Current Role of Covalent Bruton Tyrosine Kinase Inhibitors and Bcl-2 Inhibitors in Chronic Lymphocytic Leukemia (CLL) — Paolo Ghia, MD, PhD

PROF GHIA: Hello to everyone. My name is Paolo Ghia. I am Professor of Medical Oncology at Università Vita-Salute San Raffaele in Milan, Italy, where I am directing the CLL program.

So today, I am here to discuss what has been published on the topic of chronic lymphocytic leukemia in the past year. And I will try to review the most available and interesting data that came out.

In general, the data that I’m going to present are somehow the confirmation of data that we already knew. And, therefore, we are going to talk about longer follow-ups of key seminal studies that have really proven the efficacy and the tolerability of many new drugs in chronic lymphocytic leukemia. And in particular, on the BTK inhibitors and the BCL-2 inhibitors, alone or in combination.

The first study that we are going to discuss is actually a very interesting study, a very unique study, the Phase III CLL12 study that was run by the German CLL Study Group, though it was an international study. And this is a one-of-a-kind study because it was directed around patients who did not need treatment. And in particular, patients who were at higher risk of progression. And they were randomized to either ibrutinib or the BTK inhibitor, first-generation BTK inhibitor, or placebo, so just the typical active surveillance that we would do in our patients. And probably to no surprise, we already saw the 5-year follow-up and then now, we have seen the 10-year follow-up, and with the 10-year overall survival where we don’t see any difference between ibrutinib and placebo. Of course, in a preemptive study, the endpoint cannot be progression-free survival. Because in that case, of course, treatment with ibrutinib with a progression, the second progression, I will say, is definitely longer than with placebo. But the key endpoint has to be overall survival in such type of studies. And here, as you can see, the numbers are very, very similar between ibrutinib and placebo. There was a third cohort of patients who were not considered at high risk. And, therefore, they were followed in watch and wait or active surveillance. And you can see that they even had a higher percentage of patients who were still alive after 10 years. And you somehow expect this because those patients definitely had a very low risk of progression and need of therapy.

Another study that also has been interesting in the past year was a pooled analysis of 5 different clinical trials where the second-generation BTK inhibitor, acalabrutinib, had been tested. And this is a study presented by Matt Davids. And the meaning here is indeed that by combining hundreds of patients treating with acalabrutinib, we do confirm the efficacy of this type of treatment. And in particular, the plots as you are seeing, are in treatment naive patients where we do see that treatment with acalabrutinib alone or acalabrutinib in combination with obinutuzumab or another combination are very similar in terms of response, in particular, long-term outcome, for all categories of high-risk patients. So those with deletion 17p or p53 mutation, those with unmutated immunoglobulin genes, and those also with complex karyotype, though the complex karyotype here, it is still defined with the old definition of 3 or more aberrations while instead we know that in CLL, the threshold of 5 or more aberrations is what can be meaningful in patients with CLL. The interesting point is to compare the different percentage of patients who did not progress yet after 4 years. And as you can see, as expected, the patients with deletion 17p and p53 mutations have a slightly shorter progression-free survival compared to patients with unmutated immunoglobulin genes and definitely compared to patients with complex karyotype because those include definitely patients at low risk of progression. So we know that now, the life expectancy and the outcome of patients with deletion 17p or p53 mutations is definitely much improved compared to the era of immunochemotherapy. But still, probably they have a little disadvantage compared to the remaining of the patients.

In the study, they also pooled patients who were treated in the relapsed/refractory setting. And as you can see and as you may expect, the progression-free survival, the percentage of patients free of progression at 3 years, so now it’s shorter follow-up, are definitely less, as we know and as we expect. And again, there is somehow a gradient between patients with unmutated immunoglobulin genes, those with complex karyotype, and those with p53 abnormalities.

In addition, if you look at the patients in the relapsed/refractory setting with those in front line and you stratify the patients based on the line of treatment, then as we’ve already seen in the past for ibrutinib, the first-generation BTK inhibitor, we do see that the earlier line in which the drug is used, the better progression-free survival we obtain. So with roughly 10% less patients who are progression free in second-line and even another 10 or more in third line.

As I mentioned earlier, patients with deletion 17p remain patients of particular concern. So you might see that here, again, when we stratify them by line of therapy, we do see that if we wait too long, so we are in 2 or more lines of therapy, then the progression-free survival becomes very, very low. What is reassuring if the patient is treated in front-line, after 3 years, still almost 90%, 86% of them despite having deletion 17p, they are still progression free, which is, again, long-term results that are reassuring on the efficacy even in this high-risk population.

