Current Management Approaches for Patients with Chronic Lymphocytic Leukemia (CLL) — Jeff Sharman, MD

DR SHARMAN: Thank you so much for having me, Neil. My name is Jeff Sharman. I am the Medical Director of Hematology Research for the Sarah Cannon and US Oncology research network. I practice in Eugene, Oregon in a community practice setting at the Willamette Valley Cancer Institute. I’ve been asked to speak about a number of papers in chronic lymphocytic leukemia, so I’ll be hitting the highlights and look forward to any discussion you wish to have during this.

The first paper I want to talk about is the CLL12 study. This is a study conducted by the German group and really took a very provocative study design. As you probably know, watch and wait has been the established standard of care really dating back a long time from studies conducted in the 80s and 90s where patients were randomly assigned to chlorambucil or not. And of course as our treatments have evolved, the question bears repeating. Does it make sense to start therapy earlier? So this was a study that compared ibrutinib versus watch-and-wait. And what they did using sort of the German, or, excuse me, the European staging system, the Binet stage, they took asymptomatic early-stage patients, so stage A, which would be roughly equivalent to the early Rai stage, Rai 0, Rai 1, patients who might have lymphocytosis and a little bit of adenopathy, but don’t necessarily have cytopenias or bulky nodes. And they created a risk model where they could estimate who is going to need therapy pretty soon and this consisted of age, gender, IGHV status, ECOG, beta-2 macroglobulin, del(17p), 11q, and thymidine kinase which is a marker that’s pretty effective at predicting who’s going to need therapy but not one we use all that often. For patients who are at higher risk, they were then randomly assigned to either ibrutinib or placebo and then patients at lower risk continued with watchful waiting.

These are the curves from the study and if you were randomized, you either received ibrutinib or placebo. So it was a blinded study which I think is really a unique opportunity for us to consider in this field because we don’t have many placebo controlled studies in CLL. And not surprisingly, if you take on the left the group of patients at high risk for progression and you put them on placebo, they indeed have progression, and so I think that the curve on the bottom sort of validates their risk model that most of these patients are going to need therapy. And then the top curve is for the patients treated with ibrutinib and I think it looks a lot like many of the front line ibrutinib type Kaplan-Meier curves that we’ve seen. Importantly, on the right however is the overall survival and although you see a significant progression-free survival benefit, the overall survival really doesn’t pan out in any way. And so I think this does not change anything in the field, but it’s an important question to ask and the answer is no, and that’s actually very useful so a negative study still being very practice informing.

If you dig into the details of the study, there were a lot of treatment discontinuations with the ibrutinib and we’ve seen that play out in other studies, perhaps a little bit more so in this study, but some of the really interesting findings on this, I think that ibrutinib has sometimes been criticized in the field for the number of side effects, but because this is a placebo controlled study, it gives you an opportunity to really dig into that a little bit deeper and you can see that the CTC Grades 1 through 5 are actually virtually all patients. So interestingly, in a placebo controlled study, you’re still getting adverse side effects. And interestingly, if you look at those marked as serious adverse events, they were actually lower with ibrutinib than they were on the placebo study which I think highlights that patients with progressing CLL are developing symptoms and those symptoms can be serious. So disease control does have a meaningful clinical impact for these patients. And most interestingly to me was the second malignancies. You actually see fewer secondary malignancies amongst those patients treated with ibrutinib. Now this wasn’t statistically significant but I think we’ve had questions in the field in many cases about the impact of secondary malignancies for these patients.

Of course, bleeding, cardiac arrhythmias, diarrhea, hypertensive disorders were all more common on the ibrutinib but importantly, if you look at Grade 5 side effects, there were 4 on the ibrutinib arm and 1 on the placebo arm, so it is true that ibrutinib does have serious side effects and, again, emphasizes that I think early use is not necessary for better outcomes as this study shows.

DR LOVE: Did they look specifically at ventricular arrhythmias or sudden death?

DR SHARMAN: I think on this study, yeah, I mean, so they had cardiac arrhythmias and cardiac event other than arrhythmias but whether or not they characterized those as ventricular I don’t think was reported.

DR LOVE: Okay, please continue.

DR SHARMAN: That has come out in a number of other studies though and I think the field agrees that ibrutinib does have ventricular arrhythmias. I think where the debate is right now is whether or not the second generation of BTK inhibitors do. Some studies have argued that there’s methodologic problems to those. Some other studies, ones that are actually in manuscript preparation, have argued against that. So I think there’s debate as to whether or not the second generation of BTK inhibitors have those.

DR LOVE: You had an overview paper I think with acalabrutinib on that didn’t you?

DR SHARMAN: We’re writing one up and we have presented it in poster format previously but the findings of that paper which are not yet published suggest that it’s probably more agent specific than class specific but I think that there are methodologic limitations to all of these efforts to draw definitive conclusions on rare side effects but, again, I kind of tend to think that this is agent specific rather than class specific.

So the second study is a long-term follow-up that comes out of the NIH and this study started before ibrutinib was FDA approved. They were enrolling patients as far as back as January 2012 through January 2014. And the advantage of this study really is the benefit of long-term follow-up and in particular the TP53 subgroup. This study looked at patients — and to get into the study you had to be either above age 65 or have a TP53 alteration. Now we’ve had plenty of studies that have looked at the older population, but we don’t have as many studies that have looked at the long-term outcome of the TP53 abnormal. Of course, that’s the high-risk population in CLL and always has been. For historical perspective, when the CLL8 study was read out which was FC versus FCR, they included patients with 17p, and the overall survival in patients treated with FCR with 17p was really only about 2 to 3 years. So when you look at these data, I think what you want to do is put it in that context, that historical context of how poorly patients did with chemoimmunotherapy.

This study allowed patients who were either treatment naïve or relapsed refractory. The TP53 cohort was a little bit younger. Of course, they didn’t have the 65-year cutoff. And most of these were del(17p). There was a small subgroup that were identified as TP53 mutation in the absence of del(17p).

And key things to look at here, on the left is progression free survival, on the right is overall survival. The red curve is patients lacking the abnormality. The blue curve is those with the abnormality. And I think the key finding here for del(17p) is that you can still get 5 to 6 years of PFS with ibrutinib and keeping in mind that some of these patients were treatment naïve and some of them were relapsed refractory and if you look in the table down below and look at the therapy status for the del(17p), the previously treated or the relapsed refractory, they had a median PFS of just about 50 months whereas treatment naïve, their long term PFS was really quite impressive at 108 months. Now these were highly motivated patients at the time. They were taking their ibrutinib religiously and I think that as we’ve evolved as a field, I think patients and physicians have become a little bit more casual about their use of ibrutinib and so we might not see similar results in a more casually treated patient population but it shows you that BTK inhibition can be very effective. And on the right, we have overall survival by TP53 at 10 years which is just so much better than what we had with prior chemoimmunotherapy from CLL8 and so forth.

If we look exclusively at the front-line treated patients versus — so this is exclusively front line TP53 CLL, you have the PFS and overall survival here and again I think this is just so much better than historical standards that that’s the value of this presentation is the ability to see long term TP53 outcomes.

So I’ll switch then to yet another front line ibrutinib study. This was the English group led by Peter Hillmen and published in The Lancet. This study has — it was kind of interestingly it was an iterative study where they started with a randomization to ibrutinib rituximab versus FCR. They then had subsequent randomizations of FCR versus ibrutinib or FCR versus ibrutinib venetoclax. And I believe you’re going to have Dr Roeker talking about the last one on this group, the ibrutinib venetoclax. That got a lot of attention at ASH this year and was really one of the highlights and published at the same time in the New England Journal. This particular one was the Lancet publication of the ibrutinib rituximab versus FCR. This is very similar to a study that was done in the ECOG group of ibrutinib rituximab versus FCR, so the findings aren’t necessarily enormously surprising but they are shown here. In the top left is the PFS shown with ibrutinib rituximab in favor over FCR. In the English study, bottom left overall survival, no difference between the 2 arms. These studies did exclude 17p naturally but they didn’t see an overall survival benefit. Shown on the right of this is the ECOG 1912 study presented and published by Tait Shanafelt where there was a survival benefit. The overall survival benefit was small so I think that the differences between these studies are probably on the basis of patient selection and the English study had some slightly older patients and so forth. So I don’t think that you can make huge conclusions. There is a survival benefit. In one study, it’s relatively small. It’s not seen in the other study. So we would use these studies to show the PFS benefit over FCR and I think that it’s another study that shows nonchemotherapy based strategies to be advantageous in CLL.

So my conclusions from the ibrutinib studies we’ve presented is that early treatment of high-risk CLL has not replaced watch-and-wait. I think that the placebo side effects relative to ibrutinib are somewhat surprising and if anything provides some vantage point to conclude that any intervention for CLL is going to have side effects and sometimes I think ibrutinib gets a bad rap because, I don’t know, again, put it against the placebo and I think you’re able to see. TP53 mutation or deletion reduces the efficacy of ibrutinib, however, early use remains highly effective, early in terms of with treatment still indicated but using it in earlier lines of therapy. And then ibrutinib is superior to FCR in fit patients with variable impact on overall survival. Yeah?

