Introduction

DR DAVIDS: My name is Dr Matthew Davids from Dana-Farber Cancer Institute in Boston. Welcome to this symposium from Research To Practice, titled Beyond the Guidelines – Investigator Perspectives on the Management of Patients with Chronic Lymphocytic Leukemia. So I have the tall task today of playing the role of Dr Neil Love. So, big shoes to fill but I will do my best.

I’m joined by some outstanding faculty members here, as you see, Dr Alexey Danilov from City of Hope in Duarte, California, Dr Susan O’Brien from UC-Irvine in Orange, California, Dr Sonali Smith from University of Chicago in Chicago, and Dr Julie Vose from University of Nebraska, Omaha, Nebraska.

So, as usual, we’re going to start off with a survey that was done for clinical investigators. This is 25 of the folks that you see listed here, many of whom are actually attending this meeting, and we asked them these survey questions that we’re going to go through, as well as asking the audience for their answers.

Therapeutic Algorithms for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia (CLL) — Susan O’Brien, MD

DR DAVIDS: So, with that preamble, we’re going to dive right into Beyond the Guidelines in CLL. So I’m going to ask Dr Susan O’Brien to the podium. And as she’s moving up there, we’re going to start going through some questions.

So if you’re here in the audience, please pick up the iPad and vote and we’ll look at the results both from the audience here, as well as our clinical investigators. So let’s start with this first question. And imagine that you have no regulatory or reimbursement issues at all, so what would be your preferred initial regimen for a 60-year-old patient with IGHV mutated CLL without deletion 17p or TP53 mutation? We’ll assume they require therapy by the IWCL criteria. So we have a pretty young, fit patient with favorable risk disease, mutated IGHV and no TP53 aberrancy. So you can see a variety of choices here, ranging from chemoimmunotherapy with FCR, various ibrutinib-based regimens. We see the newer BTK inhibitor acalabrutinib; another one zanubrutinib, or venetoclax-based regimens.

So, please vote.

And we’ll see what our respondents said here. So we have a little bit of FCR, but ibrutinib is the most common response, as well as acalabrutinib also popping up. Not seeing venetoclax-based therapy in this response.

So, maybe I’ll start with Dr Danilov, now you’re seeing the results here from the clinical investigators, many of whom said venetoclax plus obinutuzumab. So, how do you think about this younger, fit patient with low-risk disease, Alexey?

DR DANILOV: I think it’s always a long discussion with multiple front-line options. Overall, I’m very careful about choosing chemoimmunotherapy these days. And in addition to establishing the IGHV hypermutated status as well as lack of those mutations, I typically send off next-generation sequencing panel to identify any other high-risk mutations such as NOTCH or SF3B1 that may compromise, this points to us FCR. And as we know, toxicity of FCR are significant and in this day and age with novel targeted therapies, I think the role of chemoimmunotherapy is becoming more limited.

I do think the venetoclax/obinutuzumab is a great option. It’s a time-limited therapy. It has very high response rate in this type of a patient and long progression-free survival. And emerging data suggests that use of BTK inhibitors plus venetoclax/obinutuzumab can be very successful. Therefore, it is also my first choice, which is venetoclax/obinutuzumab.

DR DAVIDS: So, 4 of the 25 clinical investigators did still say FCR. So, Susan, what do you think? For this patient, I mean is this the classic FCR patient?

DR O'BRIEN: Yes, that’s what I said.

DR DAVIDS: Why did you say that?

DR O'BRIEN: Obviously, I’d have the discussion with the patient. They may just adamantly not want chemo. But the reality is, I think that there is a cure fraction. I don’t think with any of the other therapies we have we can say there’s a cure fraction; maybe there will be, but we can’t say that. And I don’t think, even with all the small molecules that we have, that I can get a 60-year-old to live to 80, which is at least the normal life span now is early 80s. So I still would discuss chemo. Now I might not want to do it right during COVID, but absent that, I would still favor chemo.

DR DAVIDS: So we tweaked the question a little bit, and we asked the clinical investigators now, regulatory and reimbursement issues aside, what would you do for this same patient? So I think one of the things that’s interesting here is that you start to see venetoclax plus ibrutinib popping in, and I’m going to speak more about some of the data for that in my talk. But maybe Soni, can you comment on BTK plus BLC2. What’s your thought on that?

DR SMITH: I think one of the key appealing factors of the venetoclax/obinutuzumab is the time-limited aspect. And so, when it comes to novel doublets like venetoclax and ibrutinib, what we’re looking for is something that is time-limited but perhaps has more of CR rate and that’s an important endpoint for me.

DR DAVIDS: And an all-oral option as well.

DR SMITH: And all oral options. Absolutely.

DR DAVIDS: So, back to the audience. So we’re going to have you vote now on this question. So, again, regulatory or reimbursement issues aside, what would be your preferred initial regimen for a 60-year-old patient, so same age but now tweaking the IGHV status, so now IGHV unmutated, so more steadily progressive CLL, traditionally higher risk with chemoimmunotherapy, but still without truly high-risk disease, so no TP53 aberrancy.

So here you see less FCR. You see a little more acalabrutinib, and now you expect to see venetoclax plus obinutuzumab popping up.

Let’s see what our clinical investigators said. So again, venetoclax plus obinutuzumab comes up, but we also see acalabrutinib figuring fairly prominently and a little bit less ibrutinib here. So, Julie, what are your thoughts on this one for this higher risk patient?

DR VOSE: So this would not be a patient where FCR would be appropriate. So that’s out of the box there, or BR for that matter. So this is the type of patient again I have a conversation with, venetoclax plus obinutuzumab versus a BTK inhibitor. And time-limited often wins the battle with these patients and they want to get off therapy. They don’t want to have any definite therapy. So that is, in my experience, what many patients do choose in this situation.

DR DAVIDS: So this is a relatively less typical CLL patient, 60 years old. As we know, in practice, most CLL patients are older. The average age at diagnosis is around 70. It takes a few years until the patients need treatment. So let’s tweak this scenario a little bit now and talk about a little bit of a more common CLL patient, this is now a 75-year-old patient. Same choices here. IGHV unmutated disease, not high risk by TP53 status. And again, imagine that there’s no regulatory or reimbursement issues. What would you treat this patient with, now a little bit older?

So fairly similar choices from the audience. We’re seeing again acalabrutinib more commonly and some venetoclax plus obinutuzumab.

So this is the results from the clinical investigators. So, Alexey, as you think about the older patient getting venetoclax plus obinutuzumab, any particular challenges that you think about there?

DR DANILOV: Well, I think I will try to defend this regimen. Again, it’s a time-limited therapy, which is not associated with some of the typical side effects of BTKi which we see more commonly in older patients such as atrial fibrillation, difficult to treat hypertension. So those would be the considerations that might steer me away from using a BTK inhibitor in this patient population as well. So, I think again, I would agree that chemoimmunotherapy here is not a great option because of patients age, FCR is associated with high toxicity rate in this age group. However, the venetoclax/obinutuzumab as time-limited therapy is again preferred.

DR DAVIDS: Susan, could you make an argument for a BTK inhibitor for this patient?

DR O'BRIEN: No, I would also go with venetoclax-based regimen for the reasons Alexey said and then you don’t have to worry, even though the risks are small with the BTK inhibitors, about AFib, and maybe higher risk for hypertension with the BTK inhibitors, but you don’t really have to worry about either of them.

DR DAVIDS: Sony?

DR SMITH: I was going to say, I think it’s reasonable to do a BTK inhibitor monotherapy in this patient, but it is a discussion. Because the venetoclax and obinutuzumab, there’s an IV burden that’s there and we don’t know anything about his TLS risk profile. So, it’s a conversation. The acalabrutinib would be my preferred for a 75-year-old who presumably has some cardiovascular risk factors.

DR DAVIDS: So now let’s talk about a truly high-risk patient, so this is a patient with deletion 17p, remember this is only about 10% or so of CLL patients in the frontline setting. Again, a younger, fit patient, 60 years old with high-risk disease now who needs treatment. So, what would be your choice for this patient?

So I don’t see any chemoimmunotherapy use, so that’s the most important thing to not use chemoimmunotherapy for patients with deletion 17p. We see a little bit more ibrutinib coming up here, but also acalabrutinib. A little bit less venetoclax plus obinutuzumab.

So let’s see what our clinical investigators said. So, similar to the audience, reflecting more of the BTK inhibitors rather than venetoclax plus obinutuzumab here. So, Susan, maybe comment on why that’s the case?

DR O'BRIEN: I think, and this will be in one of my slides that I show, that with the fixed regimen venetoclax/obinutuzumab, although the 17p still do much, much better than if you gave them chemo, the median PFS appears to be shorter than what we’re seeing with continuous BTKi therapy. Now, is that because ven isn’t as good an agent, or is because we’re stopping the therapy? I don’t think we know the answer. But I will actually show slides pointing that out.

DR DAVIDS: And, Julie, if we tweak this a little bit, and we said it’s a 60-year-old who’s already on anticoagulation, has issues with AFib. Recent MI. You kind of load the deck with some of the typical cardiovascular comorbidities we see, is that a patient with 17p where you feel comfortable giving venetoclax plus obinutuzumab or you try to get them through with a BTK inhibitor?

DR VOSE: Of course it depends on the profile of the patient and exact information. Obviously, it depends on what kind of anticoagulation they’re on as well. So, if they’re on warfarin or they have to be on warfarin, like they have a mechanical valve or something, then I wouldn’t do that. But it goes back to some of the same discussions with the patient and monitoring the patient very carefully if you do choose a BTK inhibitor.

DR DAVIDS: So, regulatory and reimbursement issues aside, we asked the clinical investigators when you’re going to administer a BTK inhibitor as initial treatment for a patient with CLL, which one do you generally prefer? So you can see the majority are choosing acalabrutinib right now. Although a sizeable group is also choosing zanubrutinib. And there are still some people choosing ibrutinib. So, Soni, you’re going to touch on this in your talk about tolerability. How do you think about these three drugs?

DR SMITH: We have to remember that all of these agents were approved — well if they’re approved. Zanubrutinib is not approved yet in CLL, but they were approved based on comparisons to chemoimmunotherapy and not head-to-head. So it’s only recently that we’ve gotten some of that data.

I do think the safety profile is better with the newer BTK inhibitors. And I think that would drive some of the treatment choices here.

DR DAVIDS: So, what would be your most likely approach for a patient with newly diagnosed CLL to whom you decided to administer the venetoclax plus obinutuzumab regimen? Remember, this is a 1-year time-limited regimen, the way the CLL14 trial was done all patients stopped at the end of that 1-year treatment regardless of their MRD status. Let’s imagine that you decide to check MRD, and they still have detectable MRD at the end of the 1-year of treatment. So we asked the clinical investigators should you continue treatment at that point with additional venetoclax monotherapy, or discontinue treatment?

And you can vote on this as well. What would you do?

So we’ve got a split, call that a controversy. So that is a really open question in the field right now. We don’t know what the right answer is. Of course, we know what the data show, that we have 1-year of data with CLL14. We don’t know if longer treatment would be better for patients.

Let’s see what the clinical investigators said.