So another important question that we always ask is how the different novel drugs are tolerated in different subgroups of patients stratified by age. So we know that in the era of immunochemotherapy, we had really to use different therapies based on the age and the fitness of the patient because the tolerability of the treatment was very different, dramatically different between age groups. And, therefore, we had to select different treatment. Is it true that it is the same in the era of novel therapies? The general feeling is that it’s not. And this is a study that is indeed addressing this question by analyzing the patients who are older than 80 years old, so really the elderly patients where probably 1 line of treatment should be sufficient given their life expectancy. And this is the so-called Phase II CLL-Frail study where acalabrutinib, again, second-generation BTK inhibitor, was used in patients very old or also frail. And as you can see here, the overall response is exactly what you would see in any other patient with chronic lymphocytic leukemia. And in particular, you do see that the frailty score of the patients increases with the response of treatment. So suggesting the idea that the frailty of the patient, in many cases, is really associated to their disease rather than the age, per se, of the patient.

So now, we are starting a review of long-term follow-up of a number of key seminal studies, the first one being the Phase III SEQUOIA study. Dr Shadman presented at ASH the 5-year follow-up of so-called cohort 1. The SEQUOIA study is a somehow complicated study where there were 3 different cohorts, 4 different arms. Here, we are looking at the cohort of patients without deletion 17p and that who were randomized to either zanubrutinib continuous treatment, second-generation BTK inhibitor, or the traditional standard therapy for an elderly fit patient, bendamustine plus rituximab. And as you can see here, this is the progression-free survival where at 5 years, it’s almost plateauing. Meaning that it’s at 76, almost 76% compared to 80% that we had 6 months earlier. And as compared to bendamustine that was already shown at an earlier timepoint that it is overwhelmingly superior compared to bendamustine plus rituximab. The nice data and the nice evidence that are reported here is that indeed we have a very high progression-free survival after 5 years, and that is decreasing very slowly with time.

This is, again, what is now officially done in every study is to stratify patients based on the immunoglobulin gene status. And here, you do see a couple of things. The SEQUOIA study has been a key study because it really proved that patients with unmutated immunoglobulin genes, when treated with bendamustine plus rituximab, they have a much worse progression-free survival compared to zanubrutinib, to the novel therapy. And the advantage here is, for both mutated and unmutated patients, that you can see here by comparison of the lines is that though the mutated patients have a high advantage compared to bendamustine when treated with zanubrutinib, the unmutated patients have a dramatically higher advantage. Really suggesting that, as we already knew, the unmutated immunoglobulin gene status was predictive of a poor response to immunochemotherapy.

So in general, the SEQUOIA study, a Phase III, the cohort 1 has really proved and confirmed that the PFS benefit using zanubrutinib, a second-generation BTK inhibitor, is very relevant for patients compared to patients treated with bendamustine plus rituximab. And in particular, the great advantage is for patients with unmutated immunoglobulin genes. From a safety standpoint, again, the 5-year follow-up did not show any surprise. We know already well that this is a well-tolerated drug and with low rates of atrial fibrillation.

Another long-term, or probably not so long, but definitely the final analysis of a key study is the ALPINE trial. So Jennifer Brown presented the final analysis. And the ALPINE trial is a key study because it compared head-to-head the second-generation BTK inhibitor, zanubrutinib, to the first-generation BTK inhibitor, ibrutinib. And we already knew that zanubrutinib was superior to ibrutinib in terms of overall response, in terms of progression-free survival, in terms of safety, in particular, in terms of frequency of atrial fibrillation. And here, this is confirmed at 3 years. This definitely is not very long follow-up, but is consistent and reproducible compared to the previous follow-up at 18 months or after 1 year. So you can see the PFS with a difference of almost 10 points in terms of progression-free survival. And that is larger when we look at patients with deletion 17p and p53 mutation. In terms of overall survival, as we may expect, and luckily for all patients, there is no statistically significant difference, though numerically speaking, there are less deaths when using zanubrutinib compared to ibrutinib.

And in terms of safety, as I mentioned, you can see the zanubrutinib in red and ibrutinib in blue. There is a dramatic advantage in terms of atrial fibrillation while instead other adverse events of clinical interest like hypertension or bleeding remain very similar. What is also interesting, there were some initial hints that zanubrutinib could be associated with an increased risk of neutropenia. But as you can see here, the values and the frequency is very similar between ibrutinib and zanubrutinib.

