Optimizing the First-Line Management of Newly Diagnosed Chronic Lymphocytic Leukemia (CLL) — Jennifer R Brown, MD, PhD

DR BROWN: Hello, I’m Jennifer Brown. I’m Director of the CLL Center and Institute Physician at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School. And I’ll be speaking today about a number of important publications that have come out in CLL over the last year.

So first, we’re going to discuss the CLL14 study of the German CLL Study Group. And this, of course, is the trial that established the venetoclax/obinutuzumab regimen as a key frontline regimen available for CLL. At the European Hematology Association meeting this year, this was updated with 5-year follow-up. And just to remind you, this is a 1-year regimen including 6 months of obinutuzumab during the first half of the year and then continuing with single agent venetoclax. And everyone stops at a year. And this enrolled older patients untreated with CLL, but with comorbidities. And they were randomized between venetoclax/obinutuzumab and chlorambucil/obinutuzumab. The progression free survival was significantly improved with venetoclax/obinutuzumab compared to chlorambucil/obinutuzumab as shown here. And you can see that the 5-year progression free survival with venetoclax/obinutuzumab is 63%.

It turns out that the progression free survival is somewhat dependent on prognostic factors. And we see that the median has been reached for patients with unmutated IGVH at a little over 5 years and also for patients with deletion 17p or p53 aberration at a little over 4 years.

We know that the strongest predictor of outcome after venetoclax/obinutuzumab though is the achievement of undetectable MRD which was measured in the peripheral blood in this study. And this has been previously reported, but here, they updated it. And you can see that our usual cutoff of less than 10^-4 for undetectable MRD is associated with a much better outcome than detectable MRD, but it also looks like greater depth of MRD down to 10-5 or 10-6 is emerging as predicting an even better, more prolonged progression free survival with this time-limited regimen.

And also reported at EHA was the fact that overall survival is different based on MRD status, so that patients with undetectable MRD have better overall survival than those in whom it is still detectable.

So our conclusions from CLL14 is that this is a 1-year time-limited therapy, highly active.

The depth of MRD is strongly associated with progression free survival, now also with overall survival. And, as I mentioned, the duration of remission does depend on prognostic factors. So similar to what we saw with FCR where patients with mutated IGVH can have very prolonged remissions, that may be something that might emerge here in patients with mutated IGVH. But even at the current 5-year follow-up, we’re seeing a very good outcome. And then there’s the potential to retreat again with this regimen so that you’re not using up a therapy. But we have limited data on that as yet. And there’s actually a trial launching that we’re doing in collaboration with the German CLL Study Group to look specifically at that.

DR LOVE: What’s the survival show with CLL14? Overall survival?

DR BROWN: The hazard ratio is 0.72, but the p-value is 0.12. It looks like around 4 years, the curves started separating a bit and that they’re continuing to separate actually. So it’ll be something —

DR LOVE: It’s still not significant.

DR BROWN: No, it’s still not significant though.

Now the venetoclax/obinutuzumab regimen has also been studied in the CLL13 or GAIA trial, also the German CLL Study Group. And this is a trial for the younger, fit patients also untreated who have fewer comorbidities. And patients were randomized between chemoimmunotherapy which was FCR for those under 65 and BR for those over 65. Venetoclax/rituximab, venetoclax/obinutuzumab which here is called GVe or venetoclax, obinutuzumab and ibrutinib which here is called GIVe. And so we heard the results both of the endpoint of undetectable MRD and the coprimary endpoint of progression free survival in the last year. And here, you can see that the regimens that include obinutuzumab have a much better rate of undetectable MRD compared to venetoclax/rituximab or chemoimmunotherapy. The venetoclax/rituximab is actually similar to the chemoimmunotherapy whereas the venetoclax/obinutuzumab is up at 86%. And with the addition of ibrutinib is 92%. But those are rally pretty similar. And the ibrutinib actually added toxicity, cardiac toxicity, for example.

And then we see the same separation with the progression free survival curves. This is with a follow-up of about 3 years where the 2 obinutuzumab-containing regimens are separating from the venetoclax/rituximab and the chemoimmunotherapy arm. So suggesting that this is also a good regimen for younger, fit patients.

And so, again, a 1-year time-limited therapy in fit patients. The obinutuzumab-containing regimens have the highest rates of undetectable MRD and best progression free survival at about 90% for the 3-year follow-up. Venetoclax/rituximab was not better than chemoimmunotherapy. But then interestingly, I didn’t show this data, but if you subset the analysis to the patients under 65 who received FCR, the 3-year progression free survival is actually 95%. So it’s similar to the obinutuzumab-containing regimens. And this is interesting with respect to our long-term follow-up that we have from the MD Anderson data suggesting that FCR can be curative in a subset of these young, fit patients. So this is a time-limited novel agent regimen being compared to FCR where hopefully, we can get long-term follow-up data and see if it’s comparable.

Now this year, a study was published also looking at the pharmacokinetics of venetoclax in CLL14. And no significant effect of obinutuzumab was found affecting venetoclax exposure relative to single agent venetoclax. And so they concluded that a fixed dosing regimen is appropriate. They also noticed that there was no relation of baseline patient characteristics with the pharmacokinetics here. And that included that there was no effect of mild to moderate hepatic or renal impairment. Strong and moderate CYP3A4 inhibitors decreased the venetoclax clearance by about 82% and 14% respectively in a relatively limited number of patients that were evaluated. So this generally supports the current label which does recommend dose reductions and avoidance of these inhibitors during escalation.

Interestingly, there was no association of venetoclax exposure in CLL14 with the incidence of serious adverse events, neutropenia, thrombocytopenia or infection. And they state in the paper that lowering the dose is not likely to impact these toxicities. This is very interesting, I think, of course, because venetoclax does cause cytopenias and there’s a general assumption that if we lower the dose, we can mitigate those cytopenias. But this analysis would suggest that that may not be the case. They also noticed that there’s no statistically significant relationship between venetoclax exposure and progression free survival in CLL14 and say that there’s no evidence, therefore, that higher doses would increase efficacy. And this is also an interesting point because in the Phase I study that was published in the New England Journal of Medicine, there was actually a separation of the progression free survival curves based on whether patients received more than 400 mg daily or less.

So interesting food for thought with respect to venetoclax exposure. I can’t say that I’ve had great luck with dose reductions mitigating toxicity actually in terms of cytopenias. But obviously, it’s something that we’ll always try.

Now moving on to this real-world analysis from the ASH meeting that just happened early in December. This was an analysis comparing ibrutinib to chemoimmunotherapy in frontline patients in the Inform Registry. It was the final analysis of the Inform Registry. And the patient populations were not completely similar. For example, there were more 17p patients in the ibrutinib population compared to the chemoimmunotherapy population. So they did an analysis where they adjusted the frontline treatment cohorts to try and correct for that. And you can see that if they do that, the patients free of second line therapy is improved with ibrutinib compared to chemoimmunotherapy which I think overall is not a surprising result although it is dependent on the tolerability of ibrutinib. We know that if patients discontinue ibrutinib, then they do tend to relapse. The duration of time until they relapse is variable depending on their prognostic factors, how deep their remission is. The ECOG 1912 study found that it was about 2 years until patients progressed if they had come off ibrutinib for adverse events. That was after a median of 15 months of therapy. Of course, now we have the second generation covalent BTK inhibitors as well which are better tolerated.

