's a small study. But they showed relatively low rates of infection, even with this triplet therapy. I think only about 15% grade 3 or higher neutropenia. And, so very low cardiovascular events as you'd expect, and they saw about three quarters of their patients achieving undetectable MRD in the bone marrow. And actually one of the things I find novel about their study is that they allow patients to discontinue, if they can get to an undetectable MRD state, after just eight cycles of combination therapy. So that is nice for patients to potentially have a shorter regimen. Obviously we need to see if that proves to be durable, but presumably there would be some durability if they're able to get to that undetectable MRD state. So, I think zanabrutinib is another drug to watch. It does not yet have a label in CLL, but likely headed in that direction.

Matthew Davids:
I think the other thing we've seen at these meetings over the last year or so is updates on the CAR T-cell data for CLL. As we think about using three of our best drugs upfront, it is sort of natural to think if we had a patient who did become refractory to these great novel agents that we have, is there a cellular therapy that we could use? And CAR T-cell certainly could potentially fill that role. Of course the CAR T-cell story kind of got off the ground with CLL to begin with, but then it's been a bit of a challenge since then.

John Gribben:
Yeah, ever since then.

Matthew Davids:
A lot of the single-agent CAR T studies have shown 30%, 35% CR rate. So much lower than we expect in other diseases like DLBCL, where there's been an approval. We have seen data on the JCAR017, presented by Tanya Siddiqi and others, which has shown about a 45% CR rate with that product. And including patients who had been through both ibrutinib and venetoclax, so that does look promising. And I think there's some intriguing data now coming out of a variety of places, including the Hutch, looking at a combination of ibrutinib with CAR-T. Potentially having some disease control with the ibrutinib, but also interestingly, potentially enhancing the activity of those T-cells through the ITK-mediated effect of ibrutinib. So, I think it will be very interesting to see how those data mature in the near future.

John Gribben:
I guess we have alluded to the fact that that group of patients that stood out as not doing quite as well as you perhaps thought with the CLL14 data, particularly when you consider the venetoclax was first approved for TP53-mutated patients as, are the 17p-deleted patients. That the group of patients with TP53 abnormalities, and particularly those with complex karyotypes, are still the groups of patients that look as if we're not getting towards the curative approach we've be looking at. And those might be the patients that go towards CAR-T approaches. And we already know from our experience in transplant, that cellular therapies do appear able to overcome those sorts of groups of patients.

John Gribben:
And I think as you've said already, Matt, the addition of BTK inhibitors into this to immunomodulate the activity is something that needs to be looked at. There's a whole variety, of course, of ways in which the ibrutinib or acalabrutinib or zanabrutinib could be used. One at the time of collecting the cells, but then also potentially continuing that therapy after the cells are given back. So, lots of experimental approaches still to be examined in that patient. So with that said, is it transplant dead? Is CAR T-cells go to take it over, are we going to do away with transplant? Barbara, what's your view on the role of transplant in CLL?

Matthew Davids:
Yeah.

Barbara Eichhorst:
Yeah. So actually probably all of you know, I think just the number of CLL patients we've transplanted in the last years was going down to zero. However what we see now, and what is of course concern, is that we have an increasing rate of patients with Richter's transformation. Probably selecting those TP53 containing CLL clones, where we know they have a higher risk for transforming into diffuse large B-cell lymphomas. So usually right now with transplants we are going to do, the Richter's transformation, and of now very few patients being refractory to everything and in case we cannot get those patients on a CAR T-cell trial.

Barbara Eichhorst:
And so the key here is that I think we still have then a treatment option, how we can get those patients into remission in order then to do the allogeneic stem cell transplantation, and that's one of the key things. And therefore, I think it will not ... it's not dead. But it will be done on a very low level, and therefore think it's more important that patients are really transferred to those centers who have experience in getting those really to transplantation. Because these will be very few patients, and also dealing with the possible Richter transformation.

John Gribben:
So Matt, you've got some interesting approaches you're looking at in Richter's at Dana-Farber. What's your current thought about how we should be tackling Richter's?

Matthew Davids:
Yeah, so at the ASCO meeting, I gave a presentation on our study of venetoclax plus dose-adjusted R-EPOCH chemo-immunotherapy. And the idea here is using venetoclax as a chemosensitizing agent, to allow these cells to respond better to the chemo-immunotherapy. And we found actually that we had very deep responses, even in patients with TP53-aberrant CLL who developed Richter's. Because the venetoclax, we think does act downstream of TP53, right at the level of the mitochondria. So we saw, by intent-to-treat, half of our patients achieving a CR. Most of the patients who wanted to then move on to allo transplant were able to do so. So at least as a bridge to transplant, this type of intensive approach may make sense for some patients, particularly if they're younger and fit.

Matthew Davids:
A challenge of course is that many of our CLL patients are not young and fit and can't tolerate R-EPOCH chemotherapy. And so, there's a number of other approaches that I think are promising that are being evaluated. I think the experience with MD Anderson is interesting, combining ibrutinib with PD-1 blockade. We've seen some interesting data on that. So, I think that it'll be interesting to see if CAR-T has activity against the Richter's itself. We haven't seen much data on that yet, but certainly that's a promising approach as well.

John Gribben:
For anybody who's working from any company, could you please stop excluding any circulating CLL from studies with Richter's? Because it makes it very, very difficult and very unfair for the patients. But, so Susan, anything we've missed discussing here that kind of caught you for the meeting? Or do you think we've kind of covered what you thought were the highlights?