As I mentioned, when I spoke about adverse events of clinical interest, those are particularly the cardiovascular adverse events. And we already learned since the first introduction of ibrutinib that indeed the heart and the cardiovascular system in general is somehow a target also for the drug so that there are what we call now adverse events of clinical interest. And we should always keep an eye before treating the patient with any BTK inhibitors. And those are in particular a risk of atrial fibrillation, a risk of bleeding and in particular minor bleeding, but also the major risk is for major bleeding. Fortunately, they are very rare with all BTKis, around probably 1%, and most of them resolve with no sequelae. And the other adverse event of clinical interest is hypertension, increase in hypertension or less control with an established treatment. And now, it became also evident that the heart failure can be indeed induced and associated with the use of BTK inhibitors. Ventricular arrythmias remain, luckily, a very, very rare event. They have been shown earlier for ibrutinib and still remain to be explored and definitively proven or not in the case of other BTK inhibitors.

So in general, this is work by Dr Kozarac that is trying to define the cardiovascular risk so that in order to better stratify the patients when we decide to use a BTK inhibitor.

What we are looking at is more or less evaluation of cardiovascular risk that is, in general, the risk of thrombotic disease, the risk of bleeding events, it can be based also on the platelets counts. Of course, it is advisable to run an EKG before starting the therapy. Maybe in some particular cases, halter monitoring. Definitely, we have to learn and remember to measure the blood pressure in our patients. So at the end of the day, we cannot really exclude anyone from the treatment of BTKi. So the evaluation of cardiovascular risk should be done in particular to address all the ongoing issues that are unknown. So if there is an uncontrolled blood pressure, if there is an ongoing minor cardiovascular failure, if there is already a previous bleeding risk because the patient is taking anticoagulant or anything, so that we can really maximize and optimize the therapy so that the patient can start the therapy with BTK inhibitors in the best condition possible.

There is no particular subgroup of patients that should be excluded from the treatment with BTKi with the only exception of patients who are on double anti-aggregation therapy like typically after a stent. But we know that that period is becoming shorter and shorter thanks to the improvement and the research in cardiology so that typically, we can wait until the patient has the period of anticoagulation, double anticoagulation, anti-aggregation. And, therefore, we can start the BTK inhibitor if we believe that that’s the best therapy for our patient.

So here there is, again, the algorithm that you can check in detail if you want. But in general, one should really be attentive on this different aspect of cardiovascular disease in order to optimize and improve the therapy to control any particular ongoing cardiovascular disease so that we are not worsening it with the BTK inhibitor therapy.

Another seminal study which we have seen now during the past year is the CLL14 study. Phase III, 6-year follow-up. This is, again, a study from the German CLL Study Group though it was, again, an international study. And it is the seminal work that showed that the combination of venetoclax plus obinutuzumab, venetoclax given for 12 months, obinutuzumab given in the first 6 months, was superior to chlorambucil plus obinutuzumab in the elderly comorbid patients. And so we know that venetoclax/obinutuzumab was better than chlorambucil plus obinutuzumab in terms of progression-free survival. This is, of course, confirmed also after 6 years. The impressive result is that even after 6 years, more than 50% did not yet progress. And this is particularly astonishing because the patients received only 12 months, 1 year of treatment. As we already learned in the past and that is confirmed also with the 6-year follow-up is that certain genetic features may have an impact on the long-term response. So if we look at patients with p53 deletion and/or mutation, you do see the blue curve, the solid blue curve in the middle, these patients have a shorter progression-free survival compared to patients without these aberrations.

And, therefore, the median progression-free survival had been reached already a long time ago, 51.9 months, so roughly 4 years, which means 1 year of treatment, 3 years after treatment, half of the patients are already progressing. For the immunoglobulin gene status, similar though less dramatic pictures where patients with unmutated immunoglobulin genes, they progress earlier than patients with mutated immunoglobulin genes. But the 50% threshold occurs, so 50% of the patients will progress after 64.8 months, so more than 5 years. So it’s 1 year of treatment and more than 4 years, 4 years and a half of progression-free survival. The bad news because we all expect it is that the mutated cases, we know they respond very well and the median progression-free survival has not been reached, we really hoped to see a plateau like we were seeing with the fludarabine, cyclophosphamide and rituximab. At the moment, it’s not yet evident. So of course, we see the plateau with FCR after 10 years of follow-up. So we are hopeful that in the future, we will see at least a proportion of patients that will be plateauing in terms of progression-free survival.