So as I was saying, time to next treatment was longer with ibrutinib than chemoimmunotherapy. Serious adverse events and adverse events leading to discontinuation were more common with ibrutinib overall, but if you corrected this for time on therapy, they were less common for a given unit of time on therapy. I’ve always been a little skeptical of correcting for time on therapy though if the duration of the therapy is an integral part of the treatment. So chemoimmunotherapy is 6 months and done. That’s how it is. But ibrutinib is meant to be given continuously. So it should be evaluated as a continuous regimen.

So the ELEVATE-TN study evaluated acalabrutinib in the frontline setting. And we had the 5-year update on that study from ASCO this year. And this was in older, unfit patients previously untreated. And they were randomized between acalabrutinib/obinutuzumab, acalabrutinib alone or obinutuzumab/chlorambucil. And you can see that either of the acalabrutinib-containing arms significantly improved progression free survival compared to the chlorambucil/obinutuzumab which had a median PFS of about 28 months. I think the most interesting part of this study has been the progressively increasing apparent benefit of the obinutuzumab in the acalabrutinib/obinutuzumab arm compared to the single agent acalabrutinib which is now a 12% difference at 5 years of therapy. This was not a preplanned comparison, but the data do look fairly convincing in terms of the separation of the curves.

And they are associated with a higher complete remission rate in the acalabrutinib/obinutuzumab arm as shown here and a higher rate of undetectable MRD also in that arm. So I think that the finding may be real. And you may say, well we didn’t see any benefit adding rituximab to ibrutinib, why is this different? So there are 2 reasons why it may be different. One is that obinutuzumab is a much more potent antibody than rituximab and has, in fact, been shown to be better in a head-to-head trial in CLL. And then the other reason is because the BTK inhibitor itself. Ibrutinib inhibitors ITK which can affect one of the mechanisms by which antibodies work and has been shown to affect it in vitro. Acalabrutinib does not inhibit that target, so would not be expected to be antagonistic in that way.

So conclusions for ELEVATE-TN are that the addition of obinutuzumab to acalabrutinib improves 5-year progression free survival by 12%. The obinutuzumab led to a higher complete remission rate and higher rate of undetectable MRD. I’ve generally found that the addition of obinutuzumab has not been widely adopted, but perhaps based on these data, should be more widely considered. I’ve found the same thing in my practice, that many patients who choose a continuous BTK inhibitor therapy do not necessarily want to come in for all the infusions associated with obinutuzumab. And so it’s something of a change in the paradigm of how we give BTK inhibitors. It makes it a little bit more like venetoclax/obinutuzumab. And so it’s not been as popular with patients.

DR LOVE: What you were just saying about the difference there from ibrutinib, acalabrutinib was interesting. Is there a difference in the immune effects? Ibrutinib is used in a lot of situations for its immune effects. I never thought about it. I assumed acalabrutinib was the same. Is it not the same.

DR BROWN: That’s really interesting because I think when they first came out, people thought that acalabrutinib would not be the same. But the data actually suggest that it is mostly similar. If you look at the effects on T cells over time in patients treated with ibrutinib and acalabrutinib, they look pretty similar. And even some CAR T experiments in mice, for example, look pretty similar with ibrutinib and acalabrutinib in terms of the modulation of the effect. And so what that might suggest is that a lot of what we’re seeing in terms of the improvement of the immunologic milieu in CLL patients is actually disease control rather than a direct effect on the T cells so that as we get patients into a deep remission and they have fewer and fewer CLL cells, then their T cells can function more effectively.

DR LOVE: Interesting. I’m curious, in what situations, if any, are you using obinutuzumab with acalabrutinib? Sometimes, I hear people talking about younger patients although I’m not sure exactly why. In what situations are you doing it, higher risk?

DR BROWN: Right. So I talk to pretty much anybody who is going on acalabrutinib about it. The ones that I push more toward it are actually the higher-risk patients because I do find that you get a more rapid response with the addition of obinutuzumab and that tends to be beneficial, especially in the higher-risk patients and also the younger patients because they tend to be more willing to come in for visits and prefer the idea of deeper remissions. Usually, if I’m doing a continuous BTK inhibitor in a younger patient, there’s a reason, something about their disease prognostic profile, higher-risk. So then, again, I feel like getting a deeper remission and more rapid disease control is beneficial.

DR LOVE: And when you do the obinutuzumab, is that indefinitely or for a defined period of time?

DR BROWN: Just for 6 months. You have the weekly doses lead-in for the first 3 weeks, then there’s a week off, and then it’s 5 monthly doses.

So as people may be aware, this year, acalabrutinib has come out with a new formulation. It’s always been capsules and the absorption of the capsules is inhibited by proton pump inhibitors. So we’re always supposed to get our patients off the PPIs if we’re going to start acalabrutinib. And as I’m sure everyone is aware, it can be very hard to get people on long-term PPIs off them and they often have symptoms. So AstraZeneca reformulated the drug into a tablet formation which is not sensitive to the acid environment. And so people can stay on their PPIs and get the tablet formation. So this is a paper that was published just looking at the percentage of BTK occupancy comparing the tablet to the capsule. And you can see in the left panel, healthy volunteers versus patients with CLL on the capsule or patients with mantle cell lymphoma on the capsule. And on the right, we have 4 and 12-hour post-dose looking at the effect of the PPI if patients got the tablet dose. And there is no effect of the PPI. So that’s good. And pretty much, this is becoming the formulation of acalabrutinib that’s available and that people are using. They’re going to discontinue the capsule.

So characterization of the tablet shows similarity to the capsule. And absorption is similar regardless of stomach acidity. So no longer have to worry about PPIs.

So turning our attention to zanubrutinib. So zanubrutinib has reported 2 Phase III trials this year. And this is the SEQUOIA trial. This is the trial for untreated CLL patients who are over 65 or otherwise unsuitable for FCR treatment. So there are several cohorts on this study. Cohort 1 without 17p, patients were randomized between zanubrutinib 160 mg twice a day or bendamustine/rituximab for 6 cycles. And this study was published earlier this year. And then, there were 2 other cohorts. Cohort 2 with deletion 17p is actually the largest prospectively enrolled frontline cohort of patients with 17p that we have. And all of them got continuous zanubrutinib. And we’ve got about 2-year follow-up on that cohort right now. And then, Cohort 3 is looking at zanubrutinib and venetoclax, and was originally planned to be just 17p patients, and they enrolled quite a few. But then, they opened it up to all-comers, so it’s become a broader population.

So Cohort 1 data is shown here. Zanubrutinib significantly improved progression free survival compared to bendamustine/rituximab. The hazard ratio is 0.42. And the 2-year estimated progression free survival is 86% for zanubrutinib versus 69% for BR. So hopefully, these data will contribute to a label for zanubrutinib in CLL. As you know, it’s approved for mantle cell lymphoma, marginal zone and Waldenström’s, but not yet for CLL.

And then, this is the Cohort 2, just the 17p cohort. As I mentioned, an 89% 2-year progression free survival in this cohort of 17p deleted patients. So that looks very, very good.

So conclusions for SEQUOIA. This is a frontline registration trial for zanubrutinib in CLL. The 2-year progression free survival is 86%. It includes the largest dedicated prospective cohort of patients with 17p deletion who have an 89% 2-year progression free survival. And they have an ongoing cohort studying zanubrutinib/venetoclax which will, I suspect, likely be studied further in other trials.