Pretty evenly split. So if you look at the group. First of all, we asked the clinical investigators do you send MRD at the end of that 1 year? So all 20 who responded said yes. So we’re sending it, but we don’t necessarily change management because you can see if you still have detectable MRD, it’s again a 50/50 split.

I think everyone felt comfortable if you had undetectable MRD at the end of the year of discontinuing treatment.

So, Alexey, can you make a case for continuing treatment beyond 1 year here?

DR DANILOV: So, as you said, Matt, that it’s essentially still data-free area. And we don’t know that 2 years of venetoclax is better than 1 year of venetoclax in that setting. I would argue though that this is something that should be discussed with the patient. And continuation of venetoclax might potentially be considered, as we know in some patients responses made even all the time.

So, I typically discuss with the patient first whether to order MRD and what that test might mean in the end and what we’ll do with it. And if they agree to look at MRD, then we have a discussion. If it comes back positive, what to do with that number.

DR DAVIDS: So, we’re going to move on to Susan’s talk on therapeutic algorithms for patients with treatment-naïve CLL. So Susan, take it away.

DR O'BRIEN: We now have the longest front-line follow-up from RESONATE-2 that we’ve had that was just presented this year. And remember, this was the randomized trial of upfront ibrutinib versus chlorambucil as a single agent, primary endpoint was progression-free survival and cross over was allowed.

So now we have 7-year follow-up, but at a median of 6.5 years, 61% of these people are still in remission. So we still don’t even have a median progression-free survival with ibrutinib. Note that the patients, as you can see on the right with 11q are not only doing as well, and we know with chemo they do much less well than non-11q, they actually appear to be doing a little bit better in the earlier part of the curve, and no difference in outcome based on mutation status. Again, very different from chemo where that’s the most important predictor, other than 17p, of progression-free survival with any chemotherapy regimen. So, very different data.

DR DAVIDS: So, a lot of the patients have come off ibrutinib though, on this study, and can you comment on the proportion of patients who’ve come off due to progressive disease versus adverse events?

DR O'BRIEN: More come off with adverse events.

So this was at ASH last year. This is the biggest cohort that we’ve ever seen with front-line 17p. Remember, front-line patients generally are not commonly 17p deleted or p53 mutated, so usually only make up very small numbers of front-line trials. So the reason we have a bigger number here is that we saw aggregate data in this poster at ASH for four different trials — you see which trials they were there; about half the patients got it with an anti-CD20, half didn’t.

You notice that most of them had a mutation, less with a deletion. But the reason for that, because usually you’re used to seeing it the other way around, is that some of these trials actually did not allow 17p deletion, like RESONATE-2 did not. But none of them specified for p53 mutation.

And now, this one has a shorter follow-up; it’s 4 years, but you can see 4 years is 79%. That is essentially identical to what RESONATE was, the whole population with ibrutinib at 4 years. So not only does it not look like they’re doing poorly; they actually seem to be doing as well as the non-17p patients if they get ibrutinib upfront.

This hasn’t been updated in a while, but I’ll just remind you that there are some randomized trials comparing ibrutinib to what we might call more effective chemotherapy than chlorambucil. This was the 3-arm trial of I versus IR versus BR. Why the IR arm? Because we know with every chem that we have in every lymphoid malignancy, ALL, lymphoma, CLL, that when you add antibody, which has predominantly been rituximab, but true for obinutuzumab. You have better outcomes in every single lymphoid malignancy.

So they were asking the question, was that paradigm going to hold with small molecules? Are we going to do better with ibrutinib if we add the antibody, which is you can note, was front loaded and stopped after 6 cycles? And after that, it was just straight ibrutinib in both arms. So the two overlapping curves there are the progression-free survival curves. You can see absolutely no difference between I and IR. And obviously, both are significantly better than BR, a very common — I’d say probably the, up until before we had small molecules, probably the most commonly given regimen in the US.

Note that again, the numbers are very small in the 17p curves, but note how well those patients ae doing if you compare that curve to the full population curve on the left.

DR DAVIDS: So, Susan, if I have a mutated IGHV patient who’s older and wants to get time-limited therapy, is BR still an appropriate option to consider for that patient?

DR O'BRIEN: I think you could argue that. What I’m not showing you here, and again, this has not been updated since 2018. At that time the follow-up was not that long but there was no survival difference. So you could make the case, what if I give that patient BR and I get 4 years out of it. I think the median PFS was about 3.5. Plus, remember the time at which the patient progresses doesn’t necessarily mean they need retreatment even. It could be longer.

So, yeah, you could potentially buy 4 or 5 years. I’m not sure I could argue against it, particularly with no survival curve difference. Now if we see this updated someday, then we see a difference, that’s a whole ‘nother story.

At the same time that Intergroup trial was ongoing, the Intergroup was also doing a companion trial, namely comparing IR versus FCR, s this was for younger patients with CLL. Their first trial with BR was older. Because younger patients are less common, the idea was this trial can’t be three arms. We can’t power that. So why was IR the experimental arm? Frankly, it was a guess. It was a guess that, based on the chemo paradigm, that IR was going to be better than I, and we’re already answering that question in the other trial, the older person trial. So they just kind of guess and I think you can obviously extrapolate IR to I here.

And this was updated at ASH 2019, so about a year and a half ago, and we see a significant improvement in progression-free survival. So whether it’s chlorambucil, BR or FCR, ibrutinib produces longer PFS.

Of course, you heard already, we’ve discussed acalabrutinib. This was the ELEVATE-TN trial that led to the front-line approval of acala. This is a 3-arm trial, as you all know, acala plus antibody. Again, the antibody was front loaded for 6 cycles. And then acala is continued indefinitely just like we do with all the BTK inhibitors, so in both arms. And then obinutuzumab and chlorambucil was the control arm. All of these trials have had PFS as the primary endpoint.

What you can see here is, we just got the 4-year follow-up on this trial at EHA.

Interestingly, because when this first presented at 2 years, the two acala arms looked slightly separate but not that much. Now they’re actually much more separate. You know that the higher acala arm at 87% PFS at 4 years is with obinutuzumab. And obviously, both acala arms are way better than chlorambucil-based therapy.

DR DAVIDS: So how does that conversation go then with the patient? So you’re going to start acalabrutinib in the front-line setting. You have this sort of post hoc comparison. The study wasn’t powered to look at this difference, but your patient wants to really maximize PFS. Do you give the combination with the obinutuzumab?

DR O'BRIEN: Truthfully, before I saw this data, no. I wasn’t that impressed with the 2-year data. But then when I saw how the curves actually look like they’re splitting even more as time goes on, and I was very biased against using antibody because of all the results with rituximab, but right when I saw this data, I started to think, well if the patient doesn’t mind coming in for infusions, I might start giving it to them.

Again 17p cohort doing great with either acala arm. And the unmutated doing also great.

DR DAVIDS: And interestingly, those curves are not separate for the high-risk patients. You’d think adding the two drugs together would be better for the high-risk patient.

DR O'BRIEN: You would, wouldn’t you?

DR DAVIDS: It’s kind of paradoxical, right. It’s the lower-risk patients who seem to be benefiting.

DR O'BRIEN: Exactly. I had the same reaction.

And then of course, we have ven/obinutuzumab. And again, this was based on the CLL14 trial where both arms, antibody went for 6 cycles, so that’s consistent across all the antibody combo trials that you’ve seen. And then here, of course, venetoclax and the chlorambucil go for a total of 1 year. But then as we’ve already discussed on that survey question, all therapy was stopped after 1 year. Very high rates of MRD undetectability. The fact that you could even get 35% MRD undetectability with chlorambucil is amazing and basically, you can chalk that all up to the potency of the antibody. I mean it really goes to show, I think, what a potent antibody obinutuzumab is. You don’t even get castration-resistant with single agent chlorambucil, never mind talk about MRD undetectability.

So we just got the 4-year follow-up from this trial also at EHA.

Notice that the median PFS still not been reached and really looks fabulous, up there at 70-something percent at 4 years. And remember, this is 3 years off therapy, okay. These people have been off therapy for 3 years.

But this was what I was alluding to when we were doing the survey questions, note that there’s quite a big difference in the curves for the ven arm, the two blue curves are the ven arms, and we see that that’s based on the 17p or p53 abnormality or not. So the median PFS in that patient population is much less. It’s not bad, it’s about 4 years, so they got 3 years off therapy, but it’s 4 years. And what I showed you right at the beginning of my talk was that the ibrutinib data, the 4-year PFS with ibrutinib is up around 79%. Whereas here the median has already been reached. So that was, hence, my comment about probably going with a BTK inhibitor in the setting of a p53 aberrant patient.

And interestingly here, unlike what we’ve seen with the B-cell receptor inhibitors, where there consistently shows no difference in outcome, at least with ibrutinib where we have the longest follow-up out to 8 or 9 years on the relapse population. Still no difference by mutation status. Here you can see that actually there is a difference, with the mutated doing much better. Now I would say I wouldn’t use this regimen for the unmutated? No, because look at their median progression-free is on the order of years, 4.5 years, and that’s 3.5 years off therapy. So I still think that is a pretty good endpoint. And I would not say I would not use this regimen in the unmutated, where I am saying I wouldn’t use it in the p53 aberrant, or at least if I used it for whatever reason, I wouldn’t stop it.

DR DAVIDS: And it certainly raises the question of whether retreatment could be effective and prolonged PFS even further.

DR O'BRIEN: Absolutely.

In terms of the long-term toxicity, really nothing unexpected. We knew that this regimen could cause significant neutropenia. You actually see more neutropenia with the small molecule antibody combination than you do with chemo, albeit chlorambucil is a weak chemo. But very few infections because you’re not using chemo. You’re not giving drugs that damage the mucosa, etc. And very little tumor lysis, actually a little bit more with chlorambucil/obinutuzumab, which was probably predominantly from the obinutuzumab which was started first in the venetoclax arm.

So, in the last few slides I’m going to go through the two randomized head-to-heads, not because they’re front line, in fact they’re not. Both of these trials were done in relapse. But because seeing the data, it’ll be interesting to wonder if your front-line therapy choice would be different based on what you see in this relapsed comparison.

So the first one is the head-to-head of acalabrutinib versus ibrutinib, ELEVATE-RR trial. So this trial was designed specifically for high-risk population, namely those with 17p deletion or 11q deletion. Of course, I just got finished saying those 11q’s may not be that high risk anymore, but certainly at the time that this trial was designed we considered them very high risk because of their outcomes with chemo.

So all these patients are relapsed. All of them have a 17p or an 11q. It broke out about 65/45. So that’s 65% 11q, 45% 17p. You see they get randomized to standard dose ibrutinib once a day or acalabrutinib, which I’ll remind you is twice-a-day dosing. And the primary endpoint was non-inferiority, progression-free survival.

So here is the curve. You see it completely overlapping, in fact crosses at one point. So, really no difference based on progression-free survival. But there is a difference based on toxicities.

So, it’s a little hard to see the blue compared to the black, but what you see highlighted in blue there showing you significantly more AFib, bleeding, hypertension, and pneumonitis with ibrutinib. What you don’t see is what’s more common with acalabrutinib was headache, which we all know is a common side effects that’s generally transient, and cough.