DR LOVE: I was just going to say that I don’t know, are you aware that there was a Phase III trial in small cell cancer of the lung? I think it was with atezolizumab, or 2 of them, and I think it was placebo controlled. And the incidents of autoimmune side effects in the placebo group was 25%.

DR SHARMAN: Yeah, interesting.

DR LOVE: Does that ring a bell?

DR SHARMAN: Well, it —

DR LOVE: Along the lines of what you were just saying.

DR SHARMAN: Yeah. And as you know, placebo studies in cancer medicine have always been a challenge but in these sorts of studies when you can set up a study with placebo control, it’s very informative and who knows what those immune related adverse events were in that study, whether it was LFTs or who knows, diarrhea or so forth. But that is provocative for sure.

So, moving on to some second generation BTK studies. Our group had the opportunity to present results of the ELEVATE-TN study. Now this is a study that’s been previously reported but this is the 6-year follow-up and the goal of this was to perform some new analyses that I think would be a little bit provocative because the role of CD20 I would say remains very uncertain. We know that from the original Alliance study where ibrutinib +/- rituximab really showed very little with the addition of rituximab. I think the field has largely settled on that view, viewpoint that adding CD20 doesn’t provide benefit. But not all BTKs are created the same, not all CD20s are created the same. We’ve now had plenty of studies to show that obinutuzumab really does have superiority versus rituximab in CLL. And so this was a study where patients were randomly assigned to either standard of care obinutuzumab chlorambucil, acalabrutinib monotherapy, or acalabrutinib with obinutuzumab. And it was an elderly population that would be suitable for obinutuzumab chlorambucil. So, and the endpoints were PFS, OS, and all the standards.

The PFS difference is shown here and I think this was surprising to a lot of people. Keep in mind, patients got 6 months of obinutuzumab and then stopped and really at the initial data presentation, the difference between the 2 arms was relatively subtle. I think a lot of people thought it might go away. But, in fact, that benefit with obinutuzumab has continued to improve with time and now at the roughly 6 year follow-up you see a pretty significant improvement, clinically significant, statistically significant improvement with the addition of obinutuzumab, 78% versus 62%. So a total of 16% difference between the 2. I think that’s pretty meaningful. So we wanted to look into this in greater depth because we wanted to try and understand why and how. One of the things we looked at is how the overall response rate improved over time. We’ve always known that the longer somebody stays on a BTK inhibitor the deeper the responses get. And in the top 2 curves you have, in blue, acalabrutinib with obinutuzumab, and in orange acalabrutinib monotherapy. This is overall response. So you see faster responses with the addition of obinutuzumab. And over time they do narrow as the acalabrutinib catches up but they never actually meet up with one another. And then if you look at the bottom 2 curves which is the complete response, you have a pretty significant difference in rate of acquisition of complete response with the addition of obinutuzumab. And these were statistically significant differences. So you’re getting more complete responses, more overall response with the addition of obinutuzumab.

Now what we did was we actually fused the 2 groups. We said, all right, whether you’re treated with acalabrutinib monotherapy or acalabrutinib with obinutuzumab, does a CR matter? And getting a CR does matter with BTK inhibitors. And that’s something that, in a lot of our early studies — keep in mind BTK inhibitors were used in relapsed patients, we weren’t getting CRs all that often, so these were small subgroups, and we couldn’t really demonstrate any difference. But in this front-line study you can see a pretty significant difference in favor of getting a CR.

So I don’t think that the field has adopted and embraced the addition of obinutuzumab. I think there was always a little bit of concern regarding infusion toxicity and then COVID happened. People were reluctant to use anti-CD20 antibodies. But I think this long-term data shows us that if you’re going to use a BTK inhibitor it’s reasonable to consider the addition of obinutuzumab. I didn’t show the toxicity data in these slides but it didn’t add a ton of toxicity, slightly more infections. And by giving a month of pretreatment of BTK inhibitor, the infusion toxicity is pretty well mitigated. So I think it’s something that can be considered for patients.

DR LOVE: I call this practice-changing maybe. I think people will be shocked when they see this. Did I see that right? So a plus o, versus a, hazard rate was 0.56?

DR SHARMAN: There was a significant difference in PFS hazard ratio.

DR LOVE: 0.58.

DR SHARMAN: Yeah. Yeah.

DR LOVE: So, if you were to play the indirect comparison game, how would you take — knowing that it’s, you can’t do that, but everybody does it. Does this mean that theoretically — how would you compare a, versus a plus o, versus zanubrutinib?

DR SHARMAN: I don’t know. That’s a nearly impossible question to answer and I think a lot of people are even trying to draw conclusions from some of the next studies we’ll look at of acalabrutinib versus zanubrutinib.

Look, the way — often times if you’re choosing indefinite therapy with a BTK, that patient’s to some degree selected because they want ease of care. They may not want to be coming in for infusions. There’s kind of an intrinsic bias against obinutuzumab. But I think that the differences in progression free survival need to be at least brought up for the patient. And, yeah.

DR LOVE: That’s all I’m talking about in terms of practice-changing. Just bring it up. Because if you present this to a 60-year-old patient who’s working, and has a family, maybe it’s worth it to think about that 6 month investment.

DR SHARMAN: Yeah.

DR LOVE: As opposed to —

DR SHARMAN: One of the slides that was a little bit controversial with this 1, and I didn’t present it here, but was the overall survival difference. There’s clearly a statistically significant overall survival difference in favor of the acalabrutinib regimens over obinutuzumab chlorambucil. But the difference between acalabrutinib obinutuzumab and acalabrutinib, almost looks like there’s a survival benefit evolving there as well.

DR LOVE: Wow.

DR SHARMAN: So highlighting your point, yeah.

DR LOVE: Yeah, just, I mean, mention it to the patient, that’s all.

DR SHARMAN: I think it needs to be mentioned. I think that some of the people who spend a lot of time in CLL research in the US are maybe being moved off, moved or maybe a little more persuaded on this. But you get sort of people who are loyalists to various drugs.

DR LOVE: I mean, obinutuzumab’s a great CLL drug I think. I mean, and people aren’t getting it unless they get venetoclax. So I don’t know.

DR SHARMAN: Yeah. Yeah, and if you’re using BTK in the front-line setting, yeah.

DR LOVE: Incidentally, on the other end, how much do you think CD20 adds to venetoclax?

DR SHARMAN: I think it adds some. I realize it’s a question that’s never been formally addressed. There’s been some retrospective efforts that have raised question about the CD20. But, my clinical judgement based upon available data is I think that the CD20 does make a difference, and the type of CD20 makes a difference. And I think the CLL13 study is probably the best way to address that, and I have some slides coming up on that.

DR LOVE: Great.

DR SHARMAN: So with regards to the second generation BTK inhibitors, there’s 2 studies that’ve gotten a lot of press, a lot of coverage. One was the ELEVATE-RR study which randomly assigned patients to either ibrutinib or acalabrutinib. This study was done earlier. You had to have high risk features so del(17p), TP53 mutation, or 11q deletion. And in this study the PFS curves were overlapping and you couldn’t distinguish from an efficacy perspective whether there was a difference. From a tolerability — and that’s what this study was looking at. From a tolerability perspective, you see higher number of discontinuations of ibrutinib shown on the blue curve. This is the probability of remaining on treatment. So you see greater number of discontinuations of ibrutinib. And then what this study was doing was looking at sort of the gross incidents. They were calculating exposure adjusted incidents, and then they calculated this AE burden score. And I think the punchline is, yeah, you see more cardiac events, AFib/flutter, hypertension, bleeding events on the ibrutinib. And then when you adjust for exposure that makes it a little bit more. And so, it’s sort of another analysis of the ELEVATE-RR study demonstrating advantages of a second generation BTK over ibrutinib.

And then of course the other study that’s sort of like hand in glove with this 1 is the ALPINE study which is the zanubrutinib version really of the same study. Now, there were differences in the study and I think it’s important that these study differences are noted. This study occurred later when there was already kind of a growing awareness that second generation BTK inhibitors might be better, easier to tolerate than ibrutinib. In addition, this did not require high risk features. These were slightly earlier patients, so median prior line versus 2 in the other study. And you could, in theory, get acalabrutinib at the time this study was done. You could get it on a commercial basis whereas you couldn’t in the other study. So, how that impacts results I think is hard to really know. And so there’ve been a number of what they call match-adjusted indirect comparisons where both of these studies have tried to kind of make the argument that, well — because the temptation of course is everyone wants to compare acalabrutinib to zanubrutinib. And some people have said, well the ibrutinib underperformed on the ALPINE study or, and then they argue back well no it didn’t underperform. That’s what all these match-adjusted indirect comparisons are.

But this study was really just looking more at long-term follow-up. On the left you see PFS benefit that continues at extended follow-up. And they then look in the del(17p) or TP53 which would have been the group where the ELEVATE-RR study was conducted, right? And here you do see a PFS benefit and that’s been the basis on which people try to do these cross-trial comparisons. And you know, even the nature of your question just a little bit earlier was, how would you compare these? That’s what I think that a lot of people are tempted to do. They performed an analysis and said, well let’s just see how PFS does only on the patients who stay on therapy. Because on the left, you have a consort diagram that shows indeed you have 130 versus 172 patients discontinuing therapy. So let’s do a sensitivity analysis and restrict it only to those patients who stay on therapy so that there’s no impact of discontinuation on the PFS curves. And they continue to show a, you know, modestly improved PFS for zanubrutinib relative to ibrutinib.