This is real-world data comparing acalabrutinib to ibrutinib. And it’s really the largest population of patients that’s been studied, over 2,500 patients. And looking really at whether acalabrutinib is better tolerated than ibrutinib and patients are able to stay on it. So the patient populations here were also different. About 1/3 of the patients getting acalabrutinib had had a prior BTK inhibitor whereas this was not true about the patients getting ibrutinib. So if you looked at the uncorrected data, the curves were fairly similar because some of the acalabrutinib patients were relapsed essentially. But if you correct for that or limit to just the frontline patients, you can see that the proportion of patients able to stay on treatment is significantly better for the acala in the blue compared to the ibrutinib in the red. Which I think this is also everyone’s experience with the next generation BTK inhibitors.

So as mentioned, largest cohort to date. Baseline populations were not balanced. So there was no significant difference without weighting, but with weighting or just limiting to first line patients, which is probably the best way to do it, saw a significant benefit for acalabrutinib in patients being able to stay on therapy over time.

We also heard at the ASH meeting a detailed analysis of adverse events with acalabrutinib versus ibrutinib from the ELEVATE-RR study. And this looked at a burden score which took account of both the severity of the adverse event and how long it was going on for to generate a score for patients. Acala was better overall, and particularly for atrial fibrillation, hypertension, hemorrhage and musculoskeletal events. But acalabrutinib was worse for headache and diarrhea. I’ve always found it a little hard to directly translate an AE burden score into how a given patient feels. But it is pretty clear if you’re using the drugs that there are fewer side effects with acalabrutinib, I think, compared to ibrutinib with the exception of the headache.

DR LOVE: Any comment on ventricular arrythmias? Of course, we’ve heard about that with ibrutinib. I don’t know. I’ve heard a little bit about acalabrutinib. What is your take on that? And how concerned are you about that?

DR BROWN: So I’m very concerned about that with ibrutinib. I was actually the first person to report it. And we’ve since seen it in 2 randomized trials, both FLAIR, median age of the patients was 63, and then also GLOW with patients who were closer to 70. There was a 4% death rate from ibrutinib on GLOW. So it’s clearly an issue there. And actually, in ALPINE, the control arm of ibrutinib had a 2% death rate from cardiac events.

DR LOVE: Wow, that’s interesting.

DR BROWN: With acalabrutinib, I have not seen it at all with acalabrutinib. I’ve also done some evaluation of the acalabrutinib experience across several trials because we published a cardiac paper. And when we did that analysis, there was only 1 ventricular arrythmia and it was a patient who was quite ill in the ICU. Since then, just recently, Ohio State has published a paper suggesting that ventricular arrythmias might be increased with acalabrutinib also. In reading that paper, it seems that they included just PVCs as an event and that many of the patients may have had just PVCs because many of the patients actually stayed on the acalabrutinib without getting an ICD despite this. So I’m not completely convinced by that paper yet that this is something we’re going to see with acalabrutinib as well. But it is an issue with ibrutinib. And it’s in the new label actually that across the entire ibrutinib experience, there’s about a 1% sudden death rate.

DR LOVE: So please continue.

DR BROWN: Sure. Right. So that brings us to ALPINE which I was fortunate to be able to present as a late breaking abstract at ASH. This is a Phase III randomized study of zanubrutinib versus ibrutinib in patients with relapsed/refractory CLL or SLL. Patients had to have at least one prior regimen. And the planned enrollment was 600, but the actual enrollment was 652. And patients were required to have measurable lymphadenopathy. Key exclusion criteria included current or past Richter’s transformation, prior BTK inhibitor therapy, and treatment with warfarin or other vitamin K antagonists although other anticoagulants were permitted. And the patient population enrolled ended up being a more or less all-comer population with a median of one prior therapy. Median age was about 67. They were randomized then between zanubrutinib 160 mg twice per day and ibrutinib 420 mg daily. The randomization was stratified by age, geographic region, refractory disease, and deletion 17p or p53 mutation status which represented about 23% of the patients enrolled had p53 aberrancy.

So this is the take-home message that with a median follow-up of 29.6 months, zanubrutinib significantly improved progression free survival compared to ibrutinib. These are the data by IRC, but the data by investigator are essentially identical. The hazard ratio is 0.65 with a p-value of 0.002. The 2-year landmark estimated PFS, as you can see here, with zanubrutinib was 79.5% versus 67% for ibrutinib, so about a 12% improvement.

And then particularly notable, in a preplanned analysis looking at the deletion 17p patients, zanubrutinib improved the 2-year landmark PFS by about 22%, 78% for zanubrutinib versus 56% for ibrutinib. Zanubrutinib was also better tolerated with fewer adverse events leading to discontinuation or drug hold or drug interruption and fewer cardiac events with no cardiac deaths versus 6 with ibrutinib and only 1 treatment discontinuation for a cardiac event versus 14 with ibrutinib.

So this is the first demonstrated efficacy benefit in a head-to-head comparison of BTK inhibitors. And it’s a notable effect, 12% at 2 years in the entire population and 22% in the 17p/p53 aberrant population. As I mentioned, zanubrutinib was also safer with fewer drug holds, interruptions or discontinuations and cardiac safety was much better, 1 discontinuation versus 1 with ibrutinib and 0 deaths versus 6 with ibrutinib. The atrial fibrillation rate was 5% with zanubrutinib versus 13% with ibrutinib also. 

DR LOVE: I’m not an expert on the FDA, but why is zanubrutinib not approved in CLL at this point?

DR BROWN: Right. That’s a good question. They filed initially on the overall response rate analysis and then updated it with the final analysis of the overall response rate and that pushed the PDUFA date back to January. So we’re expecting it to be approved in January. But it is a good question. The EMA actually approved it several weeks ago.

DR LOVE: And, of course, the other question is, what’s going on here? I guess when it was initially presented last summer, I heard people saying, well it’s early, even in the acalabrutinib study, you saw improvement. Also, the question of the way the responses were done. At this point, are you getting questions — are people questioning it? Or you just presented it. Is your sense that this is for sure for real? And do your colleagues agree?

DR BROWN: Yeah. So I agreed back when it was first presented a year ago, it was only 1 year of follow-up, so it was very short. But we now have 2 and a half-year follow-up and the hazard ratio has been pretty stable over the last year. I have looked at this data in quite a lot of detail and I’m really pretty convinced. We did a lot of sensitivity analyses looking at whether altering the censoring or whatnot would affect the hazard ratio. And really, nothing does. A lot of people have raised the question, is it mostly due to discontinuation for adverse events rather than progression on drug? It turns out it’s about half and half, that both are true. But if you do an analysis where you don’t even include progressions for people who stopped drug for adverse events so that the only events are progression on drug or death, there’s still a significant effect for zanubrutinib with a similar hazard ratio. So I think it’s real. And we had a number of discussions at ASH where I think my colleagues are getting convinced too.

DR LOVE: That’s interesting. Biologically or pharmacologically, can you explain it?