This is overall survival. And again, there is an advantage for venetoclax plus obinutuzumab compared to chlorambucil plus obinutuzumab. And again, for patients with p53, there is no doubt patients with p53 aberration should not be treated with any chemoimmunotherapy. And again, you can see that patients with unmutated immunoglobulin genes are those with the highest advantage compared to the immunochemotherapy. Patients with mutated immunoglobulin genes, probably they have a lower advantage that is becoming evident only after a longer follow-up.

Of course, when venetoclax is involved in the treatment of patients, the important data is the achievement of measurable residual disease, previously called minimal residual disease, MRD. Two pieces of information. The first is that all patients after 6 years lost the status of undetectable MRD. So we’re not able with that only 12 months of treatment to maintain the persistence of undetectable MRD in any patient. And of course, as we know, there is an advantage in achieving undetectable MRD compared to those who do not achieve undetectable MRD. But important information is that compared to chlorambucil plus obinutuzumab, reaching 10^-4, so 1 cell, less than 1 cell in 10,000, 10^-5, 1 cell in 100,000, 10^-6, 1 cell in 1 million, doesn’t make a big difference after 6 years. While instead, it makes a huge difference when you use chemoimmunotherapy already after a couple of years of treatment. So this is the good news. And this is something that we’re going to be learning with the next follow-up to see really if and when there will be a difference in the level of undetectable MRD in terms of progression-free survival.

Another study that I want to talk about is a very interesting study because somehow we all dream of doing something like that, an adoptive duration of treatment in our patients. This is a Phase II study by Dr Thompson again using venetoclax plus obinutuzumab. After 6 years, we know that we don’t maintain undetectable MRD in patients. The patients progress and so we don’t achieve any plateau. So the idea would be why don’t we personalize the duration of the treatment based on the MRD. And so patients were analyzed for their level of undetectable MRD after 7 months. Those who were undetectable continued until 9 months, then they stopped. Those who were detectable at 7 months continued until 12, and then they stopped. Those who were positive at month 12, they continued for an extra year, and they all stopped regardless of the MRD status. Again, with the idea that still, we don’t want to do anymore continuous treatment. We want to have anyhow a fixed duration treatment so that patients can experience a drug holiday, a long drug holiday period in particular without potential adverse events and financial cost and so on and so forth. And these are the results where we do see that we have, of course, the follow-up is still short at 12 and 24 months, but it is very promising. We are well above 90%, of course, in terms of progression-free survival. It’s much higher in terms of overall survival. So it will be interesting to see in the future how these curves will be maintained.

Another important study for which we have seen a longer follow-up is the GAIA/CLL13 Phase III study. A rather complicated study again by the German CLL Study Group. And this was a study, front-line again, in which different combinations of venetoclax were compared to classic chemoimmunotherapy. FCR, fludarabine, cyclophosphamide and rituximab for a young, fit patient, or BR, bendamustine/rituximab, for an elderly, fit patient. And it was compared to venetoclax plus rituximab, which is the traditional treatment in relapsed/refractory, venetoclax plus obinutuzumab, which was already the standard therapy in front-line, and venetoclax plus obinutuzumab plus ibrutinib, so a triplet combination including also a BTK inhibitor. We already knew that the best treatment in terms of undetectable MRD and progression-free survival were the triplet, venetoclax/obinutuzumab/ibrutinib and venetoclax plus obinutuzumab, which were superior to even venetoclax plus rituximab and definitely to chemoimmunotherapy. The interesting point was that at the earlier timepoints, we didn’t see any difference between the triplet and venetoclax plus obinutuzumab. Now, we start seeing this difference though, again, not visible at 48. And we will see if with longer follow-up it might become really statistically significant.

In this case, again, I show you the results for unmutated patients and patients with mutated immunoglobulin genes. Again, patients with mutated immunoglobulin genes had always a better response and better outcome. But also, in the mutated patients, we do see a difference between the triplet and venetoclax plus obinutuzumab compared to the other treatment. The advantage is always maximal in patients with unmutated immunoglobulin genes where probably the triplet combination might show a more benefit. And probably, this can be also discussed in the light of the results from the AMPLIFY where acalabrutinib was combined with venetoclax and obinutuzumab showing a similar trend for patients with unmutated immunoglobulin genes.