Look, I think the take home points from those BTK studies is that the second generation offer some advantages to the patients. I think you have fewer subjective side effects, arthralgias, mucositis in a small number of patients, hypertension, AFib, those sorts of things. They’re just less common on the second generation BTK inhibitors. So I think that’s what you can conclude. Whether or not zanubrutinib versus acalabrutinib have differences, I don’t think either company’s going to sponsor that study and so we’ll be left with cross trial comparisons along the way.

The final second generation BTK inhibitor study is zanubrutinib versus bendamustine rituximab, and this was conducted in patients lacking 17p. So those patients were excluded. I don’t think there’re really any surprises from this study. Zanubrutinib beats bendamustine rituximab. This is a study that was a confirmatory Phase III study that got the drug approved in the front line setting, but I don’t think the findings from this study change much of what we expect about the agent. This particular poster that we reviewed was looking at the various subgroups. And, you know, are there anything that’s interesting here? I think that some of these sort of next generation markers are maybe going to evolve in importance over time. You know, BRAF mutations which we don’t normally think of in CLL as a prognostic or predictive marker, you can see some differences in outcome there. But, these sort of next generation markers haven’t totally been adopted in CLL. So I think this is more kind of an ability to look at a study that got a drug approved and look at some of these finer points.

So the conclusions really, for my second generation BTK was, is that adding obinutuzumab to acalabrutinib results in deeper responses and longer disease control. Patients discontinue ibrutinib earlier than second generation BTK inhibitors and the side effect profiles seem to favor the second-generation agents, and zanubrutinib beats BR in untreated CLL, which really serves a regulatory purpose if not a clinical purpose.

DR LOVE: So, just curious what your preference is for first line BTK nowadays?

DR SHARMAN: So if I’m doing a first line BTK, obviously from experience I have a lot of loyalty to the acalabrutinib regimen. But I think zanubrutinib is also a fabulous drug. Interestingly, where sometimes this plays out is in the copayment support programs for patients. You know, the commercial efforts between these drugs actually have differences.

So it’s not necessarily a clinical distinction. But, as you know, these drugs are very expensive and patients struggle to pay for them. So these are real differences.

DR LOVE: Yeah, but I mean, there’s a message there. If you’re comfortable enough to focus on the finances, I think there’s a message there.

DR SHARMAN: Yeah.

DR LOVE: That there’s not — in your mind there’s not that much difference.

DR SHARMAN: Right. Right. I can’t tell a difference between the 2 drugs from an efficacy perspective, and I don’t think we’ll ever have that answer in any sort of definitive prospective way. But clinically I think they’re more similar than they are different.

So, I’m going to move on to some venetoclax-based studies. And the first one I want to talk about is a long-term follow-up of CLL14. So keep in mind this was obinutuzumab venetoclax versus obinutuzumab chlorambucil and they did change the chlorambucil regimen. They gave it for 12 months so they could match, which is a little bit different than how chlorambucil had been given earlier, but that was to sort of balance the treatments between the 2. This looked at an older less fit population, cumulative illness rating scale of 6 or higher, and again, was looking for kind of a non-intensive chemotherapy group when this study was launched. And on the left is the PFS curve. And I think at this point we’ve largely come to expect that obinutuzumab is going to do better with venetoclax than it is with chlorambucil and that’s demonstrated. I think where this study’s useful is it really does give us a long-term view. And you can see that even at the 84 month mark, you have almost 40% of patients on the experimental arm, PFS. That’s really impressive for a fixed-duration therapy. On the right, they split it out by their IGHV status. And just focusing on the top 2 curves which are both the obinutuzumab venetoclax, not surprisingly, the IGHV unmutated starts to separate where the mutated do better than the unmutated. And that’s always been because the kinetics of growth are faster with the unmutated population than the mutated. So if you’re giving 12 months of therapy, that difference is going to really sort of begin in earnest around 3 years and continue to separate. So if I have a patient who’s IGHV mutated, favorable FISH, obinutuzumab venetoclax is a very appealing option. Because you can even see, you haven’t even reached a median at 7 to 8 years, well about 7 years I should say, in that population. And that’s really impressive efficacy for a nonchemotherapy-based targeted combination.

They did do a multi-varied analysis and 1 feature — you know, 2 of these things are not a surprise, the IGHV mutation status and the del(17p). Of course we would expect those patients to progress earlier. The 1 that was a little bit interesting to me is the disease bulk. So if you have lymph nodes in excess of 5 cm that seemed to have an impact. And I think as we’re evolving, either doublets, whether we’re putting a CD20 with a BTK, or a CD20 with BCL-2, or a BTK with BCL-2, that’s 1 feature I’m looking for in some of these upcoming datasets, to determine whether or not disease bulk has an impact. They showed the overall survival as well. And I think the thing that’s interesting here is, of course patients are generally going to respond to obinutuzumab chlorambucil. But really the overall survival benefit really takes shape at the 4 year mark and starts separating thereafter. So it just highlights the importance of following the CLL studies for a long time, because sometimes the impacts are not seen on the initial findings.

And that actually plays out in the next study I wanted to talk about as well, which is the German CLL13 study which was a complicated 4 arm study. You asked whether CD20 makes a difference and I would cite this study as part of the reason why I think it does. So this was looking at fit patients who were suitable for either FCR or BR because that was the control arm. And then they either got rituximab with venetoclax or obinutuzumab with venetoclax. The commercial name for obinutuzumab giving rise to the G in here. And then there was a third, excuse me, a fourth arm that actually looked at therapy consisting of ibrutinib, venetoclax, and the CD20, so triplet therapy. So chemoimmunotherapy versus 2 different doublets, versus triplet was the main thing. And they had co-primary endpoints looking at MRD at 15 months, and PFS.

And if you look in the top figure here, this is looking at MRD. Now you asked, does CD20 make a difference and you can see significantly different MRD differences between venetoclax when given with rituximab or venetoclax when given with obinutuzumab, those 2 center columns, strongly in favor of obinutuzumab relative to rituximab. Now, in CLL, generally the depth of response correlates to the duration of response. And so we’re going to look at PFS curves here in just a little bit. The bottom part of this is their overall response. So top is MRD, bottom is overall response rate. What’s relatively subtle is the difference between obinutuzumab, venetoclax, and triplet therapy. Maybe a little bit more MRD. Clinical responses appear relatively similar. But keep in mind the ibrutinib is really designed more for long-term disease control than it is the response rate.

So when we look at the PFS curves, this is where I think these long-term follow-ups, again, start to get more impressive. On the left you have PFS by treatment arm. And the difference between red and green is the difference between obinutuzumab versus rituximab. And you see a strong favor of obinutuzumab. What you don’t see, really until the 48 month mark, is any separation between doublet and triplet. And you actually are starting to see some evolution of improvement with the addition of ibrutinib here. So, again, a dataset that I’m looking at longer term to see whether or not triplet, which at this point is not standard versus doublet therapy makes a difference. They show the impacts whether you have unmutated or mutated on the right. And all the patients with mutated are going to do pretty well. The unmutated is where the difference is largely being driven in this group.

So 1 of the questions that comes up is, does fitness matter? Because if you went back just a handful of years and said, how do you select therapy for patients? One of the big questions was their fitness. And this was presented at iwCLL. They looked at how fitness impacts outcome when treated with obinutuzumab venetoclax. And the reality is, it’s largely overlapping. So this is a therapy where patient fitness level doesn’t make a huge difference. And I think that that’s a relevant feature because at least even just a few years ago that was 1 of our key driving determinations as to who to treat with what.

The next study is actually long-term follow-up of MURANO. Keep in mind, this was the relapsed/refractory of rituximab venetoclax versus bendamustine rituximab. This is a 7 year follow-up so folks have largely seen this data. There were a couple new analyses here that I think are useful for consideration. The first — and I don’t know how broadly this is debated, but it’s been a question in my mind is, is it possible that we’re curing anybody with obinutuzumab venetoclax? And the reason I ask that question is, people feel comfortable in CLL saying that FCR can cure a subgroup of patients with CLL. And we’re now seeing studies where obinutuzumab venetoclax is doing better than FCR. And so, it stands to reason, is it possible that some patients are being cured with obinutuzumab venetoclax. Having a long-term follow-up helps us answer that question. And in the relapsed/refractory setting, I don’t think that many patients would raise the question as to whether or not anybody’s being cured by rituximab venetoclax. Now keep in mind, it is rituximab venetoclax instead of obinutuzumab venetoclax and this is in a relapsed setting as opposed to a front-line setting. But what do we see? We see a PFS curve that never really hits a plateau and we’re now out at 7 years comfortably. Overall survival benefit in favor of targeted therapy over chemotherapy. But, looking at these patients who have had sustained MRD negativity, so if anybody’s going to be cured it’s going to be those who are sustained MRD negative. And maybe not surprisingly, they’re the patients with IGHV mutated lacking del(17p). There is a subgroup that’s still MRD negative. The second feature from this study is that they actually did retreat some patients, because just because you’ve had a venetoclax-based therapy, a reasonable question is can you reuse that regimen if it’s fixed duration? And the answer is yes. You can still get response rates. The PFS isn’t nearly as good the second time around. But these would be patients now getting third line therapy in this study because they’ve had to be previously treated to enroll. Then they got rituximab venetoclax, then they’re getting repeat treatment with rituximab venetoclax. But I think it’s useful to know that you can get some disease control for these patients.