DR BROWN: Right. So my best guess for that is, you know, zanubrutinib is a covalent inhibitor, similar to acalabrutinib and ibrutinib, but it has different pharmacokinetics. It was designed to actually maintain drug levels throughout the entire dosing interval and to really optimize BTK occupancy through that. So if BTK is being resynthesized during the dosing interval, zanubrutinib can inhibit that new BTK. And that’s not true of ibrutinib or acalabrutinib. They have short exposures and then are cleared so that if BTK is resynthesized, then that might have an impact. And so that seems to be the most likely explanation. Zanubrutinib is more specific for BTK than ibrutinib is, but acalabrutinib is also more specific for BTK. Now strictly speaking, the study that was done comparing acalabrutinib to ibrutinib was really a very different study. And it showed noninferiority, but it did not show superiority. But that might have to do with how the 2 studies were designed. But there is a potential biological rationale for why zanubrutinib would be better based on these PK properties, I think.

DR LOVE: Do you feel convinced enough that it kind of bothers you when you put people on acalabrutinib now, that you’re not giving the drug you want? I assume you’re still using acalabrutinib.

DR BROWN: Yeah. So that’s interesting. I — if you look at the landmark PFS estimates, the most similar acalabrutinib study compared to zanubrutinib is the ASCEND study. And if you look at the 2-year PFS for acalabrutinib in there, it’s 75%. And so we’re seeing 79 here with zanubrutinib, so that’s pretty similar. So what I would say is I’m pretty impressed by the acalabrutinib/obinutuzumab arm with acalabrutinib and you do get more rapid responses with obinutuzumab. So potentially, if patients are willing to get obinutuzumab and they want that more rapid response, I’m still leaning toward that combo. But if we’re going with single agent, then I’m going to be using zanubrutinib based on the superiority. And also, I still have less experience with zanubrutinib, so I really want to get more experience and see how patients do in my real-world or not-so-real-world practice.

My impression is that zanubrutinib is a little bit better tolerated in terms of the niggling side effects that people get, the arthralgias, myalgias, fatigue type of thing, even in acalabrutinib. But we’ll see as we get further in experience.

Treatment of Relapsed/Refractory CLL; Novel and Investigational Strategies — Deborah Stephens, DO

DR STEPHENS: Hi, my name is Deborah Stephens and I’m an Associate Professor at the University of Utah Huntsman Cancer Institute. And I am pleased to join you today to talk about treatment of relapsed and refractory CLL and including some novel and investigational strategies that will include some frontline options.

The first study that I’d like to highlight is a study called the GLOW study. This is a study specifically for treatment naïve patients, and these were patients that were older than 65 years of age, so a great representative population of our folks that have CLL. Notably, no deletion 17p patients were included in this, and that’s because of the control arm which is really a very, I would say, outdated control arm at this point of obinutuzumab and chlorambucil for 6 months. This study, the experimental arm was ibrutinib lead-in for 3 months followed by the combination of ibrutinib and venetoclax for 12 months and then all therapy was stopped. This was not an MRD-guided stop of therapy. No one was really holding their breath to find out which of these regimens would be better in terms of progression free survival. And you can see the pretty impressive difference in progression free survival curves here with the ibrutinib and venetoclax arm in blue and the obinutuzumab/chlorambucil arm in red.

So other than showing us that big difference in progression free survival, I think a really important thing is the toxicity profile. And why that’s specifically important in this, because this is an older population than was enrolled on studies such as like the CAPTIVATE study that studied this same regimen, the combination of ibrutinib and venetoclax. And so I think that’s really important for our patients. So in this study, it really showed a nice reduction of being classified as high tumor lysis risk. So prior to the ibrutinib lead-in, 25% of these patients were considered high-risk. And then after the ibrutinib lead-in, only 2%. And so that’s really big implications in terms of just patient risk and for not needing to hospitalize these patients for observation for tumor lysis.

The other things I wanted to highlight is some of the common toxicities and then, of course, cardiac toxicities. Listed here in the table, you can see the number of TLS cases. And pretty strikingly, there were 0 cases of TLS with ibrutinib/ven combination and that was because of the lead-in. The 6% seen in chlorambucil/obinutuzumab was no doubt related to the obinutuzumab therapy. Another thing, obviously, that was related to obinutuzumab therapy is the infusion reaction which is seen there in the middle of the table. There were about 30% of patients that had an infusion reaction. And so not doing this kind of infusion might also have implications in terms of how many staff are needed to monitor these patients and utilization of healthcare. Of course, very common with ibrutinib and venetoclax is diarrhea, 50% of patients experienced that. That’s pretty typical.

On both arms, about half of patients experienced neutropenia, more so with chlorambucil and obinutuzumab. I think really notable here are the cardiac toxicities because this is an older population and potentially patients with more comorbidities. And you saw that 14% of patients experienced atrial fibrillation which is pretty high compared to the only 2% on the chlorambucil/obinutuzumab arm. Again, this is consistent. We see atrial fibrillation with ibrutinib-containing regimens. But this is definitely an important side effect. There were also 4% which equals out to be about 4 cardiac deaths in patients receiving ibrutinib and venetoclax. And whether this is specifically related to the regimen or not, we don’t know. However, notable that there were 0 deaths related to cardiac deaths in the obinutuzumab/chlorambucil arm, and 2 of those deaths were sudden cardiac deaths which has been associated with ibrutinib in other studies. Also notable, there were about similar in number of patients in both arms that had Grade 3 or higher AEs. So about 3/4 of patients did have some significant AEs with treatment. So it’s not a study that’s without toxicity, and that should really be considered in older patients.

So I wanted to highlight a few takeaways. So this study was the impetus to approve ibrutinib and venetoclax as a frontline combination in all — for all treatment naïve CLL patients treated in Europe. This has not yet been approved in the United States, but my guess is it will be soon coming to your clinic. I wanted to talk through a couple of pros and cons about using this combination upfront as opposed to using maybe sequential therapy with these agents. So, of course, this tumor lysis reduction risk is really important for the patients. It does allow for a time-limited frontline BTK inhibitor therapy. I didn’t highlight this data, but they did comment that there were some patients that did relapse after this combination therapy, and they still were able to get responses to ibrutinib. And so it doesn’t mean that you can’t use this therapy — any one of these combinations or the combination in subsequent lines of therapy. Some cons of this, it is toxic, and notably, those cardiac toxicities. And the question is, would this be better with acalabrutinib or zanubrutinib? And there are several ongoing studies really to help sort that out. What we don’t know, especially here in the United States, whether — what the cost or insurance coverage will look like. As you all know, now we often have to apply for rug assistance for patients.

So are we just going to have to do that for 2 separate drugs? Or how is that going to work? And it’s really unclear at this point exactly which patient population might benefit the most from combination versus sequential therapy. And when I think about that kind of debate between combination versus sequential therapy, what I really want to see is can we cure people, at least a functional cure. Meaning, can people live out the rest of their lives without needing another treatment? And as of yet, we don’t really have that. And that, to me, would tip the scales to doing the combination upfront. So where would I use this in my clinic? I think a classic example, I have a patient that is a young patient and she has very, very bulky lymph nodes with lymph nodes up to 15 cm in her abdomen. She lives about 6 hours away from my center, so tumor lysis monitoring is really — would be very difficult. And so somebody like that, I feel like somebody who I want a time-limited therapy (give them a big risk of tumor lysis with obinutuzumab/venetoclax, I think this is — potentially could be a nice option. But we need a little bit more data about this regimen to know exactly who the best patients are to use it.