And then in the ALPINE study, again we just saw this at EHA. This is a little bit of a different design. So in this trial it’s a comparison of zanubrutinib, again given twice a day, to standard dose ibrutinib, but this is all relapse/refractory patients, not just the high risk like you saw in the ELEVATE trial, that’s number one. And then number two is that the primary endpoint is actually the investigator-assessed response, that’s the primary endpoint. So it’s not PFS. And although they have an IRC, it’s not the IRC; it’s the investigator-assessed response. And by the way, this is an interim analysis. The ELEVATE-RR was a fully completed trial. So, some maybe important differences between the trials.

So here you can see that the primary endpoint was significantly higher according to the investigators with zanubrutinib compared to ibrutinib.

And that just breaks it out for you. As we see with all the BTK inhibitors, we’re predominantly talking PRs, that’s true for every BTK inhibitor we have, not CRs.

What about just deletion 17p, they do just as well basically.

And here is the progression-free survival by investigator assessment again, showing that, per the investigators, zanubrutinib not only had a higher response rate but it had a longer progression-free survival.

And then similar idea here. This trial also has the least AFib that we’ve seen in any trial of the BTK inhibitor, zanubrutinib only 2.5%, although interestingly, although we saw a significant reduction in hypertension with acalabrutinib compared to ibrutinib, here we don’t see any difference in hypertension. So that’s rather interesting. But a very dramatic difference in atrial fibrillation.

And there was just recently a press release that the Phase III SEQUOIA trial is positive. This is the trial comparing zanubrutinib to BR for front-line therapy. So this should actually also lead to potentially a front-line indication for zanubrutinib. Right now zanubrutinib is not approved at all in CLL. It’s obviously approved in mantle cell. But it does not have a CLL approval.

So in conclusion, BTKi plus or minus obinutuzumab is a great, excellent continues therapy option.

We have the most long-term data and the best comparisons to more, I would say effective chemo with ibrutinib.

11q’s are not so high risk anymore.

That’s all you’re going to see on my conclusions.

DR DAVIDS: So we’ll just go very quickly through the cases.

DR O'BRIEN: 71-year-old has a CBC done, part of preop work for knee replacement. History of kidney stones. Has some small nodes. Is followed. 12 months later more symptomatic, nodes are getting bigger. Beginning to have mild anemia. Observation was continued.

And in 2 years, the physician decides that the patient needs therapy. Significant adenopathy. FISH is repeated, as we always do before we choose a therapy. No p53 abnormality. The plan was to order an abdominal CT to assess tumor lysis risk and then start ven/obinutuzumab.

DR DAVIDS: Thank you Susan, Just to comment on this case. So this is a fairly typical CLL patient with low-risk disease. No significant comorbidities. So this patient was treated with ven/obin. Would anyone on the panel have done something different for this patient?

DR DANILOV: I think that’s a great front-line approach for this patient. The concern will be tumor lysis syndrome and risk of it with ALC of 74,000. However, because the venetoclax is delayed until at least day 22, I delay it until cycle 2, day 1 of the obinutuzumab. Often that goes away.

DR VOSE: I agree. That will be my approach as well for that patient.

DR DAVIDS: Soni? Consensus?

DR SMITH: I agree.

Spectrum, Frequency, Severity and Management of Toxicities Associated with Novel Agents and Regimens — Sonali M Smith, MD 

DR DAVIDS: We’re going to go through a couple of more questions here.

So regulatory and reimbursement issues aside, what’s your usual preferred initial regimen for a 75-year-old patient, IGHV unmutated CLL, without TP53 aberrancy, who requires treatment and is requiring anticoagulation for AFib?

So, audience here has voted. So, most people are saying venetoclax plus obinutuzumab, probably swayed by the atrial fibrillation, the need for anticoagulation, although you still see some BTK inhibitor use.

And what about the clinical investigators? So, a little more uniform with ven/obin, although you still do see some acalabrutinib use. So, certainly it’s not an absolute contraindication to use BTK inhibitors, so that could be a great option for the patient as well. A little bit less ibrutinib use, I think maybe in light of what Susan just showed, the differences in the ELEVATE-RR study in terms of rates of AFib.

So the next question is basically a very similar patient, IGHV unmutated, 75 years old without TP53 aberrant disease, but now has bulky lymph node disease. So a lot of people have been saying ven/obin. So let’s see if that changes things here with bulky lymph node disease.

So we do see a little bit more in the way of BTK inhibitors here, actually more ibrutinib use. People are feeling more comfortable using that. Maybe they’ve been using it for a long time and have a comfort level there.

Ven/obin, not as much, maybe because of the risk of tumor lysis syndrome.

And let’s see what the clinical investigators said. So clinical investigators, maybe a little more comfortable sticking with the ven/obin. Not as dissuaded by the bulky disease. Remember, that regimen starts with the obinutuzumab, which does do some debulking during those first 3 weeks, lowers that risk of TLS. But a little bit more acalabrutinib use here. Some acalabrutinib plus obinutuzumab, maybe a possibility of trying to debulk there with the antibody as well.

Soni is going to talk to us about the spectrum, frequency, severity and management of toxicities associated with novel agents and regimens.

DR SMITH: Thanks so much. So I was tasked with looking at the data, this time through the lens of toxicity. And I’ll just remind this group that we now have an increasing number of buckets, if you will, of agents. And we’ve heard about each one of these except for the PI3 kinase inhibitors, which are really in the relapse/refractory setting. And I put asterisks by those that are not yet FDA approved for CLL. And as we’ve talked about, the key factors impacting treatment selection have been based on both patient and biologic features, and I would just remind everybody that toxicity is one of those features that we often think about.

So, the combinations are really endless. And in trying to put this together, there’s just so many doublets that are out there. And of course, we know that there are triplets that are under investigation. And while the triplets may be more active, particularly if we start to look at MRD endpoints, I think they also have potential increased toxicity and that’s another aspect that we need to think about.

So, there’s a number of off-target effects that these drugs have and these underly the toxicity that we see. And this cartoon which I really, really like, just shows the major off-target effects that we see from these agents that include atrial fibrillation. And then something that we haven’t talked about so much today, but arthralgias. I mean this is actually one of the most troublesome features that my patients note when they’ve been on a BTK inhibitor. They just have charley horses and cramps and sort of muscle fatigue.

Infection can occur. There can be GI toxicity with diarrhea. Hypertension. We’ve talked about bleeding. We’ve talked about AFib.

And some of the biologic underpinnings for why patients develop these toxicities are increasingly clear. We know that Tec kinase probably has to do with platelet function and dysfunction. ITK impacts T-cell function. EGFR may increase the risk of rashes. And then very recently, CSAR kinase was identified as the target for ibrutinib that may be associated with atrial fibrillation.

DR DAVIDS: Soni, maybe you can comment. I mean it does seem like targeting BTK itself is a bit of class effect here though. Because, for example, in ELEVATE-RR, you certainly see reasonably high rates of AFib with acalabrutinib as well. So, what’s your sense in terms of how much of this actually BTK versus the off-target effects?

DR SMITH: Well, I mean I think the CSAR kinase paper that came out, which was essentially with ibrutinib and not with any of the next-generation BTK inhibitors if you will, I think that it is an off-target effect for ibrutinib. I would assume that it’s going to be sort of similar process with acalabrutinib, but I don’t really have any data to say that.

We’ve all seen those plots where they show the kinase inhibition based on the concentration and it seems that there are fewer off-target effects even with those kinome maps with acalabrutinib and zanubrutinib.

DR DAVIDS: Yes. And I think later in the session you’ll her about pirtobrutinib from Alexey, which is probably the most specific of the BTK inhibitors and haven’t really seen much AFib yet, so I think that supports what you’re saying, although it’s early days with that drug.

DR SMITH: So we’ve talked a little bit about the discontinuation rates, and Susan talked about this as well, and there’s a couple of things on this slide I just want to point out. So first all, with the RESONATE and then the pooled analysis of prospective trials with ibrutinib, we see that the discontinuation due to AEs is somewhere between 12% to 16%. And the figures that I have at the bottom there are from the Coutre publication looking at some of these pooled data. And what I kind of take away from this is that if you look at the figure on the left, most of the discontinuations occur early and not late. So I do think that you know pretty soon whether or not a patient is going to tolerate or not tolerate ibrutinib, in this case.

And then the other piece I just wanted to point out is that most of the toxicity is Grade 1 and 2 and not Grade 3 and 4. And the challenge we have the clinic, of course, is that Grade 1 and 2 persistent toxicities aren’t always captured by clinical trials. And it turns out that these are really troubling for our patients and often lead to discontinuation.

And so then if you look at the real world evidence of ibrutinib, the discontinuation rate is actually as high as 42% with ibrutinib. And so, I think that paying attention to some of these Grade 1 and 2 toxicities in trials is really important.

DR DAVIDS: I think another thing about the real world evidence is that we have to remember when the studies were done, what time period they were looking at. My sense is the initial studies were at a time when ibrutinib was very new to practitioners. So I wonder if it would look different now that people have more experience with ibrutinib. What do you think about that?

DR SMITH: I absolutely think that’s true. People were sicker and more heavily pretreated, maybe more prone to toxicity in the earlier trials. But I also think that this is a call for patient reported outcomes in all of the trials that we do with chronic therapy. And in CLL, this would be a great model to do that.

DR DAVIDS: Susan, do you have a comment?

DR O'BRIEN: Well, my only point would be it is true that the physicians gained experience with ibrutinib over time. But the flip argument there is that there wasn’t anything else but ibrutinib. So now since there’s acala, and even if zanu is not approved you could probably get it. That would counterbalance because we know that the more options a patient has, the more likely they’re not going to put up with anything and they’re just going to want you to switch them. So, I don’t know. It kind of can go either way there.

DR DAVIDS: Good point.

DR SMITH: And I put this in there just because if we’re talking about the BTK inhibitors, there’s also a pooled analysis of acalabrutinib toxicity. And this is a terrible slide because you can’t read anything, but the main point of this was just to show that the Grade 3 and 4 toxicities were low, but it’s not that it’s non-existent. And so, of course what would be really helpful is to have a comparative trial and we just saw from Susan, results from of the ELEVATE-RR trial which shows no difference in efficacy in any of the subgroups that they looked at.

They did present, if we focus now just on the toxicity part, the differences between the rates of atrial fibrillation and hypertension. And certainly, the key take away is that there seems to be less atrial fibrillation and hypertension in patients who are being treated with acalabrutinib.

A couple of thoughts though, on that, is that — this is all comer toxicity, this is Grade 1 through 4. If you look at Grade 3 and 4 toxicity, the differences are quite as great. And then there’s also an impact of age and baseline cardiovascular risk factors that impacts the difference of toxicity between these two agents. So, while I do think that in general, acalabrutinib for me anecdotally, and certainly in some of the trials, seems to be better tolerated. I think the data is here on this slide and worthy of discussion.

DR DAVIDS: And I think this is a nice way to represent the data, too. It’s not exactly what we’re used it. It’s kind of a Kaplan-Meier for toxicities, but it does give you a sense, over time, of the accumulation with both drugs, but a little more with ibrutinib in terms of AFib and hypertension rates and the fact that, particularly hypertension can pop up later in the course on BTK inhibitors.