There was a study — and I’ll just go very quickly over this 1, that looked at sort of an accelerated ramp-up. You know, the ramp-up has been a problem for venetoclax from a sort of ease-of-use perspective. And this looked at putting patients in the hospital and increasing their dose on a daily basis over 5 days. This was prospective, where other studies have been presented that actually did this retrospectively. And, the quick story is, if they’ve received some rituximab and they’re medium risk to begin with, you could probably do this in some patients. They didn’t see much TLS in this. Where would you use this? I think if you had a patient who you really needed to get on a new line of therapy and the logistics were going to be heavily challenged to get somebody started on venetoclax you could consider putting them in the hospital. This shows that that’s doable. I don’t know how broadly this is going to be used, however.

So the conclusions from venetoclax studies is that obinutuzumab with venetoclax offers fixed duration therapy yielding impressive duration of disease control. Bulky disease may have a lower PFS along with features that we’ve already known to shorten PFS such as IGHV and TP53. Obinutuzumab is better than rituximab when combined with venetoclax and it’s not the first study we’ve seen that. We saw that with chlorambucil way back in, I think the CLL11 study. Any advantage of triplet therapy seems to emerge late and probably best in the higher risk patients. At this point I wouldn’t say that triplet therapy is standard, really doublet therapy. Obinutuzumab venetoclax can be given in both young and fit as well as older patients with comorbidities with similar efficacy. Retreatment is feasible. And accelerating ramp-up schedules remain a consideration if need be.

So, in the final studies I want to address the newest agent that we’re going to be talking about, is pirtobrutinib. Pirtobrutinib is another BTK inhibitor. It’s very different from the existing 3 BTK inhibitors. This 1 is noncovalent. And the pharmacokinetic curve on the left, if you’ve seen the pharmacokinetic curves for the covalent, those are drugs that generally get into the circulation — leave the circulation so you don’t necessarily develop a steady half-life in the covalent drugs but they rely upon their durable binding, whereas pirtobrutinib, more like hypertensive medications or diabetic medications, they’re staying in the system the whole time. So that’s 1 of the differences.

And this study, the BRUIN study, has been presented a number of times, multiple times by Dr Mato and this was looking to look exclusively at the CLL patients. Keep in mind, this was a Phase II study that enrolled 780 patients and so it was across a variety of disease. But this was looking exclusively at those patients previously treated with covalent BTK and then stratifying outcomes based upon whether or not they’d had prior venetoclax or not. So that was the 2 populations they were looking at. The good news is you get very similar overall response curves in terms of waterfall plots, whether patients have had prior BCL-2 or not. You can get responses similarly whether they’ve had prior BCL-2 or not. The overall response rate’s pretty similar, 79.7 versus 83.1. The depth of response, most of these are going to be PRs. So I don’t think you can really distinguish there. The overall response rate is similar. The problem though, is that the PFS does differ. If you’re BCL-2 naïve, median PFS is 23 months. If you’re BCL-2 exposed, median PFS is just about 16 months. I think the field was hoping that pirtobrutinib would give longer disease control than it is. Most of the patients who get the pirtobrutinib will have done so after receiving prior venetoclax and were probably getting a year and change of disease control with the drug. And part of the reason for that is this last paper I want to talk about, which is BTK resistance mutations.

I think a lot of people are familiar with cysteine 481 getting mutated to serine. That was the binding site for the covalent drugs. But what we’re seeing now is several other mutations that are more common, the T474 mutations or the L528 mutations. These are referred to as either the gatekeeper mutations or the kinase-dead mutations, and I think a lot’s going to be told about these in the coming years. In effect, acquired mutations were detected in roughly 2/3 of patients who progressed on pirtobrutinib. A lot of those were within the BTK molecule itself. A smaller fraction were not on BTK, again driving home the importance of BTK itself. The sort of bottom left figure shows where some of the other mutations occurred, TP53, PI3-kinase, PLC gamma. And then on the right is what happens to the mutation load over time. So, interestingly, in the cysteine 481 serine mutation, for most patients decreases while on pirtobrutinib. But these 474 and 528 mutations show up. Now interestingly, you can occasionally see these at baseline. So maybe they’re lurking as a subclone but then they evolve under selective pressure. So where does this become important? Well, the next class of drugs that we’re not talking about today but will be coming along will be the BTK degraders and the thought is that BTK degraders will be overcoming these mutations as well. So whether they do or not I think the future analyses are going to tell us but that’s where people are looking for this story to go.

So pirtobrutinib conclusions, and this is my last slide. Pirtobrutinib offers high response rates but I would say overall modest PFS, and the stratification by BCL-2 prior exposure significantly impacts outcome. And then, finally, BTK resistance is an evolving story in clonal dynamics evolve fairly quickly on these therapies. So I’ll pause there but thanks for letting me present these.

DR LOVE: So, just a couple of follow-up questions there, continuing with pirtobrutinib, what are your thoughts? I know there’re a bunch of studies looking at pirtobrutinib in the first line setting, even combination trials. What are your thoughts about the future or pirtobrutinib in that respect?

DR SHARMAN: So we’ve just had FDA approval of pirtobrutinib in CLL. And the expectation is that that is for patients previously exposed to both a covalent and a BCL-2 inhibitor. There is the pivotal study that is looking at pirtobrutinib versus investigator’s choice of idelalisib or bendamustine rituximab among patients previously treated with a covalent inhibitor. There has been a press release that that study met its endpoints. The data has not been presented yet and I think look for that at an upcoming conference. There’s another study in the relapsed setting where pirtobrutinib is added as a third agent to rituximab venetoclax. So essentially take the MURANO plus or minus pirtobrutinib and that study is ongoing. There is a study of pirtobrutinib versus ibrutinib in the front line setting. The challenge there is we do know that covalent inhibitors work after — excuse me. Noncovalent inhibitors work after covalent inhibitors. We don’t know whether putting a noncovalent inhibitor earlier would yield an overall PFS better than the sequence of the 2. So I think there’s some hesitation to move pirtobrutinib earlier. We will be getting a readout in Mantle cell lymphoma where pirtobrutinib is compared to investigator’s choice of 3 different BTK inhibitors. So that may be informative in the same way that zanubrutinib was versus ibrutinib in Waldenstrom’s. Sometimes you borrow across disease states. Nemtabrutinib is yet another noncovalent BTK inhibitor and it has studies that are relatively similar. But again, I think it’s not just PFS 1 but PFS 2 plus PFS 1 that’s going to be important. So, I’m hesitant to move it in the front line yet.

DR LOVE: I’m kind of curious in terms of tolerability of pirtobrutinib. The data looked good and kind of people say things that are good but I’m curious how many people you’ve treated with it roughly?

DR SHARMAN: I’ve treated probably less than 10 but enough to feel like I have a feel for the medication and I will say that it is very well tolerated. Patients generally speaking are not complaining of the drugs as they were maybe first generation BTK inhibitors and to a lesser extent second generation BTK inhibitors.

DR LOVE: Anything you see in the data or even hence in your personal experience to suggest there might be any tolerability toxicity advantages of pirtobrutinib over the acalabrutinib or zanubrutinib?

DR SHARMAN: I think the biggest question of the field is how much AFib is a class effect versus a agent specific. There’s no question that AFib is less frequent on second generation than first generation. I think the data for pirtobrutinib is still early enough and we haven’t seen direct head-to-head comparison against the other agents to be sure. I think the clinical sort of feel is that it doesn’t seem to trigger AFib, but I really want to wait and see what the data shows.

DR LOVE: Just kind of curious, when you have people on second generation BTK inhibitors, how often do you see people who’ll go, doc, are you really giving me anything? I don’t feel anything at all.

DR SHARMAN: With the second generation BTK inhibitors that’s more common than the first generation. The first generation, those patients were aware of it. You know, Neil, there’s such an interesting thing though, and this is true across all of cancer medicines, I think there’s an existential piece of taking drugs on a daily basis. And the things that drive me nuts, totally drive me crazy, are the way we educate patients regarding these drugs, right? They come in like biohazard bags. We tell them, like, don’t handle these drugs but go ahead and swallow them. People get told flush the toilet twice and, you know, things that are holdovers from a bygone era of treating cancer and I can’t blame patients if we’re treating them in this context that they get skeptical of their medications and they don’t like the “poison”. And these patients come back and they tell me, well I’m taking chemotherapy, and I’m like no, we had a huge discussion. This is not chemotherapy. But even with my best efforts I think that sometimes the perspectives are that any treatment of cancer is chemotherapy.