But the GAIA/CLL13 study also showed us already in the past and that’s confirmed with the 4-year follow-up that there is a price that we have to pay for the triplet, which is in terms of safety. So infections, you can see the number of infections in purple are in the range of those that we have with patients treated with chemoimmunotherapy. And that is also true when we look at Grade 3 or more infections. So it might be that we have a more sustained response. But it’s also true that we are exposing the patients to higher risk of infection. That, again, will be nice to talk about when looking at the data from the AMPLIFY study. And it’s something that we have to understand well so in order to better understand who is our candidates, potential candidates for the use of triplet. And again, also for cardiac disorders, the triplet has much higher cardiac events compared to any other treatment with venetoclax. Of course, we are using a BTKi, so this is always something that we have to keep in mind.

And with that, I conclude with a summary of the GAIA study. Again, we are all looking forward for more additional follow-up, longer follow-up in order to understand better the role and the placement for the triplet, venetoclax, obinutuzumab and ibrutinib.

We conclude with the CRISTALLO study. The CRISTALLO study is a Phase III trial where the combination of venetoclax/obinutuzumab again was compared to chemoimmunotherapy, but for young, fit patients or elderly, fit patients, so FCR again or BR again. So it’s including the patients who were not enrolled in the CLL14 where venetoclax/obinutuzumab was compared to chlorambucil plus obinutuzumab. The schema is very easy, 1 year of treatment with ven/obin, venetoclax given for 12 months, obinutuzumab for 6 months, and FCR/BR as usual, 6 months of treatment.

And here, you can see that the combination of venetoclax/obinutuzumab is much more potent in obtaining MRD that we already knew. This was the primary endpoint, undetectable MRD in the peripheral blood. More than 80% of the patients as assessed by next-generation sequencing. The second endpoint, which is PFS, is not yet mature. There is no statistically significant difference. But you can see that at the numerical level, there are less progression with venetoclax plus obinutuzumab.

And, therefore, we hope to see longer follow-up. But also, that at least start confirming that also in the young or younger patients, fit patients, ven/obin is an option that is very valuable, is beneficial for our patients. At the moment, definitely in terms of undetectable MRD where we know from the CLL14 that undetectable MRD tends to correlate and associate with the PFS. And in particular, we know that in the future, undetectable MRD rate will probably become or should become somehow an early timepoint, an intermediate timepoint to assess the efficacy of the novel treatment.

Last but not least, a study, the VENICE study, a Phase IIIb with single arm where venetoclax monotherapy was studied, but in relapsed/refractory patients with CLL. Arnon Kater was the principal investigator. Venetoclax monotherapy has never been tested really seriously, let’s say, in the relapsed/refractory setting because it has been almost immediately associated with rituximab. So this is a treatment really to show that even venetoclax alone is very potent. And in particular, when looking at the data from the CLL13/GAIA where obinutuzumab is so much more potent compared to rituximab when associated with venetoclax, we really wonder what venetoclax is adding to the venetoclax monotherapy if taken continuously. And you can see here that the response is very promising, meaning that with one-third of patients achieving complete response even in patients who were exposed earlier to BTK inhibitors or they were naïve to BTK or even PI3 kinase delta inhibitors.

These are the curves. What we learned from this study, unfortunately, is that the patients who have been exposed to BCR inhibitor, let’s call it kinase inhibitor, which is probably the best term, that is if you use venetoclax, you have 24 months of PFS as the median value. So we know and awareness is becoming clear to everyone that patients failing continuous kinase inhibitor, they are really difficult to treat. And, therefore, when we use venetoclax, even in combination treatment, we always achieve a couple of years of progression-free survival. Luckily, now, we will have probably very soon in the United States, they already have it in Europe, we will have probably soon BTK inhibitors of third generation which, in particular, pirtobrutinib which hopefully will be approved soon.

So in general, venetoclax monotherapy demonstrated, as we already knew but at least in a prospective study that can achieve deep and durable responses regardless of the use of previous kinase inhibitors. And there was no flag in terms of safety issues.

Novel Agents and Combination Strategies — Jennifer R Brown, MD, PhD

DR BROWN: Hello. I’m Jennifer Brown, Director of the CLL Center and Institute Physician at Dana-Farber Cancer Institute in Boston and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School. And today I’ll be discussing novel agents and combination strategies in CLL.