DR SMITH: I would have liked to have seen something like this with the other toxicities, like arthralgias. Because honestly, I don’t know, maybe I’m just biased, but that seems to be the number one reason that people come off.

DR DAVIDS: Maybe just asking the panel, what do you think in terms of most common reasons, Julie, in terms of BTK inhibitors in your population, why do they come off?

DR VOSE: I would say in my case it’s arthralgias, especially in older women. They seem to be very bothered by that and I think that’s the highest for me. Hypertension, that happens late. Definitely is an issue as well.

DR O'BRIEN: I agree with Julie, totally arthralgias, which you can understand. It’s pain. And it may not be Grade 3 or 4, but we’re telling these people that are going to be on this drug for years — although I will say, in a lot of patients, and I do try and encourage them by saying it tends to get better like most of the early side effects, but it’s pain.

DR DAVIDS: Alexey, what do you think?

DR DANILOV: I would say with ibrutinib for sure, I’ve seen a lot of arthralgias. I don’t see as much arthralgias with second generation BTK inhibitors or fatigue would be another common reason why, despite dose reductions, patients come off of ibrutinib.

With second generation BTK inhibitors, I still sometimes discontinue because poorly controlled AFib, although it’s rare as we can see on this graph. But some of these nuisance, what we call, side effects are certainly less prominent.

DR SMITH: And one other aspect with ibrutinib, because we have more familiarity with it and it’s been around for a lot longer, is that dose reductions can sometimes help. But, of course, now with having another agent where you have that at a lower level just to begin with, that’s something that’s appealing.

So, one of the clinical challenges that we face is that sometimes you’ll have somebody who’s been on ibrutinib for a very long period of time and is having adverse events that are leading to a discontinuation.

And what you see in the figure on the right is just if somebody was switched over, in this case to acalabrutinib, what was the likelihood of those AEs recurring? And for the vast majority of patients, the AEs did not recur. And then you can see the other colors there for whether or not it was lower grade, same grade, or a higher grade. But I think what’s important is that if you have somebody on longstanding ibrutinib and they stop or need to come off for AEs, one of the first questions to ask is, do they still need ongoing treatment, or do they need a treatment break? And that could be really helpful to people — to patients. First of all, we’re not curing this disease, and we don’t have a whole lot of data on MRD in clinical practice, even though we’ve talked about it in clinical trials. So, if they need treatment or not, based on their AEs, this is one of the first questions.

Options include changing to another irreversible BTK inhibitor, and both acalabrutinib and zanubrutinib are listed in NCCN Guidelines, although zanubrutinib is not FDA-approved just yet. And then reversible BTK inhibitors may be coming. And we’ll hear more about that in just a bit.

So, when it comes to zanubrutinib, we’ve heard a little bit about ALPINE trial. So this is currently FDA approved for relapse/refractory mantle cell lymphoma, and as I just said it’s listed in NCCN as an option for ibrutinib intolerance. And the AE profile — Susan actually had a much nicer table than my little summary here — but it seems to be very well tolerated and in particular, atrial fibrillation and major hemorrhage seems to be very, very infrequent.

There are a couple of AEs of interest that we’ve been talking about, and AFib and bleeding are the ones that we see quite often in clinical practice. And there actually are some really nice guidelines that are available to help manage these.

I think the key points here are that for cardiovascular risk, using some type of CAD-VASc score ahead of time, can help to determine whether or not you need to hold the drug, for example, if somebody is on a BTK inhibitor, and then whether or not you need to stop it. So there are different guidelines for that.

It’s also important to avoid vitamin K antagonists, which I think Julie mentioned avoiding, warfarin. And then of course, we want to avoid a BTK inhibitor when dual antiplatelet therapy is needed because I think the bleeding risk does get to be quite excessive.

When it comes to hypertension, diarrhea and headache, there are some pearls that are there, which includes that if you have good blood pressure control prior to starting the BTK inhibitor, I think that becomes less of an issue, maybe not a non-issue, but less of an issue. Some people have noticed that an evening dose of the BTK inhibitor may mitigate diarrhea. And of course, that’s more for ibrutinib, which is a once-a-day drug. If you’ve got a bid drug, that may not be possible. And then for headaches, both acetaminophen or caffeine have been very helpful.

So, just a brief couple of slides on venetoclax. So, first of all, when venetoclax was being developed as a monotherapy, we had severe tumor lysis syndrome leading to significant toxicity until we learned how to ramp-up the dose and prevent this. So, in two of the trials at least that I’ve mentioned here, venetoclax plus an anti-CD20 antibody offers fixed duration therapy and actually with introducing the venetoclax later and having the ramped-up dosing, there’s no tumor lysis that was noticed, or very little in these clinical trials. And the main other toxicities are cytopenias.

So what happens or how can we decide who needs TLS prophylaxis and who doesn’t? Again, there are some really great guidelines that are out there that can help us decide whether or not somebody should be considered low, medium, or high risk. So I think when we’re seeing somebody in practice it’s important to assess their TLS risk category and then options are to use either allopurinol or rasburicase and then hydration, oral versus IV. And then whether or not they need to be admitted or not. And so, these guidelines are publicly available and that was just published at ASH this past year.

So, what about in the real world? I already showed you that in the trials, tumor lysis syndrome was very uncommon. However, in the real world it seems that venetoclax toxicity may be just a little bit higher, and I think that’s not unsurprising or not surprising. There’s a 21% discontinuation rate, at least in this group that Anthony Mato pulled together, and TLS was as high as 13%. So, I think there are some differences between what we see in the trials and what we see in practice. But again, there are guidelines out there to help us with hydration, uric acid inhibitors, et cetera.

So, no talk would be complete today without mentioning COVID-19 and the ongoing pandemic. And our patients with CLL unfortunately are at extremely high risk for complications, both from their disease as well as this infection.

So this study was just recently published in Blood and looks at 167 patients who have CLL, and they had a couple of different aspects that they looked at. For one thing, they wanted to know whether or not the patients could mount an antibody response or not. Whether or not this was impacted by whether or not they were on therapy or off therapy, the type of therapy — BTK inhibitor, venetoclax, anti-CD20 — and how far they were from their most recent anti-CD20.

And so, what you see on the right is that the likelihood of a CLL patient actually mounting an antibody response is much lower. And on the bottom right what you see is that the level of antibodies that are generated is also significantly lower. And what’s really depressing is the really flat CLL, bottom right hand, where their response to the vaccine and the amount of antibodies that they generate is really, really low.

So, what does this mean when it comes to just kind of diving into it a little bit more with treatment? They looked at these patients, and maybe I’ll just have you focus on the third column, which is negative. Serologic response negative is patients who are on treatment, 84% of them had no serologic response. If you look at the type of treatment it didn’t seem to matter if it was a BTK inhibitor or an anti-BCL2 or anti-CD20, 84% to 86% did not mount a serologic response. And then if you look by the last anti-CD20 antibody therapy, at least if they had more than 12 months, half of them responded, but if it was within 12 months, none of them responded. And this was all very sobering.

So, last slide here is just that treating CLLL during this pandemic is really challenging. And the data is really confusing. On one hand, there’s data that there’s a 28% case fatality rate from COVID-19 for CLL patients on a venetoclax-based regimen. There’s another publication that says ibrutinib interferes with innate immunity in CLL and may increase their risk of major complications.

And then on the other hand, we have studies that say that BTK inhibitors may protect against pulmonary injury, perhaps by having an anti-inflammatory component. And that maybe there’s a protective role of BTK inhibitors against the infection in general.

And then a European analysis came out and said that COVID-19 severity increases with age, anti-leukemic therapy with BTK inhibitors protects. And then age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency. And that last one was kind of scary to me because it doesn’t matter if they’re on treatment or not, even if they’re off treatment there’s something about CLL that puts them at a very high risk for significant toxicity and maybe even death.

Selection and Sequencing of Therapy for Patients with Relapsed/Refractory CLL — Julie M Vose, MD, MBA 

DR DAVIDS: We’re going to change gears a little bit and move to the relapse/refractory setting. And we’ll start with a couple of questions. So, first, which second-line systemic therapy would you recommend for a 60-year-old patient with IGHV unmutated CLL without TP53 aberrancy, who responds to ibrutinib, but then experiences disease progression 3 years later on ibrutinib? So you have chemoimmunotherapy, other BTK inhibitors, or venetoclax-based therapy.

And so, in terms of the audience, we see that most are moving to venetoclax-based therapy, either with rituximab, based on that MURANO experience in the relapsed setting, or kind of extrapolating a little bit with venetoclax plus obinutuzumab which hasn’t been studied in the relapsed setting. We do know that obinutuzumab is a more potent antibody in CLL.

So, let’s see what the clinical investigators say. So most are sticking with the trial data from MURANO, venetoclax plus rituximab, although, of note, there weren’t a lot of patients who had prior ibrutinib in that study either, so we don’t have a lot of data for this population. Actually, venetoclax monotherapy is probably the best study here. But venetoclax plus obinutuzumab was also suggested by several of the investigators.

How about second-line therapy for a patient now very similar, 60, unmutated IGHV, not TP53 aberrant, but now treated with front-line venetoclax/obinutuzumab and then progresses 3 years after completing that therapy? A little bit different here because this patient responded for 3 years and then progressed rather than progressing on therapy. You can see similar choices here.

So let’s see what the audience said. So you see a mix here, but mostly BTK inhibitor-based therapy; some ibrutinib; some acalabrutinib with or without CD20 antibody. You see some votes for venetoclax retreatment here, and then also venetoclax plus obinutuzumab retreatment.

And let’s see what the clinical investigators. So most did say move to a BTK inhibitor at this point, but some are willing to make the leap to say retreat with venetoclax/obinutuzumab. We don’t have prospective data for that yet. But for a patient who had 3 years of response, it’s reasonable to think they might respond again. So, again, an area where we need more data.

And then we asked the clinical investigators, based on current clinical trial data and your personal experience, how would you compare the global efficacy of zanubrutinib to that of ibrutinib and acalabrutinib in patients with relapse/refractory CLL? So, you remember from the ALPINE study, we saw with that early data cut, that there was some separation in the PFS curves favoring zanubrutinib over ibrutinib. But remember, that’s a pretty early data cut. So most are feeling that right now we can just say that these BTK inhibitors are all about the same when it comes to efficacy. And some also noting that there’s not enough available data, I do think we need longer follow-up. I agree with that.

And then in terms of similar question comparing the BTK inhibitors, but now in terms of tolerability or toxicity, so most actually do feel like there is a difference here, some feeling that acalabrutinib has the least toxicity; some saying that zanubrutinib has the least toxicity. I mean we’re kind of fortunate that we have two head-to-head studies now of these new drugs with ibrutinib, but I think its’s unlikely we’re going to have a head-to-head study of acalabrutinib versus zanubrutinib. So we may have to extrapolate a little bit across these trials. So I think very reasonable to also say not enough data at this time to know.

And then which third-line therapy would you recommend for a 75-year-old patient with IGHV unmutated CLL without TP53 aberrant disease who responds to ibrutinib and then experiences disease relapse? And then receives venetoclax for 18 months and then progresses at that point. So this is a patient who has never had chemo, so would you go to chemo with BR? Would you go to a different BTK inhibitor like acalabrutinib or zanubrutinib? Would you think about a PI3 kinase inhibitor?