Future Directions in the Care of Patients with CLL — Lindsey Roeker, MD

DR ROEKER: Hi, my name is Lindsey Roeker. I am an Assistant Attending at Memorial Sloan Kettering Cancer Center in New York City and the CLL Program Director here. And today it is my pleasure to talk to you about future directions in the care of patients with CLL, and we’re really focusing on updated data that we’ve gotten throughout 2023, and there will be 3 major focuses today. So the first section will be looking at novel/novel combinations, the next will be looking at new agents under development, and then last we’ll look at advancements in the treatment of Richter’s transformation, which is definitely an area of unmet need in CLL.

So without further ado we’re going to start with doublet and triplet therapy. So this is a series of presentations, papers, abstracts that really focus on novel/novel combinations, meaning BTK inhibitor plus venetoclax-based combinations.

The first study is maybe in my mind some of the most exciting data that we had presented in 2023, and this is the FLAIR study. So FLAIR has an adaptive design, it’s a really cool study, where we’re looking at multiple parallel arms, so there was FCR, there is ibrutinib with rituximab, there’s ibrutinib monotherapy, and then ibrutinib with venetoclax. And this is an analysis of ibrutinib and venetoclax versus FCR.

So the primary endpoint here is progression-free survival, and this is our look at these data. So patients who required front-line therapy with CLL who were no older than 75 and did not have more than 20% of a deletion 17p by FISH were randomized to receive either 6 cycles of FCR or ibrutinib and venetoclax. And this was given for a total of 2 to 6 years, and it was MRD adapted. So we’ll talk about how the duration of therapy was determined based on this study at the next slide.

This is the schema that shows us how we think about therapy duration for the study. So patients had serial MRD checks by flow with a 10-4 sensitivity throughout their treatment duration. And when a patient was found to have undetectable MRD they then had a repeat test 3 months later. If that one was undetectable then they had peripheral blood and a bone marrow biopsy 6 months after that first test. If all 4 of those tests were undetectable then the first timepoint where it's checked was where they were considered undetectable, and they received therapy for twice that duration. So if it took a year to be undetectable you get 2 years of therapy. If it took 3 years to be undetectable you get 6 years of therapy.

And the idea here is based on some modeling that suggests that not only are we trying to get people MRD negative, but we might be able to achieve a functional cure with the idea that if you really drive the CLL into such a deep remission that there are only miniscule numbers of cells left, then potentially you could have this functional cure, and that was the idea that this study was built on.

So a look at the outcomes data. These arms were fairly well balanced in terms of baseline characteristics, as well as high-risk features. There were a couple tiny little differences here, so trisomy 12 was a little bit more common in the ibrutinib and venetoclax arm, normal karyotype a little bit more common in the FCR arm, but overall pretty well balanced.

And on the bottom left-hand side you will see the primary endpoint. So this is progression-free survival. Blue is I + V, the red is FCR. You can see that I + V has a really significant progression-free survival benefit with a hazard ratio of 0.13.

In an interesting turn overall survival is actually also improved for I + V over FCR. So you can see that there were 9 deaths in the I + V arm, there were 25 deaths in the FCR arm, and that is a significant difference. So we see both a significant improvement in progression-free and overall survival, particularly for unmutated patients.

So when they broke it down into looking at those with mutated patients the progression-free and overall survival benefit actually isn’t there, but they then also broke down by cytogenetics and found that regardless of cytogenetics there is a significantly improved PFS. So particularly for those with unmutated FCR and regardless of cytogenetics there is a progression-free survival and overall survival benefit of I + V when compared to FCR.

And I think this is a great study because that control arm is a real treatment. We’ve seen a lot of things compared to obinutuzumab and chlorambucil or treatments that we’re really not using, and FCR I think was a solid control arm in this study. So that’s an overview of FLAIR.

DR LOVE: Just curious of the obvious question is where would, for example, BTK alone fit on that curve or where venetoclax with obinutuzumab fit on that curve.

DR ROEKER: Absolutely a great question, and ibrutinib arm is within FLAIR. The study design is there were prespecified analyses here, so I don’t know that we’re going to have kind of that head-to-head BTK monotherapy versus venetoclax/obinutuzumab. That certainly will not be answered in this study, but I think that is like one of the most important questions and one that we really do need the answer. So it’s a great point, like that doesn’t help us really answer that question.

DR ROEKER: The next study that we’re going to look at is CAPTIVATE. So this is a Phase II study that has a really cool study design. There were both fixed duration and MRD-driven cohorts. So for the fixed-duration cohort everybody got 15 cycles of ibrutinib and venetoclax. For the MRD-adapted cohort you get 15 cycles of I + V and then based on your MRD status you’re randomized to different arms.

This was an updated analysis with additional follow up, and the focus was really on those who had received fixed-duration therapy. So it included all of the fixed-duration cohort plus that number of patients who had been randomized once they had undetectable MRD to receive a placebo because in practice they only received those 15 cycles.

So there were 202 total patients who had received fixed-duration ibrutinib plus venetoclax, and they’ve seen 53 progression events; so 49 with CLL and 4 with Richter’s transformation. And one of the big questions in these combination therapies is what do we do when people progress. Is it feasible to utilize these novel agents again? Because obviously if we use all of our best drugs up front and can’t subsequent retreat people that’s a problem.

So this was the first look at how do we — or a look at how we can retreat people. This is a look at basically the patient who did versus did not progress in the line on the left — or in the table on the left. And you can see that the patients who did progress had higher-risk features. I think that’s unsurprising, right, people who have higher-risk disease have their disease come back quicker. And on the right-hand side we see for those who did progress when they progressed. And we can see that complex karyotype and deletion of 17p, those are the patients where progressions tend to happen more and tend to happen earlier, so in that first 2 years.

They also in this study collected 40 patient samples at the time of progression and did not find any BTK or PCLγ2 mutations, which is a big question, like if you receive that fixed-duration therapy are you going to be resistant to BTK retreatment. There was 1 BCL2 mutation identified in this cohort of 40 patients. It is the noncanonical one, so it’s not the mutation that we know confers resistance to venetoclax. This is a mutation that’s always been described as co-occurring with the canonical mutation, so the clinical significance of this I think still needs to be worked out, but there was 1 of those observed.

Here’s a look at the overall progression-free survival with this 5 years of follow up. You can see that there’s a numerically shorter progression-free survival for those with complex karyotype and deletion of 17p in this cohort, and then they looked at the retreatment data. So in those patients who had progressed they were retreated, 21 with single-agent ibrutinib, 6 received ibrutinib and venetoclax, and here you can see that the overall response rates are really, really high. The patients treated with ibrutinib who are not recorded as responders there were reasonable reasons for all of them. One was like nonevaluable. One unfortunately had a Richter’s transformation. There was a COVID related like unable to assess response, that kind of thing.

So fixed-duration I + V we think might mitigate the risk of developing resistance mutations. If people are receiving fixed-duration therapy they’re not necessarily progressing, acquiring these resistance mutations, and patients can be successfully retreated with ibrutinib-based therapy. So I think this provides a lot of reassurance regarding the approach with dual novel agent approaches.

Now we’re going to move on to GLOW. So CAPTIVATE was a Phase II study. GLOW was the big Phase III study. A bit of a different population. So the patients in GLOW are older, have comorbidities, and this is a Phase III randomized study. So they were randomized to receive either I + V for a fixed duration, this is 15 cycles, or chlorambucil and obinutuzumab, and patients were randomized 1:1. This is an updated analysis, so we now have up to 55 months of follow up with the GLOW study.

Here’s a look at progression-free and overall survival. So progression-free survival obviously significantly better with I + V. Initially the overall survival curves had looked concerningly like the survival for I + V, had been lower than chlorambucil versus obinutuzumab. Those curves have now crossed. So with 54 months of follow up the estimates are 85 versus 64%, so seeing some updated follow up there where those curves are splitting even a bit more.

They then looked a bit more into landmark analyses from the end of therapy. So they’re looking at MRD status at the end of therapy and how that predicts ongoing progression-free survival.

So everybody in this analysis got to the end of that 15 cycles ibrutinib and venetoclax or the 6 cycles of chlorambucil and obinutuzumab. And you can see the red curves are ibrutinib and venetoclax, the black curves are chlorambucil and obinutuzumab, and it’s stratified by MRD status. So the darker curves are undetectable MRD, the lighter curves are MRD detectable. And for I + V, regardless of whether you achieve MRD or not, you are doing better than if you received chlorambucil versus obinutuzumab. Think that’s not particularly surprising.

We do see the difference between those who had achieved versus not achieved undetectable MRD at 42 months is 78 versus 70%. So you can see kind of the differences there based on how deeply patients respond.

They then went on to look at even more landmark analyses to really suss out like who is benefitting, how do we need to achieve undetectable MRD, that kind of thing. So the top curves look at based on IGHV mutational status, and I think the big take-home here is that mutated IGHV patients, regardless of whether you achieved MRD undetectable status or not, do very, very well. So the mutated patients are those top 2 curves, the dark blue one and the light blue top one. The patients who had unmutated IGHV who received — who achieved undetectable — sorry, undetectable MRD do better than those who are MRD detectable. So especially for the unmutated IGHV patients MRD status really does matter.