So related to this because it’s looking at a venetoclax/ibrutinib combination is the FLAIR study. Now this is an adopted study that set out to actually study something different, but it adapted to the times nicely and has 2 new comparator arms on this study. So this is for patients who are less than 75 years of age, so a little bit on the younger side of patients. These are treatment naïve. They did not include any patients that were TP53 mutated in this study. The control arm of this study is ibrutinib for up to 6 years, and I’ll comment on when you can stop this, versus ibrutinib for a 2-month lead-in followed by the ibrutinib combination with venetoclax for up to 6 years. And in this study, they stopped therapy after MRD was deemed undetectable, which was defined by flow at less than 10^-4, for 3 months running. So you had to have 1 analysis and then 3 months later, it also had to be MRD undetectable. Primary endpoint of this study is MRD eradication. And what was an interesting finding that was presented at ASH 2020 is that how the MRD was achieved in that IGHV unmutated group. Now this is a group that’s traditionally found to be a high-risk group, and that’s shown in the lighter blue color here. And what it shows is that the IGHV unmutated patients were quicker to achieve MRD undetectable status, 55% at just 9 months of therapy. And at 24 months, 83% of them had achieved MRD undetectable which was higher than they saw in the un — in the mutated patients.

So takeaways from this. In this frontline treatment with ibrutinib and venetoclax, patients with IGHV unmutated status were more likely to achieve MRD undetectable status and achieved it at a faster pace than those with IGHV mutated patients. I didn’t highlight this data, but another thing they commented on is that 80% — 83% of the patients with deletion 11q cytogenetics compared to only 55% of patients with deletion 13q did achieve MRD undetectable status within 2 years of treatment. So what does this mean? Maybe unmutated IGHV and deletion 11q CLL are particularly responsive to the ibrutinib/ven combination. Maybe these subtypes are more dependent on B-cell signaling and that’s why we see this. But what was not shown is the difference in progression free survival and overall survival in these patients on this study. And so I think longer follow-up is going to determine if this quicker gain to MRD undetectable or more likely to achieve actually correlates with PFS and overall survival.

DR LOVE: I’m not sure if I missed this, but did you show the MRD negativity rate in the ibrutinib alone arm?

DR STEPHENS: I didn’t because it was essentially almost 0.

DR LOVE: Really?

DR STEPHENS: Uh-huh.

DR LOVE: Wow, that’s interesting.

DR STEPHENS: Yeah.

DR LOVE: That’s been known? You don’t see MRD negativity with BTK?

DR STEPHENS: You can see it. It’s just much more rare to see it with this patient population.

DR LOVE: That’s really interesting. Please continue.

DR STEPHENS: So the next study I’d like to highlight is a different strategy termed venetoclax consolidation. And in this particular study, this was a smaller study, 45 patients. But what was done is patients who had CLL or SLL with some sort of high-risk feature, so whether that be deletion 17p, complex karyotype, deletion 11q, a persistently elevated beta-2 microglobulin level or any combination of these high-risk side effects, who had been on ibrutinib for at least a year that had not achieved a complete remission with MRD undetectable status. So what these investigators did is they started the patients on venetoclax therapy at the standard dose of 400 mg daily and patients could continue for up to 24 months max. And what that means is they recommended stopping venetoclax after a patient achieved CR and undetectable MRD in the bone marrow for at least 6 months. So they had to have 2 consecutive 6-month bone marrows that were negative by flow x 10^-4. Ibrutinib could then be discontinued at any point at physician discretion. The median follow-up of this study was about 3 years.

And the best cumulative rate of undetectable MRD was 73%. So about 3/4 of these patients were able to go on to achieve undetectable MRD. The CR or the CR with incomplete count recovery rate was 57%. And why you see differences here is because to determine the CR rate, these patients have to have all lymph nodes less than 1.5 cm. And so sometimes, you’ll see that there has been a significant decrease in the lymph node size, but maybe they still have a small retained lymph node of 1.6, 1.7 cm so they don’t meet criteria for CR. So in this study, about half of these patients did go on to discontinue both ibrutinib and venetoclax therapy. They did comment in those patients, in all patients, 45 patients, there were 4 patients or 9% that did have progressive disease. One was during the combination of therapy, 3 were during ibrutinib maintenance and 1 was during Richter’s — 1 was due to a Richter’s transformation.

So take-home from this study, this venetoclax consolidation did result in a high rate of undetectable MRD at 3/4 of the patients and a high rate of CR, so about 60% of patients were able to achieve that. Most of these patients who were able to achieve undetectable MRD at the end of venetoclax remain in MRD undetectable status. This is at about 3 years. So it does seem to be an effective consolidation strategy. And the authors commented that the future directions included a high-risk co — or very high-risk cohort with deletion 17p and complex karyotype. And then they also want to study patients who are on treatment with acalabrutinib doing the same strategy to try to discontinue both acalabrutinib and venetoclax therapy. And so what we don’t know, because this is the single arm study and it’s a small study, is this consolidation with venetoclax, is it better than sequential therapy with venetoclax? So should we be treating this early or is it better just to wait until patients have a relapse on ibrutinib and switch over to venetoclax therapy?

The next combination therapy that I’d like to talk about is acalabrutinib, venetoclax and obinutuzumab. This was a nice study for treatment naïve patients that had a couple of different cohorts. They had an all-comer cohort which was 37 patients. And then they had a higher-risk cohort which was TP53 or deletion 17p mutated cohort and that was 31 patients. And this study, it was a little bit different in terms of the starting times of these different drugs. So acalabrutinib 100 mg twice daily started at cycle 1. There was a 1-month lead-in and then obinutuzumab was started. They used that for cycles 2 through 7 in combination with acalabrutinib. And the venetoclax ramp-up started at cycle 4. There were a couple of different timepoints on this study, cycle 16 and cycle 25. And both venetoclax and acalabrutinib could be stopped at those timepoints if MRD was negative by flow x 10^-4. So notably here, I’ve shown the MRD undetectable rates at cycle 16.

And you can see that actually, between the 2 cohorts, so TP53 wild type and TP53 mutated, both had a really high rate of MRD undetectable status, so over 80% of patients were able to achieve that with this regimen. 63% of the patients on study did discontinue acalabrutinib and venetoclax therapy. And at the time of this analysis, the median time off therapy was 19 months, but a pretty big range from 0 to 30 months. And this is specifically the patients that discontinued therapy. In that specific subgroup, 4 of the 43 patients or 9% had a relapse of CLL and 3 of those were MRD recurrence only, 1 was an actual CLL clinical progression. So really good rates after this follow-up of about a year and a half. So in all of the patients, so 68 of the patients, both cohorts, I wanted to just highlight that there were 5 patients who either had progressive disease or death, and that’s 7% of the patients. One was a CLL progression which I mentioned already, 3 were transformation events and 1 was a COVID-related death just reflecting the time that these patients were accrued on the study.

So for this combination study, I think there’s a few takeaway points. So this AVO combination did result in high MRD undetectable rates, greater than 80% regardless of TP53 mutation status. So they also resulted in durable responses after discontinuing of therapy. And this does support time-limited therapy option, even for patients with high-risk disease. So the future directions, there is an ongoing AMPLIFY study. This does compare AVO versus acalabrutinib/venetoclax, so do we really need the obinutuzumab, versus chemoimmunotherapy in the frontline setting. So what I really want to know and what I think will be interesting with longer follow-up is will the durability of response be maintained in the high-risk subgroup with longer follow-up? You have a question?