The first trial that I wanted to highlight is AMPLIFY. AMPLIFY was a Phase III multicenter international trial, which compared acalabrutinib/venetoclax, acalabrutinib/venetoclax/obinutuzumab and FCR or BR, investigator choice in terms of a primary endpoint of progression-free survival. So the primary endpoint was reported at ASH in 2024 and has recently been published in The New England Journal of Medicine. And that’s shown in the left curve, where you can see that the 3-drug combination of AVO resulted in an estimated 3-year progression-free survival of 83%. The 2-drug combination of AV resulted in a 3-year progression-free survival of 76%, and the chemoimmunotherapy arm had a 3-year progression-free survival of 66%. So this was significant for the comparison of AV to chemoimmunotherapy and for AVO to chemoimmunotherapy. There’s no planned comparison between the AV and the AVO arms themselves.

I would draw your attention also to the data on the right, which is a planned analysis looking at progression-free survival by IGHV status. And what’s particularly interesting is that we see that even with the higher-risk, unmutated IGHV the patients on the AVO arm had a very similar progression-free survival to the overall group at 83%. Typically we would expect that the progression-free survival for the unmutated patients would be worse than those with the mutated IGVH, but it’s actually quite similar. And then in the AV arm we do see some decrease to 69% for unmutated IGVH compared to the overall cohort, and then certainly also with the chemoimmunotherapy. The median PFS was not reached for AV or AVO and was about 4 years for chemoimmunotherapy.

In terms of rates of undetectable MRD in evaluable patients, that was about 45% for AV, 95%, for AVO and 73% for chemoimmunotherapy. That was measured at the end-of-treatment timepoint. The end-of-treatment timepoint for AV and AVO is about 14 months. Most of that’s the combination of acalabrutinib and venetoclax. Obinutuzumab is given between months 2 and 7 in the arm that got obinutuzumab. And then for chemoimmunotherapy it’s obviously a couple months after the 6-month mark.

So what about the results? Well, this is the first potential registration trial in the United States for a BTK/BCL2 combination, the first registration trial for a second-generation BTK inhibitor. I’m sure people are aware that ibrutinib/venetoclax has been studied in multiple trials, including the GLOW trial, which was a registration trial. And that regimen has received approval in Europe but did not receive approval in the United States due to safety concerns, particularly cardiac events with ibrutinib in the older patient population. So in the United States we haven’t yet had a combination of BTK and BCL2, and hopefully we will soon hear about an FDA approval for this.

The acalabrutinib/venetoclax arm was really very safe and very easy. The rate of adverse events in terms of neutropenia, which was the most common adverse event, was really rather low, and infections, Grade 3 or higher, were only 12%, which is lower than almost all of our front-line therapies. So I view this as potentially applicable to most any CLL patient, well tolerated and easy.

The AVO 3-drug regimen was very effective. As we discussed, it equalized outcome in the unmutated and mutated IGVH patients at 3 years. This is at a cost of somewhat more neutropenia and more infections, and so that’s something to bear in mind. Particularly in this trial at the height of the pandemic there were more deaths on AVO compared to AV or chemoimmunotherapy due to COVID. I think that’s probably a unique feature of what happened during the pandemic, though, and that would not happen now.

And so the AVO arm is particularly good for higher-risk unmutated patients, perhaps those with bulky lymphadenopathy who are young and able to handle it.

Now, in parallel, my colleague Dr Davids presented a 3-drug acalabrutinib/venetoclax/obinutuzumab regimen for patients with high-risk 17p-deleted disease. And in this study the regimen went for 25 months, but patients with undetectable MRD could stop after 15 months. And we now have 4-year progression-free survival for this cohort, and that’s 96% in the patients without p53 aberration and 70% in the patients with, despite pretty comparable rates of undetectable MRD in the patients with and without p53.

This PFS, I think, is still reasonably good for these p53-aberrant patients. How it compares to patients on continuous BTK inhibitor is obviously not clear since we don’t have a head-to-head trial, and we also don’t know how readily people can be retreated after this time-limited regimen.

So this is a longer MRD-guided AVO regimen that was studied in patients enriched for 17p-deleted disease, where it was highly effective in inducing undetectable MRD remission, with a bone marrow undetectable MRD rate of about 85%. The durability, as we just discussed, is somewhat reduced compared to the 17p-wild-type population, but nonetheless, it does look better compared to venetoclax/obinutuzumab, where we see that the 17p-deleted patients have a median PFS of about 4 years. There is an ongoing head-to-head trial in the German CLL Study Group comparing a 3-drug regimen of acala/ven/obin to ven/obin in patients with high-risk 17p-deleted disease.