And then we’re looking at time to next treatment, and the same kind of theme emerges here. So for mutated IGHV patients do very, very well, unmutated IGHV patients who are treated with ibrutinib and venetoclax do very, very well, and unmutated patients should not be receiving chlorambucil and obinutuzumab. So chemoimmunotherapy for that cohort is not the right choice based on these data.

So overall this is telling us that MRD status at the end of treatment predicts PFS, especially for those with unmutated IGHV. It seems to be a less significant predictor for those with mutated IGHV. And we see that I + V improves time to next treatment for those with unmutated IGHV versus chlorambucil and obinutuzumab.

The thing that I’m trying to figure out is — I’ll tell you the real question I have. I don’t know why I never noticed this before.

But the real question I have is why do you see in less than 5 years 37% of these people dying in the control group. Do you see people die of CLL like that?

DR ROEKER: This was through COVID. It’s a high proportion for sure. It was through COVID, so I think that’s part of it.

DR ROEKER: So there were 19 deaths in I + V, and there were 39 deaths in chlorambucil and obinutuzumab. Of those 39 deaths 13 were infection related in chlorambucil/obinutuzumab, 7 were second primary malignancies, 4 were cardiac, 4 were sudden or unknown. Progression was very rare cause of death, so that was only 2. And vascular disorders were 3. And then in the I + V arm there were 3 infection-related deaths, 3 sudden or known deaths, 1 progression of disease, 2 vascular disorders, and 2 other. So a significant difference in overall survival with a hazard ratio of 0.453; that has a significant p-value.

And then in terms of deaths we’re seeing excess infection-related deaths in the chlorambucil/obinutuzumab arm. We’re seeing more second primary malignancies in the chlorambucil/obinutuzumab arm.

DR LOVE: So in summary I would say this trial showed a very significant effect not only in PFS but also in overall survival except — difference, except that most of the deaths were not from CLL.

DR ROEKER: Yeah. The CD20 effect in the subsequent risk is real, and I think that we really learned that lesson through COVID.

People were very hesitant to use CD20 antibodies through COVID. I think a lot of our primary concern was about ability to respond to vaccines, but I think this proves — this is a big deal. Like it’s bad when people have CD20s in terms of their infection risk, especially in the setting of a pandemic.

DR LOVE: When the data was presented did they discuss that or bring that up in the discussion?

DR ROEKER: Yeah. So they went through the summary of deaths. The COVID-related deaths were 2 on the ibrutinib/venetoclax arm, 7 in the chlorambucil/obinutuzumab arm, so there’s a difference there. But it’s total infectious related deaths was 3 versus 13, so there’s also other infections that were not — are not directly COVID related but infection-related deaths.

So next up we’re going to look at a relapsed/refractory study, and this is an update with up to 4 years of follow up. Patients received 15 months of ibrutinib and venetoclax, and then the next steps were dependent on MRD status. So those who were MRD positive at that point continued ibrutinib monotherapy. Those who were MRD undetectable were randomized in a 1:2 ratio to continue ibrutinib versus observation with venetoclax and ibrutinib retreatment upon MRD relapse. So this did not require CLL progression according to iwCLL. If they had an MRD relapse they were retreated at that point.

The primary analysis was done when the last patient reached 27 months, and that had shown a favorable risk/benefit profile of MRD-based cessation of ibrutinib and venetoclax. The primary endpoint had already been reached, and the progression-free survival post stopping in Arm B, meaning the patients who had stopped and then retreated, was 98% at 12 months.

So here we have a look at the patient characteristics. So we see the full cohort of 225 patients. And breaking this down 72 patients had achieved undetectable MRD and were randomized either to Arm A or observation. So I’m going to pull up the curves and show you that basically Arm A, the ibrutinib continued patients, were in blue. The green arm is those who went into observation. And then the red arm are those who continued ibrutinib maintenance, so that was either because they were MRD detectable or they went off protocol before randomization. So that was a total of 37 patients. We see 153 altogether in that cohort.

And we can see that overall and progression-free survival for those who achieve undetectable MRD, regardless of whether they’re randomized to continue ibrutinib versus treatment cessation with retreatment at MRD relapse, is excellent. So that’s reassuring. Those who do not achieve undetectable MRD notably have an inferior overall and progression-free survival, so we’re seeing that.

We also see the time to next treatment on the right-hand side, and we see that those who were not randomized, meaning they had detectable MRD at the end of those 15 cycles, did have — the proportion requiring retreatment was higher.

Here’s the safety at 3 years after the 15 cycles of I + V. Those who continued ibrutinib had a 31% discontinuation arm, so this is the patients who remained MRD detectable. About a third stopped. The most common reason was because of toxicity. For the patients in Arm A, meaning they had achieved undetectable MRD and then were randomized, 54% had discontinued. Again, the most common reason was toxicity. So we’re seeing that theme that we’ve seen before in terms of prolonged BTK monotherapy can be associated with toxicity.

Here’s a look at treatment reinitiation, and I think reassuringly we’re seeing that for patients who are observed after I + V and are retreated many are able to achieve really deep responses. So 40% of the patients experienced an MRD relapse. There were some who came off therapy. So of the 19 who had MRD relapses 4 of them are off protocol, but of those patients who had the MRD relapse the median time to that relapse was about 2 years. And we see that the patients who relapsed were enriched for the high-risk features, so TP53 aberrations and complex karyotypes. And patients are able to achieve deep responses, so 47% actually were able to achieve an undetectable MRD state when they were retreated with I + V.

So overall these data show us that patients who achieve undetectable MRD and stop therapy do very well. They can stop, and then they can in many cases be successfully retreated upon MRD progression, which I think is similar to the lesson we had learned with the earlier data set. So reassuring.

The next study is an Alliance study. And we see this is a Phase III looking at older adults who were randomized to receive ibrutinib/obinutuzumab versus IVO, so ibrutinib, obinutuzumab, and venetoclax. And we’re seeing that for those who received ibrutinib and obinutuzumab they continue ibrutinib regardless of response. For those who received the triplet therapy and achieve undetectable MRD those patients discontinue ibrutinib. Anybody who has detectable MRD does continue ibrutinib, so MRD stopping role here. And primary endpoint was progression-free survival.

This study was designed to detect if IVO improves progression-free survival compared to ibrutinib/obinutuzumab. And the data released were released after the study met its predefined futility threshold, so the hazard ratio was predefined, and these data were released because of that. So we’re actually seeing that there is not a benefit to IVO over ibrutinib/obinutuzumab, so the triplet does not improve outcomes versus IO — and for the treatment of older patients with CLL.

And interestingly, COVID-19 was the leading cause of death in both arms. So there were 11 COVID-related deaths in the ibrutinib/obinutuzumab arm versus 19 in the ibrutinib/ven/obin arm, with 13 and 11 additional deaths from other causes respectively. So here you can see the progression-free and overall survival curves, where IO is maybe — they’re not significantly different, but we see that IO is maybe a little bit on top.

If we censor out the COVID-related deaths they’re actually entirely overlapping, so there were more deaths observed in those who had received the triplet versus doublet. And the progression-free survival for patients treated with IVO was not impacted by either MRD or response status. So these data suggest at least for older adults the triplet does not provide benefit over the doublet, especially in the setting of a pandemic I guess is what we’re learning from this.

So the next study we’re going to be looking at is the CLL2-BAAG trial, and this is a study of acala, ven, and obin in relapsed/refractory CLL. And this is follow up data that’s looking at efficacy, as well as circulating tumor DNA analysis, which was a fun topic to explore at ASH this year.

So patients receive optional debulking with benda, then they undergo the induction therapy, which is considered obin in cycle 1, addition of acala in cycle 2, ven in cycle 3. And then patients are treated until they achieve undetectable MRD with a max of 24 cycles of maintenance, so that maintenance starts down the road, and the primary endpoint here was undetectable MRD. 76% of patients had achieved undetectable MRD after 6 months of triplet therapy. And here we are taking a look at the efficacy data.

So we see that the median treatment duration, which was guided by MRD, was just under 15 months, and this is a curve looking at the time to undetectable MRD in the peripheral blood. So we’re seeing that patients are able to come off therapy relatively soon and that the rates of undetectable MRD in the peripheral blood are very, very high with this triplet.

7 of the 10 patients with positive MRD after that first induction period then achieved undetectable MRD during maintenance. So for the patients who are not getting there it does seem like further therapy allows for deeper responses in a majority.

And here’s a look at progression-free and overall survival, which at 30 months estimates is obviously excellent with 100% overall survival and 88% progression-free survival.

So my take-home here is that treatment with AVO in a relapsed/refractory population is able to achieve high levels of undetectable MRD. And then some of the data that the authors had presented was about the ctDNA, and this was showing that for the patients who have molecular relapses we catch some of them with MRD but not all of them, and ctDNA does seem to enhance our ability to detect early molecular relapses beyond what we’re able to detect only with MRD testing.