So, a bit of a mix here. So, some are saying they would use chemoimmunotherapy for the first time in this patient; some would go to acalabrutinib. There’s a little bit of vote for the idelalisib or duvelisib, the two PI3 kinase inhibitor drugs approved in relapsed CLL.

In terms of the clinical investigators, a little more PI3 kinase use here with duvelisib being the most common response, but some of the clinical investigators did also suggest chemoimmunotherapy. And a few smatterings of other answers. But I think importantly, also some of the more investigational therapies come up here, CAR T, pirtobrutinib and a newer approved delta inhibitor in other lymphomas, umbralisib, not yet approved in CLL.

And so, based on current clinical trial data, your personal experience, how would you compare the global efficacy of this newer PI3 kinase delta inhibitor umbralisib approved in relapsed follicular and marginal zone lymphoma? But how would you compare that to the data we have for idelalisib and duvelisib in CLL? And we’ll see some data about this in the talk.

You can see the choices here.

So some are favoring umbralisib here in the audience, but a good number of people don’t know or are saying not enough data, which I think is a very fair choice.

And let’s see what the clinical investigators said. So it looks about the same, although there are few who thought that umbralisib might be more efficacious. Of course, no head-to-head data here looking across the different studies.

Based on the current clinical trial data and personal experience, how would you compare the tolerability and toxicity of umbralisib to that of the approved PI3 kinase inhibitors for CLL, idelalisib and duvelisib?

So the audience felt like umbralisib either had the least toxicity or half felt like they didn’t know. In terms of clinical investigators, felt pretty confident that umbralisib has the least toxicity, although some did note not enough available data here.

So with that, I’m going to turn it over to Dr Vose to talk about selection and sequencing of therapy for relapse/refractory CLL.

DR VOSE: Thank you. So, talk about a few cases and then go over some of the data on this type of patient. So these cases are actual cases from my clinic recently who inspired these.

So, a 61-year-old female who was diagnosed about 10 years, so pretty early, with CLL. Six years ago she developed anemia that required therapy where she was IGHV mutated and FISH: del 13q. She received FCR at that time, she was pretty young and in good shape and had a complete remission.

Now, so it’s 6 years later, she had a rising lymphocytosis and new anemia and thrombocytopenia that requires treatment. FISH was redone; still showed deletion 13q. So this patient really has many different options left for therapy. There’s BTK inhibitors. Venetoclax-based regimens, etc. So lot of different options for this type of patient.

DR DAVIDS: And Julie, can you comment on prognostic markers for this patient? So you mentioned that FISH was retested. Do you think that’s important to do before next line of therapy?

DR VOSE: Yes. I always retest the FISH when I’m starting a new therapy for patients. Of course, the IGVH mutation does not change. That does not need to be retested. Also, the 17p deletion and mutation probably should be retested as well when you’re going to restart therapy. So, I always do that.

So these are the NCCN Guidelines for this type of patient, so CLL/SLL without deletion 17p or the TP53 mutation. And you can see lots of different options here, preferred regimens, certainly BTK inhibitors or venetoclax-based regimens. PI3 kinase inhibitors. We’ll go into some of these data for all of these. But lots of different options for this patient. So you want to look at, of course, what their other medical issues are. What the different preferences are for the patient. And lots of different things and talking about what other medications they’re on. Lots of things you need to look at when trying to look at these options for these patients.

So, what happens to these patients? So single-agent ibrutinib, of course we’ve had now for a long time and we do have fairly good long-term follow-up for patients on the early trials. So, relapse/refractory CLL, 5-year experience published by Dr O’Brien a few years ago. If you have, as this patient did, relapse/refractory and still the FISH shows deletion 13q and no other abnormalities, you can see that the patients, as far as their progression-free survival and overall survival, is really excellent long term, even 5 years. Whereas certainly some of the patients with the higher-risk lesions as we know deletion 17p or deletion 11q, perhaps maybe do not do as well. But this patient fits into the very best category there and that certainly would be an excellent option for these patients. So, BTK inhibitors in general.

DR DAVIDS: Since we have Susan right here, maybe Susan can you just comment on the patients in this analysis, like what was the typical patient like? What was this population?

DR O'BRIEN: This was one of the worst patient populations I had seen at that time. Honestly, and I’m not exaggerating when I tell you there were people who were basically going to get offered hospice were to be on this trial, not because their performance status was so bad, but because they had 9 prior regimens. We couldn’t even think of something to give them. And this was also one of the first trials — it wasn’t that way when it started, but it was amended part-way through, where after the amendment, there were no hem eligibility criteria. I had never seen a trial that didn’t have hem eligibility criteria. I mean there were patients going on after that amendment who were transfusion dependent, red blood cell, platelets, etc. So this was an incredibly poor population.

And I’ll just point out that the two median PFS that you see there for 17p and 11q at the time this was presented, they were better than any published front-line progression-free in those two risk groups. So just kind of startling how dramatic this drug was in changing outcomes for people.

DR DAVIDS: Yes, 26 months doesn’t sound that long, but when you think about the population of patients as you’re describing, it’s quite impressive. And those results I think have begun to improve for the relapse 17p patients in more recent times in the less heavily pretreated group.

DR VOSE: Pretty remarkable. I wish all of our drugs could have that kind of outcome here.

So this is another important trial, the ASCEND trial, relapse/refractory mCLL, about 300 patients and they were stratified by deletion 17p, ECOG status and the number of prior therapies. And randomized 1:1 to acalabrutinib 100 mg bid, or idelalisib plus rituximab or bendamustine/rituximab in that arm. And you can see that the key primary endpoint was progression-free survival.

There was a crossover that was allowed on this trial as well, which, of course becomes important when you’re analyzing overall survival and some secondary things.

So in this trial, the IRC-assessed PFS, you can see was superior for the acalabrutinib versus the other arm. And you can see that the median risk was not reached in the acalabrutinib at the time this was published. So, very positive again for the BTK inhibitor as compared to this other arm.

We talked a little bit previously about the MURANO study, but this also was a very important study, a Phase III study, that looked at patients, relapse/refractory CLL, almost 400 patients, again stratified by deletion 17p. They were allowed to be done at the local lab and responsiveness to prior therapy. There was a venetoclax 5-week ramp-up starting at 20 mg up to 400, of course as we do today. And in the ven/R arm, almost 200 patients when they got up to the final dose of 400 mg per day, plus rituximab, as noted, versus BR. And then of course the venetoclax patients continued that venetoclax for 2 years in this relapse/refractory subset.

And then they looked at subsequent retreatment afterwards as possible crossover to the ven/R after progression in the BR arm.

So PFS and OS benefits were seen and lots of times in CLL we don’t see any overall survival benefits, but this trial did show that. And the patients in the venetoclax arm, you can see that median PFS and also there is overall survival advantage at the 5-year mark even long after the end of treatment there, that’s noted at the lower part.

So, again, a very important trial that we use every day now in our clinical practice, this methodology.

DR DAVIDS: So, Julie, I challenged Susan before to come up with an argument to use BR in the front-line setting. So I’ll challenge you to the same way, can you use BR in the relapse/refractory anymore for CLL patients?

DR VOSE: I would say mostly no, unless they’ve absolutely kind of failed everything else and I feel that they can handle that. But I can’t remember the last time I used that honestly in that patient population.

DR DAVIDS: Yes, I think it’s a pretty rare circumstance these days. I mean based on the OS benefit here from MURANO, if they’re a venetoclax candidate it’s a pretty compelling case to use venetoclax —

DR VOSE: Absolutely. So, another interesting part of this study was of course the MRD analysis, so undetectable MRD at the end of treatment was analyzed and also along the way in the study. At the end of treatment, MRD, looking at that, if they had a negative MRD was associated with improved outcomes, as you can see on this slide. So the green arm there shows that there is an improved PFS, also looking at even the OS does appear improved on the undetectable MRD. If it was slightly positive, if it was sort of in between, if it was highly positive, then it was not a very good outcome and patients progressed pretty quickly.

The question is, what type of MRD to do on these patients? And in clinical practice using that, sometimes is tricky getting it paid for by insurance, et cetera, so those are some points of discussion perhaps for some of our questions later.

Then there’s always the important part, what are the efficacy of subsequent treatments after the patients fail venetoclax/rituximab in patients with relapse/refractory CLL? And this was an abstract from this year that looked at what actually happened to those patients that failed that study – that therapy with Ven/R.

So in patients in that study, in the Ven/R arm, this looked at what their subsequent therapy was, and you can see in the blue there about 50% of the patients on the ven arm were treating again with that, about a quarter with a BTK inhibitor and almost a quarter with chemoimmunotherapy.

In the BR arm, you can see a much higher percentage actually went on a BTK inhibitor and not that many patients went on to ven.

But what were the rates to that therapy? And you can see again that it was broken out by the Ven/R arm or the BR arm, and the patients’ overall response rate was not that much different in the two; however, the patients that originally got BR did have a higher CR rate when they subsequently had a ven-based therapy as it compared to the patients that got a repeat ven therapy, overall response rate the same but less CRs. So, sort of an interesting analysis.

And subsequent response to BTK inhibitors were actually quite high in both arms, but in most of our studies most of these patients get a PR and not a true CR. There was a slightly higher CR rate in the patients who previously got BR when they get a BTK inhibitor. But the overall response rate is not that much different.

DR DAVIDS: And I think as we mentioned before, most of these patients were BTK inhibitor naïve. So these days, as we’re using more BTK inhibitor upfront, and then the patients get venetoclax, we may not expect similar high response rates to subsequent BTK inhibitor therapy.

DR VOSE: Yes, there’s a slide that we’re going to go over in just a minute that shows a little bit of that.

DR VOSE: This breaks it down by patients that were BTK naïve, patients that were previously exposed or resistant. And you can see the overall response rate is quite a bit higher of course in the BTK-naïve patients as compared to the patients who’ve been previously exposed. Probably not too surprising.

So here’s another case, a patient, a 75-year-old who was diagnosed with CLL about 11 years ago. Seven years ago, he developed anemia, lymphadenopathy, requiring treatment. And his original profile, he was IGHV mutated, and he had deletion 11q. At that time, he received ibrutinib and had really good tolerance to it and good response. But 3 years ago he had a rising lymphocytosis again with some anemia, lymphadenopathy. A FISH again was tested and found to be deletion 11q. And he received venetoclax/rituximab as per the MURANO study. But he now progressed, unfortunately. And when FISH was tested again, he still had the deletion 11q, but had a new deletion 17p unfortunately.

So lesser options potentially for this patient, PI3 kinase inhibitors. Would you do other BTK, other anti-CD20 antibodies? Different combinations? Would you do a CAR T-cell in a 75-year-old? So, lots of different things to discuss in this patient population.

So treatment recommendations for relapse/refractory. You can see in this, basically taking them out of the NCCN Guidelines, and you can see there’s lots of different options, of course depending on the patient’s comorbidities, age, etc, their creatinine clearance. And looking at different options there below based upon clinical trials.