The Germans have also studied acalabrutinib, venetoclax and obinutuzumab in relapsed CLL. And this is an interesting study because it was really rather heterogeneous in terms of the patient population and their prior therapy, but most of them had high-risk biomarkers, 76% unmutated IGVH, 32% with p53 aberration. About 40% had a prior BTK inhibitor/venetoclax.

They had optional debulking with bendamustine followed by initiation with obinutuzumab first, whereas the other regimens we’ve been discussing all start the BTK inhibitor first. In this one obinutuzumab started first, then acalabrutinib, then venetoclax. And there’s MRD-guided maintenance phase after the initial induction of 8 months. So the overall rates of undetectable MRD were actually quite high, 75% postinduction, and the best undetectable MRD was 93%. And the 3-year progression-free survival is 89%.

This is really fairly impressive for the 3-drug regimen in a relapsed heterogeneous cohort, and I think it does underscore the potential of using this in later lines.

On the right you can see at the top the time to undetectable MRD and MRD dynamics. And in the green, the patients who achieve undetectable MRD do so at widely variable times, which is exactly what we observe clinically. Whereas there are some, in red, who don’t achieve undetectable MRD. And we see that in most of these studies, that a certain percentage, 10 to 20% of patients, no matter how long you keep treating them, will not get to undetectable MRD. And we don’t understand the biology of that as yet.

So again, this is a heterogeneous group of heavily pretreated patients, where I think the regimen’s surprisingly effective, with a 3-year progression-free survival of 85%. But this issue of using MRD guidance and then some patients may not get to undetectable MRD, what do we do about that? Do they stay on 2 drugs indefinitely? I think that maybe that’s not the best idea because then when they progress they’ll be resistant, but then how long do we continue before we stop? And these are issues that are not readily studied in most clinical trials or readily studied comparatively, so that’s something that we’re going to have to start to assemble a body of literature on from the many variable experiences.

I think that the efficacy of the regimen does underscore the importance of trying to avoid the development of resistance to our key mechanism, BTK and BCL2. Although we do know that combinations can still work in patients individually resistant to either drug, but it probably won’t work for as long.

There’s interest, of course, in combining zanubrutinib with venetoclax, and we’ve heard updated data from SEQUOIA Arm D. SEQUIA, of course, is the registration trial front line for zanubrutinib. And Arm D is a combination of zanubrutinib and venetoclax, which starts with a 3-month lead in of zanubrutinib and then has combination therapy for 12 to 24 cycles, depending on undetectable MRD early stopping rules, and then zanubrutinib monotherapy until disease progression or toxicity.

Now this study had very strict discontinuation criteria, where patients have to have 2 bone marrow biopsies to confirm, in addition to peripheral blood. And so not all patients have always had all the bone marrow biopsies, and most patients are therefore continuing on treatment even beyond cycle 28, when they continue zanubrutinib until they meet the strict stopping criteria.

Now you’ll notice on the right also that the rate at which undetectable MRD, shown in the light and dark green, accrues is taking a little bit longer. We only start to see a good chunk of the bar out at about week 60, and as we get to week 108, 132, there we’re seeing more than 50% of the patients with undetectable MRD. Now the patient population that’s been reported so far in this study is patients with 17p deletion, and that may be why there’s a longer time to undetectable MRD.

So again, relatively slow achievement of undetectable MRD, which doesn’t really worry me. I think that is probably due to the 17p deletion. The very strict stopping criteria means that most patients have continued on therapy, and that does raise the question is this really a time-limited regimen, which we were discussing a little bit before with respect to the AVO regimen. It may be, though, that with the 17p-deleted patients a longer treatment duration is preferred. But again, we don’t really know that. And at the moment there’s not really any progression-free survival data. Response rates are extremely high, but we don’t have progression-free survival data from this cohort yet, so that will be eagerly awaited.

Now turning our attention to novel BCL2 inhibitors, sonrotoclax. So sonrotoclax is in development, and it has about tenfold potency in vitro greater than venetoclax, and it also has activity against the primary BCL2 resistance mutation, G101V. So that’s been studied in an omnibus Phase I study that includes a combination cohort with zanubrutinib, so BTK/BCL2 combination.

And we had an update on this at ASH last year, where you can see on the left the response rate is essentially 100% already by week 24 at both dose levels of sonrotoclax, 160 and 320. And the CR rates go up and reach about 40% by week 48, which is quite reasonable. And then on the right the rates of undetectable MRD are also quite high, 78% in the 320 mg dose by week 24 and up to 91% by week 48.