DR LOVE: I’m so glad to see this slide because literally when I sat down this morning I had already written out the question I’m about to ask you. Imagine you’re talking to a medical student, not even a fellow, and can you please explain, I know this seems crazy, what exactly you do when you test for MRD versus ctDNA. Like what’s the difference?

DR ROEKER: Great question. Yeah, totally. So MRD you’re looking for CLL clones that are circulating, so you’re looking for the actual disease cells in the peripheral blood.

DR LOVE: Cells.

DR ROEKER: So you can do that by flow, where you’re detecting based on the immunophenotype of the cell, or you can do that by clonoSEQ or next-generation sequencing testing. And that is a look at IGHV mutational sequencing, basically, and I think of this as a barcode. So like you get a barcode at baseline, and then you scan all of your blood cells, and you say per million nucleated cells can we find any cells with the barcode that matches the disease barcode. And that’s your MRD test.

ctDNA is looking for free DNA. So this is more of a look at nodal relapse is the thought process. So you’re not actually having the cells circulating through the blood, but there are cells somewhere, and that might be a nodal or a splenic compartment, and ctDNA seems to pick that up.

The next study I want to bring up is actually a trial in progress. So this is a combination of zanubrutinib and venetoclax, so the third approved BTK inhibitor. We’ve talked about ibrutinib, we’ve talked about acalabrutinib, this is zanu with ven, the doublet. And the idea here, this is an IIT where they’re looking at — the patients receive zanu and ven up front, and then if they — the next steps are dependent on the MRD status, so those who are undetectable are observed. Those who have detectable MRD then actually have the addition of obinutuzumab.

So maybe we don’t need this triplet for everybody, maybe we should be adding in the obinutuzumab when we’ve proven that they need it after doublet therapy. And that’s the idea behind this protocol. It will be very exciting to see kind of how successful this approach is and how patients do with this.

The next combination that I want to bring up is the combination of pirtobrutinib with venetoclax with or without rituximab. And these are data from the Phase IB study. So this was BRUIN, which was the Phase I/II study that led to the approval, FDA approval, for pirtobrutinib for relapsed/refractory CLL. This was a relapsed/refractory population. Patients could have received a prior covalent BTK inhibitor if they did not receive a prior BCL2 inhibitor. And this was the Phase IB portion where patients received either PV (pirto and ven) versus PVR (pirto/ven/rituximab), and it was 15 patients in the doublet arm, 10 in the triplet arm.

And here’s a look at baseline characteristics. So the groups were fairly young, with a median age overall of 66, people had good performance statuses, about two thirds had received a prior BTK inhibitor. And we saw some CYS481S mutations in this cohort, so 40% had CYS481S mutation.

Here’s a look at the waterfall plot for these patients. So the doublets are on the left. The triplets are on the right. You can see that the overall response rate is 96% for both of these arms. They’re not meant to be compared. And here’s a look at progression-free survival. So patients did well — relapsed/refractory patients did well with this doublet or triplet. 71% were able to achieve undetectable MRD after a year of therapy, and all patients received 2 years of therapy and then stopped.

This is a combination, the PVR combination’s actually being explored further in a Phase III study. And thinking about safety, there were no DLTs in either arm. With the doublet arm there were a couple of cases of tumor lysis syndrome, and this might be because there was a relatively short lead-in with pirto, so that has been addressed in the Phase III. And I think we’ll see a safe combination that will be compared to venetoclax/rituximab, the MURANO regimen, to really inform treatment in the relapsed/refractory setting. So overall pirto and ven with or without rituximab seems to be very effective, with high overall response rate in a relapsed/refractory population, and there were no DLTs observed.

Okay. Now shifting gears a little bit. We’re going to look at some new agents in CLL. So we’ve talked a lot about combination therapies. Here we have nemtabrutinib. So this is another noncovalent BTK inhibitor, and this was a paper that was published in Cancer Discovery. We see the Phase I data was of this agent being used in 47 patients, 29 of whom had CLL or SLL. You can see the baseline characteristics here.

I’ll draw your attention to the fact that there were a lot of patients pretreated with BTK inhibitor — covalent BTK inhibitors, including acala and ibrutinib. 82% of the CLL patients actually had a BTK mutation going into this. We see that the overall response rate in CLL is 36%, but that’s for the whole study. For those who had received at least the recommended Phase II dose the response rate was 75%, and the median progression-free survival was just shy of 17 months.

In terms of toxicity we saw some heme toxicity, so anemia, higher-grade anemia at 11%, higher-grade neutropenia in 24%, higher-grade thrombocytopenia in 13%. Most common non-heme AEs were weight gain, cough, fatigue, and back pain. So we’ve got another noncovalent BTK inhibitor that is being developed and has activity in CLL regardless of CYS481S status, as well as in other non-Hodgkin’s lymphomas.

The next study I want to highlight is looking at liso-cel. So this is 24-month median follow up of TRANSCEND CLL 004, and this is a look at liso-cel. So patients with relapsed/refractory CLL had their cells manufactured, received lymphodepletion, and then received liso-cel. The primary endpoint was CR or CRi rate, and there was also a look at secondary endpoints, including overall response rate and undetectable MRD rate.

And there was a look at basically the full study population, which included 137 patients, and then also those who had progressed on a BTK and had had prior venetoclax with failure, and that was a specific cohort that was evaluated. The primary endpoint was the CRi rate in that double-refractory population, so starting out with 82 patients, but once you get to the patients who were efficacy evaluable it’s 54. You can see that in the full study population 60% had progressed on a prior BTK inhibitor, 100% in this double-refractory population.

Here’s a look at the full study population on the left and the double-refractory population on the right. I think some of the key take-home points here are that those responders do incredibly well, but the rate of response is somewhere in the 20-ish-percent range. So the CR rate is about 20%. The overall response rate in the double-refractory population was 44%, and the overall response rate in the full study population was 48%.

So we see that for those who respond they do very well and have durable remissions. And that’s kind of my take-home here. You can have double-refractory disease, and if you achieve a CR with liso-cel you do have that prolonged progression-free survival.

Next up we’re looking at sonrotoclax, which is a second-generation BCL2 inhibitor, and this was studied in combination with zanubrutinib. This is an ongoing Phase I/II.

So patients were getting sonrotoclax as monotherapy as part of the study, but this report is really looking at the combination of therapies. And there was a dose escalation for sonrotoclax, and then the expansion was exploring 2 different dose levels, so 320 versus 160, along with zanubrutinib at standard dosing.

Here’s a look at the baseline characteristics. So median follow up at this point is about just shy of 10 months. Patients were overall young, and the proportion with high-risk disease was like 25% had TP53 aberration, 62% had unmutated IGHV.

Here’s a look at the safety. So we see that AEs were common with this combination, and we did see some dose holds with relatively few discontinuations, so only 1 patient required a dose discontinuation.

Here’s a look at the toxicities. Overall lots of low-grade stuff, but high-grade toxicity really only included neutropenia and then hypertension.

And here’s a look at the overall response rate, which is 100%, so incredibly effective. This is a look at MRD, and we can see that there are really high rates of MRD undetectable status, as well, with 100% achieving uMRD at that higher sonrotoclax dose level by week 48. So overall a really effective combination.

Here’s the PFS curve. It’s always good when those look like straight lines. So here we see that this is incredibly effective.

This is given as a continuous therapy, so a little bit different than some of the combinations that we had seen previously.

So overall sonrotoclax and zanubrutinib is well tolerated with low rates of high-grade toxicity, and the overall response rate is 100% with this limited follow-up.

And now we’re going to finally go into the Richter’s transformation section of this. So we know that Richter’s transformation is a tricky situation, and patients often do not do particularly well with chemoimmunotherapy. so looking at some new approaches.

The first is a study called MOLTO. So patients received obinutuzumab, atezo, and venetoclax, and this was a study done in 28 patients. You can see the schema on the right-hand side in terms of when patients received what. But this was all previously untreated Richter’s, so this is a front-line study.

And here’s a look at the baseline characteristics. So in terms of this patient population the prior lines of therapy for CLL the median was 1, and the time from CLL diagnosis to Richter’s was about 4 years. We then see the baseline biological characteristics in the bottom of this table, so about half have a TP53 — just under half have a TP53 aberration, and just under half have complex karyotype.

Here’s a look at the swimmers’ plot. So you can see that patients received this triplet combination in the blue line, if patients progressed we can see what they — that they received second-line therapy, and we do have a number of patients who have remained alive in continuous remission and also some who have undergone curative intent allogeneic stem cell transplant.

So out of the 19 responders 40% are in a continuous remission — sorry. Out of the entire population 40% are in a continuous remission, so we’re seeing some efficacy here.

So obin, atezo, and ven has activity in this untreated Richter’s transformation population with an overall response rate of 68% and a median PFS of 16 months, which compared to chemo — historical chemoimmunotherapy studies is favorable.

So the next study I want to look at is also in Richter’s transformation, and this is a combination of tislelizumab, which is an anti-PD-1, as well as zanubrutinib, so the combination of these therapies. Patients could have received no prior lines of therapy or 1 prior line of therapy, and they received 6 cycles of induction followed by 6 cycles of consolidation. For those who achieved a response or at least stable disease they could continue until progression.