So, PI3 kinase inhibitors, many have been tested in CLL. There are two that are currently approved for relapse/refractory CLL, idelalisib that’s approved after failing two prior therapies, and duvelisib, which is a dual PI3 kinase inhibitor, also indicated after two therapies.

There have been studies for the other two PI3 kinase inhibitors. We’re going to go over one here in just a minute for the umbralisib, but not technically FDA-approved for that case.

So this was recently presented by Dr Gribben, a Phase III trial, that was the UNITY trial looking at umbralisib combined with ublituximab versus obinutuzumab plus chlorambucil in patients with relapse/refractory CLL.

So umbralisib is a dual inhibitor, as you can see here, and has the structure as compared to the other ones. It is more potent in those particular isoforms and is oral, once daily.

This is the design of the UNITY trial. So, umbralisib plus ublituximab, U2, kind of catchy term there, and was 800 mg once daily and then you can see the other doses there, compared to what was called the standard of care, obinutuzumab plus chlorambucil. And primary endpoint was the IRC-assessed progression-free survival. And secondary endpoints as noted. About 420 patients in the trial.

So, the IRC-assessed progression-free survival, these are obviously previously treated population. You can see the PFS median there of the U2, 19.5 months versus 12.9. And the 2-year PFS, 41 versus 25.

Of course, we’re always concerned about toxicity with this type of agent, and this shows some of the events of clinical interest for PI3-specific abnormalities: increased liver function studies, colitis, pneumonitis, rash, opportunistic infections. They were slightly higher in the U2 arm, although the severe ones, Grade 3 or 4, were not high but they were definitely a little bit higher than the obinutuzumab/chlorambucil, as you can see here.

DR DAVIDS: So, Julie, having recently reviewed these data, obviously we don’t have head-to-head studies of the PI3 kinase inhibitors, how do you feel like the umbralisib data look compared to duvelisib and idelalisib, both in terms of efficacy and safety?

DR VOSE: It’s so hard because there’s no head-to-head comparison. I’ve used a lot of these in different studies, so not a head-to-head comparison, but I would say that umbralisib probably is a little less toxic from using it. As far as the outcomes, I don’t know that. We’re not going to be able to tell that until we have a head-to-head comparison really.

And just to finish up here with the ALPINE study. Again, we talked about this a little bit a minute ago. So a randomized trial of zanubrutinib versus ibrutinib for relapse/refractory. And you can see here the outcomes that Susan talked about, with respect to the overall response rate, primary endpoint actually was an improvement in the zanubrutinib. We’ll be seeing this I’m sure further presented with longer-term outcome soon.

So take-home messages. I think there’s lots of different options for these types of patients, it depends on a lot of their profile, what their other medical issues are; what they had before. And we can retreat these patients in some cases with what they’ve had before, depending on circumstances. But lots of different options.

So you need to look at the side effect profile. Talk it over with the patient and see what the most appropriate is.

I didn’t really go over cellular therapies today, but of course, those are something that potentially there’s clinical trials and may be appropriate depending on what their particular profile is. And certainly for those with TP53 abnormalities and who have failed these other regimens. That’s an option to consider. And of course, all of our clinical trials.

Thank you.

DR DAVIDS: Thank you so much, Julie.

So I promised that we’d try to get some audience questions. I have a couple that I wanted to bring in before I go on to the next session. First of all, I’m going to direct to Alexey and if you could maybe sum up your approach in 30 seconds or less to Richter’s syndrome. We haven’t really mentioned that yet, but how are you managing Richter’s syndrome these days?

DR DANILOV: So, Richter’s syndrome is obviously a very high-risk disease, unmet medical need. And my belief is that most of those patients need to go on clinical trial. Eight percent of Richter’s syndrome patients are clonally related to CLL and often, when we treat those patients, we don’t know whether they are clonally related or not. And if they’re clonally unrelated, they may be fine, doing well with R-CHOP; however, if not, then my approach is a clinical trial with novel agents. Often because of readily progressive disease, you might need to administer some chemotherapy, and that could be BR/pola, that could be R-CHOP. But ultimately, clinical trials with bispecific antibodies, CAR T-cell therapy, or novel immunotherapy combination approaches — We have a trial with PI3K/PD-1 combination approach — is, I believe, the way to go with these patients.

DR DAVIDS: Thank you. And then we had another question for Dr Smith about COVID and CLL. Is it true that CLL patients have a higher chance of fatal complications compared to other heme malignancy patients?

DR SMITH: That’s a really good question. The data in some of the other heme malignancies is actually lower, there’s just not as much that’s been published. But I do think that there’s something to innate immune deficiencies with CLL patients that’s not just the B-cell lesion, I think there may be something else there as well. So my guess, not based on any data that’s comparative, is that CLL, for whatever reason, has a higher risk. It might also be because these are older patients, in general. So, that may be part of it.

Novel Strategies Combining BTK and Bcl-2 Inhibitors in CLL — Matthew S Davids, MD, MMSc 

DR DAVIDS: So we’re going to move on to novel strategies combining BTK and BCL2 inhibitors in CLL. We’re going to start again with some questions.

So first question, do you believe there’s a benefit to administering a BTK inhibitor in combination with venetoclax as opposed to sequentially in patients with CLL? We asked our clinical investigators there, pretty evenly split. Susan, what are your thoughts on this?

DR O'BRIEN: I’m trying to remember what I said. I think I don’t know the answer, although that wasn’t an answer, so I don’t remember what I chose. But I think it’s a really interesting question and I do not know what the answer is.

DR DAVIDS: Tough one right now. Soni?

DR SMITH: I was just going to say that I think benefit needs to include the toxicity profile. So it’s not just benefit, but it’s like the risk-benefit. And one of the things I didn’t talk about as much in the ending of mine is the financial toxicity. So that is another piece of it.

DR DAVIDS: Great point. Alexey?

DR DANILOV: I would say that combination of venetoclax and BTKi gets you time-limited oral-only therapy. So if you consider that a benefit, that’s a great benefit.

DR DAVIDS: Fair point.

Have you or would you administer ibrutinib or acalabrutinib in combination with venetoclax to a patient with CLL outside of a clinical trial setting?

So a 50/50 split here. Half haven’t and would not. Half haven’t and would for the right patient. No one has said that they’ve done it.

Now let’s see the clinical investigators. So, actually the clinical investigators have been willing to make that leap. So, 10 of the 25 have done this already. 9 haven’t done it yet but would do it for the right patient. And 6 have not done it yet and would not, based on the currently available data.

So I’m going to talk about some novel strategies for this combination in CLL, and this goes back a while. So, back in 2014 or so, we first started getting interested in this question. On the lab side this is one of our earlier papers looking at sort of preclinical combination of BTK and BCL2 inhibition. Number of groups around the world were working on this and it was very apparent from the start that these were going to be synergistic combinations. I like to show my graphic of Achilles here because these are really the two Achilles’ heels of CLL pathophysiology: the BCL2 pathway with the mitochondria and the B-cell receptor signaling pathway. That’s a nice schematic from Adrian Wiestner, from the New England Journal from a couple of years ago, showing how targeting these two different areas of the cell can be profoundly synergistic, both by targeting those microenvironmental signals for proliferation, but also that cell death machinery which can very quickly kill CLL cells which depend very heavily on BCL2 for their survival.

So this moved into the clinic fairly quickly. One of the early studies was done at MD Anderson. This was Nitin Jain’s investigator-initiated study of front-line ibrutinib plus venetoclax. And very early on, from that study, they saw very deep responses. On the left side you can see the IWCLL clinical response. You’re seeing the clinical remissions very early on, complete remission in well over half of patients even after just a few months. And nearly all patients achieving am IWCLL complete remission eventually. And then the orange bars are the rates of undetectable MRD in the bone marrow which also go up over time. This was designed mostly as a 15-month regimen, although in this study they could extend into a second year of therapy. And you do see this continued deepening of response over time.

We’ve seen just recently some updated data from this study. They continue to show very high rates of undetectable MRD, both in the blood and in the bone marrow. And you can see on the right that this has translated into an excellent progression-free and overall survival. Very few events so far. The follow-up here was short, but the follow-up continues to obviously mature over time and we’re seeing very few progression events still.

Now, one of the questions in my mind was that okay, these are previously untreated CLL patients, of course they’re going to do well with this very potent combination. What if we brought this into the relapse setting, in a group of patients treated previously with chemoimmunotherapy? We know this is a much more difficult population. And so, that was the subject of the UK CLARITY study, combining ibrutinib and venetoclax, similar regimen here of an ibrutinib lead-in. That’s done to debulk the patients and reduce the risk of tumor lysis syndrome, and then the venetoclax combination given for at least 15 months.

This study was interesting in the way they designed the length of therapy. It was based on the time that it took to attain undetectable MRD. So patients who took longer to get to undetectable MRD would go on a longer course of ibrutinib plus venetoclax. Those patients who had a more rapid response to therapy could get off therapy more quickly. And you can see on the right, both in terms of peripheral blood and bone marrow undetectable MRD rates, that they’re quite good — they’re sort of the purplish bars toward the bottom, and you can see those rising over time. So even in this relapsed situation, as you get out towards 2 years of therapy, you’re kind of approaching well over half of the patients in undetectable MRD state. This study actually looked at even deeper levels of undetectable MRD, down to 10^-6 in some cases. So, very, very deep responses.

And to me, the Kaplan-Meier curves were really outstanding. I mean those are flat curves in a relapsed CLL population. Follow-up still relatively short from this data cut. But nonetheless, I think it’s a very impressive result, even in this relapsed population.

So, possible critique of those studies is that they were smaller studies. What would happen as this got explored in a larger setting, multi-center? And so, the CAPTIVATE study is one of the first to look at this. CAPTIVATE is a bit of a complicated study. It’s an international study that has two main cohorts, there is an MRD cohort at the top there, and in this regimen there’s an MRD-guided randomization after the 15 months. So, patients who have confirmed undetectable MRD get randomized to placebo or ibrutinib. Patients who do not have undetectable MRD confirmed get continuous ibrutinib or ibrutinib plus venetoclax. That aspect of the study was previously reported. I’m going to focus on the fixed duration cohort, which was just more recently reported at the Spring meetings, and this looked at a 15-month regimen for all patients, regardless of what the MRD test looked like at the end of those 15 months.

And we just saw these data recently. Here’s the primary endpoint of the study, which was the CR rate in patients without deletion 17p, so you can see that on the left. This is about 56% of patients, so quite impressive. TP53 aberrancy was seen in about 17% of this population, so a little bit higher than the general CLL population, so reasonably high-risk group. And, nonetheless, well over half of patients achieving a CR here. And similar rates in patients who had deletion 17p versus not.

This was a young population, median age of 60 here. And you can see the range from 30s up to 71. And that will be important as we talk about toxicities.

Before I mention that though, I just wanted to comment on the undetectable MRD rates. So you can see they’re quite high, about three quarters of patients in the peripheral blood, about 60% or more in the bone marrow achieving undetectable MRD with this all-oral novel agent regimen, so really quite impressive. This seemed to be similar in patients with bulky disease versus not. You can see that the undetectable MRD rates were a little bit higher in patients with unmutated IGHV versus mutated IGHV. Some of that may have to do with kinetics of response and when things were measured, but certainly very high rates of undetectable MRD across the different genomic subgroups.