DR LOVE: Yeah. Do you know what the MRD negativity rate is in single arm studies with venetoclax and del(17p), you know high-risk?

DR STEPHENS: Yeah. It ranges in the studies. It’s generally around 60 to 70%. And so this is a higher rate than we have seen with those studies with venetoclax not including a BTK inhibitor.

DR LOVE: It’s interesting. You were saying the MRD negativity is very uncommon with BTK, so I assume that applies for high-risk. So it’s kind of interesting that people, for a variety of reasons, seem to use BTK in that situation in spite of the fact that you don’t see MRD and you do see it in those patients with venetoclax. Do you think that is real? Do you think there’s a benefit, you know, better choice BTK in a del(17p), for example?

DR STEPHENS: I do think that there is synergy between the 2 agents. It’s been shown in preclinical study. And it’s possible that there are some drug interactions that maybe potentiate the effects of these drugs because, not only in this study, but it’s been seen in other studies, you know, ibrutinib, venetoclax, obinutuzumab, other things. It does look like the combination can get people into a deeper response than any of the drugs individually. 

DR LOVE: Okay. Please continue.

DR STEPHENS: Thanks. So another important study to look at, especially in the relapsed and refractory group, is the population of patients that were treated with venetoclax and rituximab on the MURANO study which did establish the standard of care as venetoclax and rituximab in the relapsed group. This study, just to remind you, the MURANO study was for patients relapsed and refractory CLL that had 1 to 3 prior therapies. 380 patients were enrolled on this study. These patients were randomized to either bendamustine and rituximab for 6 cycles versus rituximab for 6 cycles combined with venetoclax for 24 months. And most recently, they published this study with a median follow-up of 5 years. So, of course, sometimes difficult to show because patients with CLL do have the benefit of living long lives, but there was a really clear benefit in overall survival by using venetoclax and rituximab compared to bendamustine and rituximab at 82% versus 62%. So 3 years after the end of venetoclax/rituximab therapy, the progression free survival was about 38%. And so definitely did see some relapses. But what was interesting is they looked at kind of timepoints until this. And so in patients who had undetectable MRD status at the end of therapy, the median time to MRD conversion was 19 months. And so about a year and a half before you started to see on average the MRD start to show up. And then of those 47 patients that had MRD conversion, there was only clinical progressive disease in 19 patients. And that median time from MRD conversion to clinical progressive disease was about 24 months. So that adds another 2 years where maybe the CLL is there, however, the patient is not having any clinical sequalae related to it.

So some takeaways from this, this fixed duration venetoclax/rituximab maintained overall survival benefit over bendamustine and rituximab in relapsed and refractory CLL. I think this is one of the important studies of many that highlight that chemoimmunotherapy in the second line setting for patients with CLL really should be avoided unless there’s no other option, just because all of these targeted therapies really have so much more benefit in overall survival. And, again, MRD was detected — detectable at a median of 1.5 years, but clinical progressive disease did not curve for another 2 years after MRD was detected. And so these patients still are having this time period of about 3 and a half years where no therapy was required. And so some of the questions from this, what’s the best thing to do for these patients? Is it better to intervene early on minimal residual disease? Or is it best just to leave the patients alone until they have clinical progressive disease? Because, again, these patients were not having any clinical sequelae for about 3 and a half years. So that’s a question that’s not answered in this particular study. But now, there’s a lot more data about retreatment with venetoclax causing some remission. And would that be better if they had a lower burden of disease at the time of retreatment? Or would it not be because resistance mutations to venetoclax can also develop?

Another study looking at comparison of chemoimmunotherapy in the second line setting for patients with CLL is the ASCEND study. This patient was — this study was for patients with relapsed and refractory CLL, and 310 patients were randomized on this study. The experimental arm was acalabrutinib 100 mg twice daily which was given indefinitely. And then the other arm was an investigator choice. You could either give bendamustine and rituximab for 3 cycles or you could give rituximab for 8 doses plus idelalisib until disease progression or intolerance. Now, this study has a median follow-up of 47 months, so good, long follow-up. And these data were presented at ASCO 2022 and demonstrated that acalabrutinib maintained progression free survival benefit over the experiment — the control arm which was idelalisib/rituximab versus BR. And at 42 months, the progression free survival was a very big striking difference of 62% versus 19%. Acalabrutinib was able to prolong progression free survival in the high-risk subgroups as well. And they looked specifically at deletion 17p and unmutated IGVH. Of course, the other things to note, because we are all curious about these cardiac side effects in patients treated with BTK inhibitor therapies, originally thought to be a lot less with acalabrutinib. And there was a head-to-head study called the ELEVATE-RR study that did show a lower rate of atrial fibrillation with acalabrutinib versus ibrutinib where in this study, we still saw atrial fibrillation at 8% which is consistent with what we’re seeing in the other studies. And the rates of hypertension, which is also a known BTK inhibitor side effect, is at about 8% at this time point. 

So this study with 4 years of follow-up, acalabrutinib maintained progression free survival benefit over the idelaR/BR arm in relapsed and refractory CLL. No new safety signals were identified in either of the groups. And, again, I think this is just another study in strong support of avoiding standard chemoimmunotherapy in relapsed and refractory CLL.

So there’s a lot of buzz about the BRUIN study. And the BRUIN study is a very large Phase I/II study that looked at a drug called pirtobrutinib, formerly known as LOXO-305. This is different from the other BTK inhibitors that I’ve been talking about because it’s a noncovalent BTK inhibitor, and it binds in a C481-independent manner. And so initially theorized to have responses even in patients who had mutations that would render the other covalent BTK inhibitors ineffective. So I’m going to talk specifically about a cohort of patients on this BRUIN study that had prior BTK inhibitor therapy. And there were 247 of these patients. Again, this was a Phase I/II study and so patients were treated anywhere from 25 to 300 mg daily. However, most of the patients were treated at the recommended Phase II dose which is 200 mg daily. Really notable about this drug, the most common AEs were almost all Grade 1 and 2, and they included fatigue, diarrhea, neutropenia and contusion. But you see really low rates of this. If you’ve treated anyone with this drug, you can see a striking difference that most of these patients have essentially 0 side effects with this drug which is really important for this population. Grade 3 or higher AEs were rare. The rate of atrial fibrillation was only 3% which is, of course, lower than we’ve seen with other of the covalent BTK inhibitors like ibrutinib, acalabrutinib and zanubrutinib. And one thing that’s notable in this group with prior BTK inhibitor therapy, 82% of people were able to respond to pirtobrutinib. And then specifically, another high-risk group of people have had both a BTK inhibitor and a BCL2 inhibitor lie venetoclax. There were 100 of those patients on this study, and 80% were able to achieve an overall response to this drug which is great.