And here’s a look at baseline characteristics. So median number of prior lines of CLL-directed therapy was 3. We see that complex karyotype was present in under half. And in terms of high-risk cytogenetics 20% had (del)17p, overall 35-ish-percent had either a TP53 deletion or mutation.

Most patients had prior exposure to a BTK inhibitor or a BCL2 inhibitor, no one had prior RT-directed therapy, and all of these patients had large cell histology. So we did not see any Hodgkin’s transformations in here.

Here’s a look at the swimmers’ plot. The overall response rate was 58%, and the 6-month duration of response rate was 75%. One-year overall survival is 75%, so median PFS about 10 months, median time to next treatment about a year. So this is a combination that does seem to have activity with median PFS of 10 months, which provides us another option for patients with Richter’s.

Finally we’ll look at pirtobrutinib. So this is in Richter’s transformation, and this is looking at a single-agent drug in Richter’s. And patients here we can see that the median number of lines of prior CLL-directed therapy was 2. The median prior lines of Richter’s-directed therapy was also 2. Patients were eligible up front if they were considered chemo ineligible, but everybody else had received chemotherapy.

So this agent shows that the overall response rate’s about 50% with a CR rate of about 13%. You can see the waterfall plot on the right-hand side. And we see that with about 10 months of follow up the median duration of response is 7 months. So this is a great bridge for patients. I don’t think it’s a durable answer, but it does seem to have single-agent activity in Richter’s, which is a situation where patients often don’t have a lot of options.

And with that I want to conclude and thank you all for your time and attention.

DR LOVE: Another random question as I was listening to you, any situations where you have or would try to access pirtobrutinib for transformed disease outside a trial?

DR ROEKER: I have used it, yeah. So it’s not a durable solution, but some of those — like I’m a little bit biased because I treated a lot of patients on BRUIN, and some of those longest lines in the swimmers’ plot were my patients, so I’ve actually had quite a bit of success with that agent. I’ve used it as a bridge to get to transplant. I’ve used it as a bridge to get to CAR T. I think that it does have a role in Richter’s, and I think that the single-agent efficacy for people who end up getting fairly beat up from chemoimmunotherapy in a lot of situations is really incredible.

DR LOVE: So another kind of random question. Do we have any data on covalent BTK after pirtobrutinib or other noncovalent?

DR ROEKER: Great question. No. But that is actually the topic of a study that I think is going to be done. So it’s going to be looking at acala after noncovalent.

DR LOVE: Have anecdotal responses been seen? Have you ever tried it?

DR ROEKER: I have an N of 1 who had — I have a patient who had received ibrutinib like a long time ago, had developed a CYS481S mutation, was on BRUIN, progressed through BTK — through noncovalent BTK then was treated with venetoclax; in the process of being treated with venetoclax actually had the BTK mutation disappear and now has relapsed with CNS disease. So because of that I’m treating with ibrutinib, which you know has CNS penetration, and I’ve proven through CNS biopsy that he does not have CYS481S mutants in his brain, so I’m now treating with ibrutinib monotherapy, and he is responding.

DR LOVE: Wow. Wow. Great case.

DR ROEKER: Which is pretty incredible because we tried some other things before we got to ibrutinib that didn’t go so great, so we’re pretty excited about that response.

DR LOVE: I think of these things, I know they’re completely irrelevant, but like in lung cancer they started out with a TKI for EGFR and then they got a much better one, osimertinib.

DR ROEKER: Yeah.

DR LOVE: But then there were situations where people relapsed on osimertinib, and they responded to the first line, which seems counterintuitive, but I was just curious if we knew that.

DR ROEKER: It totally does, and I think that’s going to be really important data as we figure out all of our sequencing questions for sure.

DR LOVE: Another question. I’m really ruminating a lot on this survival thing that we were thinking about because outside of CLL, in the general medical oncology realm in terms of how people view CLL, I mean I think people view that it’s great because you can keep them feeling good, et cetera, but you’re not going to affect their mortality. But I’m wondering, maybe you really are affecting their mortality, and maybe it’s not enough to pick up in the trial, but the way you’re affecting it is through infections, particularly if there’s something like COVID going on. It’s like a different concept.

DR ROEKER: I think that is entirely true.

DR LOVE: It’s almost like visualizing treatment as like a palliative versus more substantial, and I think that maybe that’s happening.

DR ROEKER: There is a piece of this that’s real. I mean there are a lot of patients who do great with CLL for sure. There are also patients who don’t, and I think the infectious risk, that’s a real thing. And I think that we’re also seeing that treatments have toxicity, and some of it’s not like these on-treatment toxicities where they’re having cardiac toxicity and dying while they’re getting therapy, but there are long-term implications of what we choose, and I think that that is going to — it’s going to be interesting to see. I mean the doublet versus triplet combination proving that triplets are no better — definitely no better than doublets I think is important, right? I think there are long-term consequences of those decisions.

DR LOVE: Another question is in general outside of clinical trial, I know I’m sure most of your patients go on trial, do you have a favored first-line BTK inhibitor at this time?

DR ROEKER: Great question. So I use them differently in different situations. I think that the toxicity profiles are very different. So if I have patients who have comorbidities that make me think that one thing or another is going to be a problem I definitely direct them in one direction or another.

I also think that there is a lot that we need to learn about resistance mechanisms, and that was a huge theme of ASH this year for CLL, was how are patients developing resistance mutations. Particularly as we’re learning more about how patients progress through noncovalent BTK inhibitors with pirto we want to know how — are we conferring resistance to a second line of therapy through a first line of therapy. And there was that concerning presentation about resistance mechanisms picked up through zanubrutinib, and that was kind of the initial data from Australia was suggesting that maybe some of the mutations that confer resistance to pirto are actually acquired with zanu.

The data during ASH made it clear that it’s not a majority of patients, but we are seeing people who are developing those resistance mutations with zanubrutinib. So I’m thoughtful for my very, very young patients because I know that we’re going to need to use all of these lines of therapy, and I certainly don’t want to affect the efficacy of my next line of therapy with my first.

DR LOVE: Could you give me an example or 2 of a patient you would favor acala for, an example or 2 of a patient you would favor zanu for?

DR ROEKER: Yeah, absolutely. So acalabrutinib the headaches can be really bothersome, and there can also be some neurologic effects that are like imbalance and kind of some vague like disequilibrium, that kind of thing. So patients who have migraine histories or patients who have baseline neuropathy or some balance issues I tend to favor going with another BTK inhibitor.

For zanubrutinib the toxicity that seems to be most significant is GI in terms of lifestyle effect, so patients who have underlying IBS or a history of abdominal pain, things like that, I do tend to favor acalabrutinib.

And then for my really young patient who I am fairly confident I’m going to need pirtobrutinib down the line if they’re not interested in a clinical trial, which is always my first go-to, and they’re not interested in fixed-duration ven/obin, which is another common consideration, that’s a patient where I maybe favor acala a little bit more while we’re figuring out the resistance mutation piece.

DR LOVE: What kind of situation do you think about transplant and when?

DR ROEKER: Great question. So it’s interesting because it’s the double to triple-refractory patient who is young and fit. And I have not actually transplanted someone in a very long time, and I just had a patient who I was considering it and sent her to transplant for consideration, and they were like eh, I don’t really want to. It’s like okay. So mostly because she’s been doing well on clinical trials, and we have CAR T if and when relapse has happened.

And obviously that’s not foolproof, but as I’ve been kind of exploring like who are the patients where we should be considering this, one of the big pieces, I think, is we do see relapses after transplant, and we do see toxicity. So I think we have a lot of promising investigational agents in the pipeline, and we’re able to treat people well with those, so I think for a lot of patients transplant is becoming less and less of a consideration.

DR LOVE: So one final question, which is I hear people telling me, surveys get done, and stuff gets published, et cetera, that for example in the United States a significant fraction of patients get treated with first-line BR, like maybe a quarter of them.

DR ROEKER: Or CD20 monoclonal antibodies, single agent.

DR LOVE: Okay, CD20 monotherapy.

DR ROEKER: Yeah.

DR LOVE: Right. And I’ve heard numbers like 25, 30% of people, which seems incredible. And I guess my question is A) do you think that’s correct, and B) a lot of people, whenever you see it, conclude that it’s because the doc’s not following — whatever, not up to date, although it’s so hard to believe they’d be that out of date. But I wonder how much of that is — because you mentioned the issue of insurance and financial. Do you think that like maybe in the community they don’t have the ability to access some of the ways to get the drugs? Or do you think that is part of it?

DR ROEKER: I think that’s absolutely part of it. I think there is probably a minority where I’ve used BR, I know how to use BR, I’m just going to continue using BR, right? There is going to be a subset of patients that are in that bucket.

Then there’s the financial piece, right? So there’s the realities of the hoops you have to climb through to get novel agents approved. There is the appeal of fixed-duration therapy, and I think that that’s real, and venetoclax/obinutuzumab is obviously a very effective approved fixed-duration therapy, but it also requires quite a bit of stuff, right? Venetoclax dose escalations in CLL are resource intensive, and I think that that’s probably a proportion of patients as well.

So I think it’s all of the points you mentioned.