Susan O'Brien:
Oh, yeah, I think you did a great job covering pretty much everything that I can think of. I guess the question would be, are there any interesting new molecules? That one thing we didn't cover are the noncovalent BTK inhibitors, but I don't actually think we saw any update at that meeting. So if we were sticking to the meeting, no. But I think those look very interesting, in terms of having an option for patients failing a BTK inhibitor. That would allow you to sort of, if you will, save venetoclax. Because if those drugs work and the preliminary data on the Phase I certainly suggest that they do work in the setting of the BTK mutation, and if you look at the Ohio State data, it looks like the majority of patients with CLL who develop clinical resistance will have a mutation. Not all, but many. It seems like those are very interesting new class of drugs that I think may be very promising.

John Gribben:
Well, of course you had the huge experience of working in CML. So you're very used to the idea of sequencing the use of inhibitors, in the setting of inhibitors, and then knowing which inhibitor to go to in the setting of particular mutations. Can you see a time that we start to do this in CLL? I would suggest of course, that we'd then be getting assays. You've already alluded to John Byrd's group, of course, and Jennifer Woyach's done a lot of work in terms of sequencing a lot of their patients. But most of us are not in the position to be looking for sequencing routinely the way they are there. But can you see a time where eventually you ... if more and more of these agents become available, that these assays will have to become available the way that we're used to doing for CML?

Susan O'Brien:
Yes, I think it could be. Of course it will raise the practical question that if you detect the mutation and their again, and Ohio State data suggests that you can often detect it several months or up to nine months even before the disease shows clinical resistance. Is there actually any benefit in changing earlier? In CML, we know that there actually is. In CLL, I think that would be an open question. Do you really need to check early? Because if you change early ... I mean intuitively it kind of makes sense, right? That if you know there's a clone that's going to lead to resistant, and that's a low level of clone and you intercede at that point in time, maybe the patient's going to do better. But just having the ability to know that there's a mutation and having another drug to switch to ... which we really already do. Because we have venetoclax, right?

Matthew Davids:
Sure.

Susan O'Brien:
And yet nobody's suggesting that we should be monitoring for the mutation. So in the, can I see a future where we are doing that? Yes. Do I think it's here now? Clearly no.

John Gribben:
The other kind of class of drugs that are emerging, I didn't see much about it at this meeting. Unless I just missed something, and some of the thousands of posters there. But MCL1 inhibitors, Matt, so you of course spent a lot of time thinking about BCL2 family and the interactions with it. So where are we, what are you hearing about and what are you thinking about in terms of the MCL1 inhibitors appearing?

Matthew Davids:
Yeah, I mean I think the next front here after BTK inhibitor resistance is going to be venetoclax resistance and overcoming those mechanisms. And we've seen recent reports on the BCL2 mutations, but I do think functional resistance to venetoclax is also going to be important. And we have data to support that, now that MCL1 may play an important role in venetoclax resistance in CLL. So, there's a number of direct MCL1 inhibitors. That are in the clinic in various stages, early phase clinical trials where we have not seen data yet. There are some concerns around the possibility for cytopenias and cardiovascular toxicities based on some of the preclinical models. So, I think a careful exploration of these drugs in the Phase I setting is certainly important.

Matthew Davids:
But obviously an interesting next step, if they do prove to be safe, would be to then combine with venetoclax, which could be a very potent way to kill CLL cells that are even becoming resistant to venetoclax. There's also indirect ways to inhibit MCL1. So for example CDK inhibitors, an example of one of those is voruciclib which is now in a Phase I/II study. So a lot of different ways to approach that, but it's still early and we haven't seen a lot of data.

John Gribben:
The German CLL Study Group, lots of studies ongoing, lots of these studies are going to take a very long time to read out. But what are we expecting to hear next in terms of results or preliminary results from the German CLL study group, anything coming close to readouts that you were, can hope to see in meetings coming forward?

Barbara Eichhorst:
Yeah, so we will probably have next year and beginning of next year. The readout of the CLL13 or GAIA trial, which we do together with the HOVON and the Nordic Group. And so then the question is not so new. Because it's again comparing venetoclax-based treatment versus chemo-immunotherapy. Venetoclax plus obinutuzumab is now approved for all patients that are frontline, but in fact we do not have data on the fit and young patients. So, the study will close that gap. And on the other hand, the study will address also the question. So it's not powered, but we also will see rituximab-venetoclax versus obinutuzumab-venetoclax and also adding ibrutinib. So looking at how intensive we should, we could modify the treatment, better antibody, does that matter in combination with venetoclax? Then with the next trial, the CLL17 trial, as many other studies in the US comparing now novel combinations against each other. In Europe, we will do ibrutinib as continuous treatment versus venetoclax plus obinutuzumab versus ibrutinib-venetoclax. As there are two fixed-duration treatments versus continuous treatment.

John Gribben:
Wow, doesn't time go fast? So, I think we've probably just about wrapped up what was there. I think one of those years where nothing brand, brand new appeared on the scene. But not surprising, if you consider what's been so new at the meetings we've seen over the last few years. But a lot of consolidation, a lot of new information. So I think all that remains for me now is to thank you, Barbara, Susan, and Matt for your time today and the opportunity to have this discussion, I've certainly enjoyed it. To thank all of you for joining us for CLL Sessions on VJHemOnc, and we look forward to seeing you again very soon. Thank you very much.

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