A median follow-up of 19 months. And at this timepoint, all of the patients who had prior BTK inhibitor therapies, again, heavily pretreated, median of 3 prior therapies, the median progression free survival was a great 20 months. Those patients who had prior BTK inhibitor therapy and BCL2 inhibitor, even more heavily pretreated with a median of 5 prior therapies, they did enjoy a progression free survival of about a year and a half with this drug. And yet, these are short numbers compared to what we see in most CLL studies, but this is a really high-risk population. And really, when you compare this to other available drugs like, for example, PI3 kinase inhibitors like idelalisib in this setting, you only see really a 4 or 5-month PFS on those drugs. And so this is really a huge benefit for these patients. They also noticed several different — noted several different subgroups, and there no difference in the PFS curves for C481 mutated versus wild type which I’ve shown here. They also looked at age less than 75 versus age greater than 75. No difference in PFS between those 2 groups. They looked at deletion 17p and/or TP53 mutated versus wild type, and no difference between those 2 groups. So a couple of really high-risk populations showing great responses to this drug.

So takeaways from this study with a median — with 1 and a half years of follow-up. Pirtobrutinib shows efficacy in heavily pretreated and high-risk patients including C481S and TP53 mutated CLL. The toxicity profile continues to be veery well tolerated. And although this has been a really great advancement in the field, you can see that CLL with prior BTK inhibitors an BCL2 inhibitors is still an area of unmet clinical need and we need better therapies for these patients.

Also interestingly, published in the New England Journal of Medicine in 2022 was a small study looking at resistance to pirtobrutinib. This was a small study. It was only 9 patients. And so, you know, we gain the information that we can from it, but just note that it is a small patient population. And 7 of the 9 patients did develop a new BTK mutation. And I’ve shown their graphic here which is the location of their different BTK mutations and the number of ones that were developed. Now this is kind of a modification of the table that they showed, hopefully to make it a little bit more understanding. What they did is they looked at all these different BTK mutations, which are listed on the lefthand side, and they looked at all of these different BTK inhibitors, and covalents are listed on the left — or on the right, and the noncovalents are listed on the left. And they essentially tested CLL with these different BTK mutations to see which drugs could have a response. And so the top line is easy, wild type BTK, all of these drugs look like they have great and normal inhibition. The bottom line is fairly easy based on what we know now. The C481S mutations, of course, all the covalent drugs have decreased binding to that because that is their binding site and necessary for activity.

And all the noncovalents have normal activity with the C481S. What I think is really interesting is what’s in between. So you have all these different mutations and the different BTK inhibitors have different susceptibility to them. And so are we getting to a timepoint where we have lots of different BTK inhibitors available? Maybe we can just choose which BTK inhibitor would work best for the patient based on their mutation profile. Maybe that’s something that we could move to in the future. And then also, what’s notable is the second from the bottom, there’s an L528W mutation. This mutation seems to be particularly bothersome because there was also another paper published early about zanubrutinib resistance, and these mutations were seen disproportionally high in the zanubrutinib patients. And so as we move to using zanubrutinib in earlier lines of therapy, will that negate the ability to use pirtobrutinib after zanubrutinib? I think this is still really an area of active investigation.

So takeaways from this study in this small sample of 9 patients, CLL resistance to pirtobrutinib has now been described. And 7 of 9 developed new BTK mutations. And all the BTK inhibitors tested had different abilities to inhibit the described mutations. So, again, these are big, scary mutations and so this is the reason why a lot of people feel that caution should be used in moving pirtobrutinib to the frontline setting because most of these mutations will render all the covalent BTK inhibitors ineffective. Of course, this is a moot point if we can see that pirtobrutinib causes years and years of progression free survival which doesn’t make us think we need to figure out how to still sequence these drugs.

DR LOVE: Are any of the other noncovalent agents have similar level of data or are they way behind?

DR STEPHENS: All of them are significantly behind pirtobrutinib. You saw the size of that Phase I study. That was only 1 cohort and it was 247 patients. But nemtabrutinib or ARQ-531 is probably the next closest behind which is also a very effective drug. And it is moving into Phase III studies right now. Some are open and accruing. And so I think we’ll see a lot more about that drug coming up as well.

DR LOVE: So you mentioned zanubrutinib, and I think Jennifer is going to cover this, but I am curious what your thoughts are about the data that was just presented at ASH.

DR STEPHENS: Yeah, I think that those data were very good and impressive data because this is the first time that a head-to-head BTK inhibitor study has shown a difference in progression free survival advantage of zanubrutinib over ibrutinib. And there were a lot of patients that had to discontinue ibrutinib secondary to toxicities, and so maybe that makes up some of the difference. Maybe people just aren’t able to stay on drug as long. And there is potentially some preclinical, you know, or the PK data of zanubrutinib might explain. It does have better inhibition of BTK with a higher IC50 that’s maintained continuously over 24 hours. So maybe it’s better inhibition of BTK.

The one thing I would caution, we do have the ELEVATE-RR study with longer follow-up and that is like 4 years of follow-up. And that study compared acalabrutinib to ibrutinib. And that one did show completely equivalent PFS with eventual overlap of the PFS curves. But if you kind of take a slice out of that and look at that at 2 years, the acalabrutinib curve was actually higher than ibrutinib at 2 years. And at about 30 months or 3 years, that’s when the curves overlapped. And so I think, you know, if we’re going to really see a difference long-term, I think hopefully, we’ll see the longer-term follow-up support that as well. I think, in general, zanubrutinib is a great drug, has a great toxicity profile. And so I think once this gets approved for CLL here in the United States, I do think a lot of people will go to it as a frontline, you know as their first choice in terms of BTK inhibitor.

DR LOVE: I’m just trying to get a feel for this because I know when the data was originally presented last summer at EHA, people brought up what you just brought up, the fact that acalabrutinib early on and they brought up the way the study was done, how response is. So they were, you know, people generally were interested, but they didn’t seem ready to change their practice or want to use it. Do you think, it’s kind of early and I don’t know how much interaction you’ve had about it, but do you think that’s still going to be the feeling or do you think this is going to be practice changing?

DR STEPHENS: I think it will be mixed. And I think any patients that are still on acalabrutinib, I don’t think anybody is planning to switch them over to zanubrutinib. But I do think that when you — when patients — or when physicians are starting therapy with single agent BTK inhibitor therapy, I do think this data does affect practice because it really does show an advantage of PFS. And, again, we just have longer follow-up with acalabrutinib and so we’re starting to see more cardiac toxicities with acalabrutinib. And, of course, that’s a big deal that people want to pay attention to. And I don’t know yet. Zanubrutinib does seem to have lower toxicities at the same timepoint in terms of cardiac toxicities. But maybe with longer follow-up of zanubrutinib, are we going to see an increase in their cardiac toxicity associated with it as well? I think we probably will, but to what extent? So I don’t know. I think one really great thing to note is that patients with CLL have very good treatment options because we’re talking about small differences in all of these, you know, progression free survival, big differences in toxicity. I think it's the longest discussion I have when I talk with a patient about what to start them on frontline therapy.

DR LOVE: Please continue.

DR STEPHENS: The next thing I want to shift my focus to is CAR T-cell therapy and where does it sit for CLL. As you know, this is moving forward, has multiple approvals in other types of B-cell malignancies. I wanted to highlight the TRANSCEND study which looked at lisocabtagene maraleucel which is a CD19-directed defined T-cell composition CAR T product. This Phase I/II study that was recently published, there were 23 patients with relapse or refractory CLL, so a relatively small study publication. About half of those patients had prior treatment with BTK inhibitor and BCL2 inhibitor. It showed a really great overall response rate, 82%, with a 46% CR rate and 75% MRD undetectable rate. So all really great responses. And notably, the progression free survival was very similar between patients who were refractory to both BTK and venetoclax versus those who were not refractory to both of those. And so another good — some more good data for this relapsed and refractory population.