So I mention toxicity. I think obviously, that’s very important as we’re putting these new drugs together. So you can see here that generally, the toxicities were relatively low grade. You do see diarrhea commonly with both of these drugs on their own. You see it in about 60% of patients when you do the combination. Some nausea, neutropenia and arthralgias, as we know with ibrutinib. The rates of Grade 3 are higher. Cytopenias were relatively low. Neutropenia being the most common in about a third of patients. But relatively low rates of infections in this CLL population, 8% with Grade 3/4. And in terms of AEs of clinical interesting, relatively low rates of atrial fibrillation, 4%; major hemorrhage 2%. So, overall, a well-tolerated combination in this young population.

Dose reduction was required in about 20% of patients, but only about 5% of patients had to discontinue due to an AE.

So of course, that’s the younger CLL population. What about looking in the older, more typical CLL population and that was the subject of the GLOW study. This is another one that just reported out at the Spring meetings, so hot off the presses.

This was a relatively small Phase III study, 211 patients. They were randomized 1:1 to this same 15-month course of ibrutinib plus venetoclax, or a standard 6-month course of chlorambucil plus obinutuzumab. And the primary endpoint of this study is progression-free survival by an IRC.

Remember, with CAPTIVATE, median age 60, so here median age 71 with patients up into their 90s. So this a more typical CLL population. And on the right, you can see the primary endpoint of the study, PFS, certainly clearly favored ibrutinib plus venetoclax over chlorambucil plus obinutuzumab.

And as you look at the rates of undetectable MRD, these were also higher with the ibrutinib/venetoclax, compared to chlorambucil/obinutuzumab, 52% in the bone marrow; 54% in the peripheral blood. At first glance, this seemed a little lower than what I was showing you with CAPTIVATE, but this was actually, in GLOW, the MRD specifically 3 months after the end of treatment, only at that timepoint. And if you look actually at the third bullet down on the right, if you count best undetectable MRD rate, as they did in CAPTIVATE, it gets up much higher, up to 68% in the bone marrow and 80% in the blood. So actually quite similar to what we saw with CAPTIVATE in this older population. So it’s clearly a very active regimen in the older population.

However, we did see more toxicity in this group. You can see I+V, the left-hand column there, Grade 3/4 neutropenia was about 35%, but infections were about double what was seen in the younger population, 17%. You see more Grade 3/4 diarrhea 10%, as well as hypertension and atrial fibrillation. And so, these are all things that need to be beared in mind. The discontinuation rate was about 10% here, so a little bit higher than we saw with CAPTIVATE.

In terms of overall survival, it’s still early for this front-line study, so there’s no difference in overall survival between the two arms, IV and chlorambucil/obinutuzumab. But I do think this table is informative in terms of the causes of death in the two arms. You do see a little more in the way of infections with chlorambucil/obinutuzumab. Whereas with ibrutinib/venetoclax, you do see some cardiovascular related deaths, including a couple that occurred during the 3-month ibrutinib lead-in. So I think this speaks to patient selection and really understanding the risk factors and comorbidities of your patients as you think about using these types of regimens.

So if two is good, then maybe three is better. So, this is from a review we did a couple of years ago looking at combining BTK and BCL2 with CD20 inhibition to really hit the cell in three different ways. And this is being explored in a number of different trials now, one of the first to be published was the IVO study of ibrutinib/venetoclax/obinutuzumab led by the Ohio State group. And here you can see excellent results in terms of the PFS and OS. But in terms of safety, again seeing hypertension at a relatively high rate, infusion related reactions, which may have been related to the fact that they used obinutuzumab first without a BTK inhibitor in this study. High rates of Grade 3/4 neutropenia in about two thirds of patients. You still see arthralgias, headache and atrial fibrillation. So, certainly an active regimen.

This has become the comparator arm in the US Cooperative Group studies. The Alliance study and the ECOG study are both using IVO as the comparator to IO. So we’ll be getting a lot more data on this triplet therapy over the years.

But in the meantime, several groups, including our own, have been looking at the newer BTK inhibitors in triplet regimens. So we presented the AVO study, acalabrutinib/venetoclax/obinutuzumab at ASH last year. Which you can see the way the regimen is designed; we actually start with the BTK inhibitor first before doing the obinutuzumab. We did find that this helped reduce the rates of infusion related reactions, which we did still see in about a quarter of patients, but they were all low grade. You see the headache, as we normally do, with acalabrutinib in 80% in our study, but only 2% Grade 3 or higher. And as Susan said, this is usually transient. And then we see about a third Grade 3 or higher neutropenia, 11% hypertension. But importantly, low rates of Grade 3 or higher infection, one patient with Grade 3 infection, one patient with AFib and one higher grade infusion-related reaction. And we’ve seen no major bleeding or febrile neutropenia with this triplet.

On the right, you can see that the iwCLL response has looked good so far at cycle 16, which is after that 15-month period of therapy, 44% have achieved a CR, and we’ve seen high rates of undetectable MRD in an intent-to-treat analysis, 77% or so in the bone marrow and 83% in the peripheral blood. So, still relatively early with this triplet. I’d say it’s been well tolerated and certainly looks efficacious.

And then the group at MGH and Memorial Sloan Kettering has been looking at zanubrutinib with obinutuzumab and venetoclax. They call this BOVen study from the old name BGB for zanubrutinib. And you can see sort of a similar schema here, a little bit different order starting with both the obinutuzumab and the BTK inhibitor at the same time. But once again translating into excellent efficacy. One of the unique elements of their study is that if patients got to undetectable MRD after 8 months of therapy, then a couple of months later they could discontinue. So, then shorter than that 15-month time period. So it will be interesting to see the durability, but they’ve seen very high rates of undetectable MRD with this triplet. And again, a very favorable looking safety profile with some cytopenias, diarrhea, minor bleeding. But, overall, a well-tolerated triplet therapy.

So, where are we heading now in front-line CLL? There are quite a few Phase III trials going on around the world. I’ve selected some of them here that I think will be very interesting. So, in particular, the UK FLAIR trial and CLL13 are likely to read out very soon. These are some of the largest trials that we’ve seen over the last few years, and these are comparing chemoimmunotherapy to some of these different novel agent-based regimens that I’ve mentioned, including the IV doublet in FLAIR and the IVO triplet in the CLL13 study.

And then in the US, as I mentioned, we have the two ongoing Cooperative group studies, and so those will not report out for a while, but obviously will be quite important once they do.

One of the very interesting studies going on right now is the ACE-CL-311 study, because this is comparing the AVO triplet to the AV doublet to chemoimmunotherapy. So I think this will be helpful in terms of understanding whether we need to add the antibody. It’s a common question that I’ve gotten with our study, do you really need the O with AV or is AV enough? And the answer is we don’t know. But this study will certainly help to answer that question.

I think one of the most important studies in the field right now that just recently opened earlier this year is the CLL17 study, and this question has already come up a few times on the stage is whether it’s better to give sequential novel agents as single agents or whether to give combinations for time-limited periods. And that’s exactly what CLL17 is trying to answer, so comparing ibrutinib as a continuous therapy to a time-limited ibrutinib plus venetoclax to a standard venetoclax plus obinutuzumab time-limited therapy. But of course, it’s going to be several years until we have the answer to that question.

And we’ve been working collaboration, myself with Anthony Mato and Jeff Sharman, of getting the MAJIC study off the ground, hopefully by the end of this year. This is going to look at the time-limited combination of acalabrutinib and venetoclax versus venetoclax plus obinutuzumab. And this is actually MRD-guided therapy in both arms, so trying to really figure out that question that I asked before, is 1 year of venetoclax enough with venetoclax/obinutuzumab? May patients benefit from a second year. So, hopefully, this study will help to address that question.

So, my conclusions for combination BTK and BLC2 currently in CLL. There’s certainly a strong scientific rationale for this combination. We saw data from the early studies showing excellent efficacy both in the front-line setting and in relapsed CLL. And now we’ve seen also more mature studies of this combination showing excellent efficacy. And I would say better tolerability, specifically of ibrutinib/venetoclax in the younger patients as compared to what was seen in the older patients.

I think there’s promising triplet therapies now in development, and I think in particular this next generation of BTK inhibitors, since we’ve seen from the head-to-head studies, they may be a bit better tolerated. I’m very curious to see how these data evolve in the triplet setting. And hopefully we’ve been able to highlight in all of our presentations that there’s still a lot of unanswered questions in CLL, so active participation in clinical trials remains critical.

So, this is a real patient of mine who’s 78. Had prior prostate cancer, appendicle carcinoid, both were cured with surgical resection. Has a 20-year history of supraventricular tachycardia, managed with diltiazem. And was diagnosed with trisomy 12 unmutated IGHV CLL back in 2012. Had some gradual progression on watch and wait, but by 2018 had more steady progression of CLL. Saw me in the Fall of 2018 for a consultation.

I repeated the prognostic makers and unfortunately, in the course of that 6-year time period, the patient actually had acquired deletion 17p at a low level, but also a TP53 mutation and had had fairly rapid evolution of the disease over the prior few months. You can see the counts there; the white blood cell had shot up to 233. There was some evolving anemia and bulky lymph node as well as fatigue.

So, this patient enrolled on our AVO trial and was treated, and you can see even after the first 3 cycles had a dramatic reduction in the white blood cell count, down to normal. In our study with AVO, we do a 4-week venetoclax ramp-up to try to simplify that a little bit and was able to do that without any tumor lysis syndrome. And at the end of the 15 months of therapy had achieved a CR with undetectable MRD by FLOW and discontinued all therapy at that time.

This patient is now on observation. Is still in CR with undetectable MRD about 20 months after completing therapy.

So I want to just take a minute to ask maybe a couple of our panelists. So this is a patient now who’s been treated with AVO, so probably three of our best mechanisms, maybe Soni I can start with you. If this patient relapses, how are you going to treat them now?

DR SMITH: And he’s already 78. So if he were younger, I think —- well, first of all, this is all a time-limited therapy, so it depends on really how much time he has between the most recent therapy and progression, and then whether or not he needs treatment at the time of progression. I think for a younger person I would think of CAR T. Some people would argue that in older — age is not the criteria, so I think that still could be something. But if we wanted to go with another agent at this point, if there’s been a sufficiently long enough time, I’d probably go back to a BTK inhibitor again. You could think about PI3 kinase inhibitor. I think that would be very reasonable.

DR DAVIDS: Anyone else have any thoughts?

DR DANILOV: I think it depends on how they progress. So, if they progress with C481S mutation, maybe BTK inhibitor wouldn’t be the best choice. And how much time elapses. If he progresses at the time when he’s 88, we still can hit him hard with venetoclax/obinutuzumab, right. And I think there are many answers here. But it’s great data. Very encouraging data and wouldn’t stop me — thinking about the future wouldn’t stop me from using this regimen.

Other Promising Investigational Agents and Strategies — Alexey V Danilov, MD, PhD

DR DAVIDS: So we’re going to transition to our last module here.