Of course, I can’t talk about CAR T without mentioning the important toxicities which notably, cytokine release. And about 3/4 of patients did have that, but only 9% had Grade 3 or higher, so one of the more tolerable CAR T-cell products. Neurotoxicity is also important. 30% had any grade neurotoxicity, 21% of that was Grade 3 or higher, so notable toxicity. So great response rates, but really important toxicities, especially when you’re talking about treating a patient who may be up into their 80’s with this therapy, this is definitely very — can be challenging for them to recover after this treatment.

So some of the takeaways here, this is also high-risk relapsed or refractory CLL population. This liso-cel led to deep remissions. 75% had MRD undetectable disease. However, I just showed you the data with pirtobrutinib in a similar population. And so especially in patients treated with BTK and BCL2 inhibitor, PFS is similar to what was seen with pirtobrutinib and then CAR T has more toxicity and cost than pirtobrutinib. And so toxicity may limit the population that can receive CAR T-cell therapy. And the other question is, should we be using CAR T as a bridge to more definitive therapy? And so, for example, my really high-risk patients that have Richter’s transformation, I am referring some of those that are candidates for allogeneic stem cell transplant after they — I get them into a CR with CAR T. Again, just want to highlight that CLL patients that have prior treatment with BTK inhibitor and BCL2 inhibitor is still an area of unmet need.

I want to shift gears for the last 2 abstracts that I want to talk about, just some exciting recent data published — or presented at ASH 2022 specifically focusing on what I think is probably the greatest area of unmet need for patients with CLL which is Richter’s transformation. Again, that’s a transformation from CLL into more aggressive lymphoma, most often diffuse large B-cell lymphoma. These patients have very poor survival. The quoted median survival of these patients is about 6 to 9 months. And so that BRUIN study that I mentioned with pirtobrutinib, the noncovalent BTK inhibitor, also had a cohort of patients with Richter’s syndrome, 82 patients with Richter’s syndrome. Believe it or not, that is a huge study for this patient population. And so I commend the planners of the study for getting this many of this really high-risk population on the study. They were heavily pretreated. If you put together the median prior CLL and Richter’s treatments, they had 4 median prior therapies, but up to 13 prior therapies. About 1/3 of them had prior BTK inhibitors, 1/3 had prior BCL2 inhibitors, and even 11% had a prior CAR T before going on this study. Really notable, there were 52% of patients that responded which is a tough thing to achieve for patients with Richter’s transformation. And I think even more notable, there were 10 patients on the study that got a CR with just a single agent BTK inhibitor therapy which I think is pretty notable. The median progression free survival is still really short, 3.7 months, but the median overall survival is 13.1 months. And remember, the expected survival for these patients is 6 to 9 months and so really, although it’s small numbers compared to what I talked about with CLL in general, this does likely represent prolongation of their lifespan. The other thing I wanted to highlight is just the duration of response. And, of course, you see kind of quickly, you see a lot of patients fall off this duration of response curve. But there are patients down at the end of the curve which looks like it stabilized a little bit. And so are there patients that maybe can have longer-term response to this drug? I think that this is an interesting curve to consider.

So the takeaway from this, pirtobrutinib led to responses in heavily pretreated patients including 13% complete responses. PFS and OS are still short. However, the authors noted that there were 6 patients that were able to proceed to curative intent allogeneic stem cell transplant after being maintained on pirtobrutinib. And so maybe, again, should we be using pirtobrutinib as a bridge to more definitive therapy like allogeneic stem cell transplant? And, again, Richter’s syndrome really remains an area of unmet need.

The last abstract I want to highlight is another one about Richter’s syndrome that was presented at ASH 2022. This is very early preliminary data, but definitely caught the eye of lots of people. And this is the EPCORE study. And this was a cohort of just 10 patients with Richter’s syndrome. It was a little bit les heavily pretreated. You could only have 1 to 3 prior treatments for Richter’s. And epcoritamab is a bispecific antibody to CD3 and CD20. It was given subcutaneously. It was given weekly for the first 3 weeks and then every other week until week 9 and then — or until month 9. And then, it was given every month starting cycle 10 and higher. Median prior CLL treatments was still quite high at 3 prior CLL treatments was 0 to 7, not quite as high risk of a population as I just talked about on the pirtobrutinib study. There were 60%, so 6 of the 10 responded. And 5 of the 10 ha a complete remission which I think, again, is really notable. As a class, these bispecific antibodies do have a risk of cytokine release, and 90% of patients experienced this, but all of them were Grade 1 or 2 and most of it was with the first full dose given. They ramped up the dose slowly. And at cycle 1 day 15, gave the first full dose. And most of that cytokine release came around that time. The median time for first full dose at that cycle 1 day 15 to CRS was 13 hours, so most of these patients, they were hospitalized for monitoring and they experienced it during that first day. And the median time to resolution was 3 days. Zero toxicity — or neurotoxicity was listed as 0. You see that as a difference from the CAR T studies.

I think what was notably missing, and I did not show it because it was not shown, is the duration of response which I think will be really important to see from this study. So takeaways, in a small study of 10 patients with Richter’s syndrome, epcoritamab delivered 60% overall response and 50% complete response rate, had a great toxicity profile with only low-grade CRS, but did require hospitalization for monitoring for this CRS. The follow-up of this study is really short. And I do think it’s really important to figure out information about duration of response because is this something that’s going to cause long-term remissions or, again, is it something that we need to use as a bridge to more definitive therapy? And, again, can’t say enough about how much Richter’s syndrome is an area of unmet need.

DR LOVE: Yeah. So I was shocked when I saw the pirtobrutinib study with Richter’s. I was asking people at MD Anderson had they treated people, et cetera. I never — I’d heard about BTK plus R-CHOP in diffuse large B-cell. So what do we know about BTK in diffuse large B-cell and BTK alone in Richter’s?

DR STEPHENS: Yeah. So BTK in diffuse large B-cell, it’s really a very small patient population that has any responses and mostly, the activated B-cell subtype of diffuse large B-cell. But really, in diffuse large B-cell, you haven’t seen a large uptake, you don’t see any approvals of BTK inhibitors there just because it’s really a small population that can benefit. And one of the areas I tend to use it most, because I also treat some patients with diffuse large B-cell, is when people have CNS disease. And I use it as a supplement to others because it does penetrate into the CNS really nicely and clear disease there. So not huge efficacy in general de novo diffuse large B-cell lymphoma. And as far as single agent Richter’s treatment with BTK inhibitors, there’s some data. It usually causes at least like stable disease, but it’s very short remissions. And so there does seem to be something special about this BTK inhibitor therapy, maybe some mechanism that we don’t yet understand that’s causing these good responses in Richter’s syndrome.

DR LOVE: So the real question to me is what about pirtobrutinib in diffuse large B-cell?

DR STEPHENS: Yeah. That’s a great question. And I actually don’t know off the top of my head if that’s an area where they’re targeting. I know they had a large study that included all different B-cell malignancies, but I don’t think I’ve seen reports, and I may just not have seen them, specifically, of a diffuse large B-cell cohort. I think that’s a great question.