So we asked, if you could access pirtobrutinib, which Alexey is going to talk about in a minute. This is a newer BTK inhibitor, so if you could access pirtobrutinib for your patients with relapsed CLL today, would you want to use it in clinical practice? Yes or no?

So the audience, 85% said yes.

What about our clinical investigators? Yep, almost everyone. We had one hold out. I don’t think it was anyone on the stage here. But everyone was excited to try pirtobrutinib for this relapsed patient.

Next question. In your opinion, with CAR T therapy eventually become a part of standard treatment algorithms for patients with CLL? So our clinical investigators overwhelmingly thought yes, there’s a bright future for CAR T-cell therapy. A couple were a little more skeptical.

And then at what point in the treatment course are you referring patients with multiple relapsed CLL for consultation regarding CAR T-cell therapy? First? Second? Third relapse? After third relapse? Not referring patients.

And let’s see what our audience said. So most are saying second, third, or after third relapse. So, kind of a little bit all over the place there. Most are referring for CAR T therapy consultation.

And in terms of the clinical investigators, kind of split between second and third relapse, although some also waiting until after third relapse. So, again, an area of controversy where we don’t know what the time frame is to bring CAR T into the picture.

So, Alexey is going to talk to us about promising investigational agents and strategies in CLL.

DR DANILOV: Thank you very much. I’ve been given the enviable task of stargazing a little bit, which, by the way works way better in Hawaii than Los Angeles and Susan can attest to that. And I’ll start with something which is fairly close, one of the closest stars, maybe even a planet now, is pirtobrutinib, which is one of the reversible non-covalent BTK inhibitors. So, as you know, ibrutinib undergoes covalent binding and it binds to the ATP binding pocket of BTK. And when the pocket is mutated, as you can see a little triangle there, ibrutinib only undergoes reversible binding. And that seems to be not enough to inhibit BTK activity in a sustained fashion.

So, several non-covalent BTK inhibitors have now been designed and ARQ 531 and LOXO-305, or pirtobrutinib, seem to be fairly selective for BTK, although both of them still inhibit TEC kinases.

So, pirtobrutinib is very potent and selective towards BTK for probably one of the most selective inhibitors we have to this day. Here are some of the clinical data in xenograft models, where it inhibits both BTK wild-type and C481S mutation, essentially with the same efficacy as opposed to ibrutinib.

And we recently heard the results of the Phase I/II BRUIN study which enrolled multiple cohorts of patients, but the largest cohort was actually patients with CLL. Over 100 patients were enrolled. And here are the characteristics. If you can see, I highlighted in red here that 86% of patients had received prior BTK inhibitor. And two thirds of those patients actually discontinued for progressive disease and some discontinued for toxicities.

So, we know that 27% had C481S mutated status and others had BTK wild-type. But anyway, this is essentially a high-risk group of patients as we think of CLL these days.

So, since this was a Phase I/II study, we’ll start with toxicities. And as you can see, there is still some of the typical BTK related toxicities. You see a little bit of hypertension. You see a little bit of atrial fibrillation. And the rate right now is almost background, but also the follow-up is less than a year. The follow-up is still really short. And remember, even with drugs like ibrutinib, it took us a while to see these typical toxicities with longer follow-up. So, I think the jury is still out how these cardiovascular events we will see here. But some of the typical events also included fatigue, diarrhea, contusion. But overall, the drug was really well tolerated and only 5 out of 323 patients discontinued due to treatment emergent adverse events. Again, the follow-up is really short, so we’ll see how it’s sustained over time.

You can see lymphocytosis just like you’d expect with BTK inhibitors early on and then it disappears. And also, consistent with what we see with BTK inhibitors, response deepens over time, as you can see 68% response rate by 6 months, goes up to 6% with 10 months of therapy.

DR DAVIDS: Can I stop you a minute there. Maybe speak a little bit to why that is. So it does look the response rates not that high sort of early on and then goes increase over time.

DR DANILOV: So, as you know, it depends on how we assess the response. Everybody benefits early on. However, to get to 50% reduction of lymphadenopathy often takes time. There are some holdouts of lymph nodes somewhere which, maybe that’s what we read in the first place, and delays assessment — delays calling response. But clinical benefit happens very early, as you know.

DR DAVIDS: I would agree. We put a lot of patients on this study. And I can speak to the fact that a lot of them were put on very quickly and just haven’t gotten to response assessments yet. Maybe they’ve only hit one response assessment. So a lot of those patients, over time, will develop responses, but as you’re saying it takes time.

DR DANILOV: So, as you can see here from this swimmer’s plot showing lymphadenopathy, almost everybody responded, or almost everybody benefits, including patients with BTK C481S mutant disease, which is denoted by a star which I know you cannot see very well, but trust me, it’s there, many patients. And you can see graphs for duration of response and progression-free survival. Very impressive. So, hot off the press, there was also a presentation at the EHA meeting, which showed that this drug, LOX-305, may also have efficacy in Richter’s transformation. So only 17 patients, so very early data. Not clear how this is going to play out, but very encouraging data so far, with the majority of patients deriving clinical benefit. And at the time of short follow-up, arguably progression-free survival is still not quite reached, though there is clearly some patients who may benefit from this drug for a few months, maybe even longer. So, overall response rate is 67% with two patients achieving complete response.

So there are some prediction models that suggest, preclinical data that suggests that there will be potential resistance to these non-covalent BTK inhibitors. We haven’t seen that in the clinic yet, or at least it hasn’t been reported. But we can expect that of course nature probably will find a way.

In the lab, we investigated another non-covalent BTK inhibitor which, actually at the same time, targets SYK. As you know, SYK is a valid target in CLL. SYK inhibitors produce responses. And here is some preclinical data in ibrutinib resistant models, where you can see that this particular drug, luxeptinib, actually does work in vitro against ibrutinib resistant cell lines and concurrently inhibits BTK, SYC and phospho AKT in contrast to ibrutinib.

There are several ongoing pirtobrutinib studies. The drug is heading towards registration. So we probably will have access to it in the clinic in the near future.

DR DAVIDS: Let me stop there for ibrutinib, just a couple of questions. So I think the first is, let’s imagine it does get approved later this year, next year. So, where would you start using it in your practice first?

DR DANILOV: So I think we’ll see what the approval being. So I think one of the most interesting approaches would be to maybe use it concurrently with drugs like acalabrutinib or zanubrutinib, so that you could potentially suppress the BTK resistant clone from the start. So, one might argue for this approach, or use it in place of current BTK inhibitors as your first-line strategy. But I think we will have to see more toxicity data and also have to have comparison with these inhibitors to go with that approach.

DR DAVIDS: I’d say for my practice, I’d probably use it first in patients who might be progressing on ibrutinib or acalabrutinib, where I can see the data looked pretty good so far, and its way to keep them in the class and on that therapy maybe before switching to venetoclax. I think an interesting question is, where is this drug heading in the future, in addition to the registrational Phase III relapse studies you showed, they’re also planning front-line studies. So, what’s your feeling about this drug as a front-line option in the future maybe?

DR DANILOV: Well, I think time will show. I think at this point, even in the relapsed setting, the data is very limited, as you know. Follow-up is really short. It clearly works great. But I think this front-line setting and the planning hopefully will show us where the dice fall.

So, stargazing a little bit further. CAR T-cells have certainly made a huge impact in therapy of diffuse large B-cell lymphoma and mantle cell lymphoma. There are multiple — I can say multiple — products approved now.

So this particular TRANSCEND CLL004 trial, which was presented by my colleague Tanya Siddiqi form City of Hope, had two cohorts. One of them was a monotherapy cohort of liso-cel in patients with CLL, relapse/refractory or ineligible for a BTK inhibitor or failed prior BTK inhibitor. And the second cohort, same eligibility criteria, but it also incorporated ibrutinib. As you know, there is enough preclinical data suggesting that BTK inhibition concurrent with CAR T may enhance responses and maybe mitigate some toxicities. So the primary objective was safety for this study.

So this is the patient population for the monotherapy cohort. And like Susan was saying, this is actually reminiscent of some of those ibrutinib studies where some patients had up to 11 lines of therapy and median number of therapies was 4. And 74% of those patients actually progressed on ibrutinib, as you can see highlighted in red. And on the right column, you see a subgroup of patients who are dual progressors or double refractory, as we call them now, in CLL. That’s a fairly new term, so refractory to both BTK inhibitor and BCL2 inhibitor venetoclax. So, highly unfavorable patient population. Two thirds had deletion 17p or mutated p53 and up to 90% of patients had in total that and complex karyotype. So very difficult to treat patient population.

In terms of toxicities, fairly typical of what we see with CAR T-cells, 75% all grade CRS, 2 out of 23 patients had Grade 3 CRS. Also, as expected, some neurotoxicity. Just maybe linger on the CRS numbers a little bit. I’ll tell you why a bit later. Seventy-five percent total and 9% Grade 3 and higher.

And this is what happened in terms of efficacy. Overall response rate was 82%, so this is very impressive. Again, double refractory patients, refractory to BCR inhibitors, 46% complete response rate. And 68% of patients achieving rapid response within 30 days.

Interestingly, so far median PFS comes out at 18 months, so like we expect with CAR T-cells, some patients will respond, achieve CR, and may have durable response. And some won’t respond as well or have short-lived responses. But interestingly also here, which is a bit different from what we see with other CAR T-cells, is Richter’s transformation seems to be so far, the most common reason for disease progression. And while there is some encouraging data with CAR T in RT patients, it seems that we are not fully addressing the mechanisms of CAR T, despite these cellular immune-based therapies.

These are plots of duration of response and progression-free survival. Again thinking of patients who received 11 lines of therapy, including novel therapy. This is very impressive.

And this is the second cohort, which is a combination of liso-cel product with ibrutinib. And at least in this small study, what we can see the all grade CRS is still about 74- 75%, similar to what you saw with the monotherapy cohort. And Grade 3 CRS happened in one patient. But you still see some neurologic events. So I guess we’ll have to see longer follow-up with this combination to see how these toxicities pan out.

In terms of efficacy, just very effective regimen as well. It’s 95% response rate. But again a small study. It’s difficult to say whether this is better. Many patients do achieve minimal residual disease. But again, for a small study, it’s difficult so far to say whether combination therapy with ibrutinib is better than liso-cel alone.

So who are potentially the candidates for CAR T-cell therapy when we think of CLL? Of course, the double refractory patients who have failed BTK inhibitor and BCL2, they have very little options, so pirtobrutinib is becoming an option now on clinical trial. But we will see how durable those responses are. But certainly those patients are good candidates.

I would even argue that maybe single refractory patients with high genetic risks also may be good candidates for CAR T-cell therapy because as far as we know, we would like to dream that it might be curative for some of these patients. And we know from patients with DLBCLL, the more lines of therapy you use, the less well you may be doing overall.

We need a little bit of work trying to figure out whether comorbidities matter in terms of predicting survival in CAR T-cell, and of course they do. The more comorbidities these patients have, the worse outcomes they seem to enjoy.

So there has to be some selection of these patients for CAR T-cell therapy.

There is also a plethora of noel and emergent targets in CLL. And I’m not going to linger over this too much.

But I’ll just list them here, very interesting targets, Mcl-1, Bcl-xL, which are currently under development as well as allogeneic CAR T-cells.