So sonrotoclax and zanubrutinib are demonstrating substantial antitumor activity in treatment-naïve CLL. As I mentioned, sonrotoclax is more potent in vitro, yet so far there’s been quite limited tumor lysis on this study. The ramp-up schedule is pretty much as complicated as venetoclax, although in some of the later studies they are trying to simplify it to make it easier than venetoclax.

This study does represent the highest undetectable MRD rates we’ve seen with any BTK/BCL2 combination if you don’t have an antibody. But it’s also a selected Phase I population at selected centers, so it needs longer follow-up and more broadly multicentered trials to see if these rates of undetectable MRD hold up. There’s also been only 1 progression event so far, but, again, follow-up is relatively short.

Pirtobrutinib is a noncovalent BTK inhibitor, which was approved by the FDA about a year ago, a little over a year ago, for patients relapsed after BTK and BCL2 inhibitor. And there is a large Phase III program in place for pirtobrutinib, and at ASH this past year again we heard the first results of one of the randomized trials with pirtobrutinib, which is the BRUIN 321 study comparing pirtobrutinib to investigator choice of idelalisib/rituximab or bendamustine/rituximab, with about two thirds of the patients having received the idela/rituximab rather than the BR. Patients were either venetoclax naïve or venetoclax treated, about half and half, as you can see here.

And so the study met its primary endpoint of improved progression-free survival for pirtobrutinib compared to idela/R or BR. And here we’re looking at the time to next treatment or death data, where we can see that it’s about 30 months for the venetoclax-naïve cohort and about 20 months for the venetoclax-treated cohort. This is not surprising, I think, because we don’t know if it’s a specific effect of having venetoclax treatment beforehand or just extra line of therapy, more heavy pretreatment.

So this is the first Phase III registration trial not only for pirtobrutinib but also in patients who have had prior covalent BTK inhibitor treatment. And pirtobrutinib improved progression-free survival compared to investigator choice of idela/R or BR. The outcomes are somewhat poor overall, underscoring, I think, the high-risk nature of this group of patients who have progressed on covalent BTK inhibitor. And again, underscoring the importance of what I mentioned earlier, that the advantage of time-limited therapy is that perhaps we can maintain patients’ sensitivity to covalent BTK inhibitors rather than waiting for them to progress.

Another interesting outcome of this study is that these are the first data with a PI3 kinase inhibitor in patients after covalent BTK inhibitor. And so we do see that idelalisib/rituximab has activity, with about a year of clinical benefit. So that is an option that’s on the market available for these patients as well.

Pirtobrutinib has also been combined with venetoclax and rituximab. This was done at part of the Phase I BRUIN trial originally, 2 cohorts, pirtobrutinib/venetoclax or pirtobrutinib/venetoclax/rituximab. And you can see on the left the waterfall plot. Essentially all patients responded, and the undetectable MRD, below that, looks quite good. The regimen was well tolerated.

And on the right the PFS curves look pretty good, although there are about 10 to 20% of patients who are progressing before they finish the treatment because it’s a 2-year regimen.

And so this was a Phase I study. The combination was well tolerated; no issues with it. Everyone stopped after the 2 years of therapy. There’s a high response rate and high rate of undetectable MRD. I already mentioned about 20% progression during the 2-years of therapy, but that does reflect the heavily pretreated nature of the population. And we need longer follow-up of the durability after patients discontinue therapy at 2 years, particularly in the patients after covalent BTK inhibitor. We don’t really have data about the safety of discontinuing venetoclax in that population, and so that will be interesting to see in this study how long people do once they’ve come off the pirtobrutinib/venetoclax. And this was the basis of another one of the pirtobrutinib Phase III registration trials, which is fully accrued, but we have not yet seen data. That being venetoclax/rituximab plus/minus pirtobrutinib in the relapsed setting.

We also heard data from the MD Anderson at ASH combining pirtobrutinib with venetoclax and obinutuzumab in the front-line setting. And you can see here that the rates of undetectable MRD, even as early as end of cycle 7, were 93%, and were up to 98-100% by the end of cycle 13. Now this was at the price of somewhat more toxicity than we’ve seen with some of the other 3-drug regimens. The Grade 3/4 neutropenia rate was 60%. 60% of patients required G-CSF. There were 4 patients with neutropenic fever. And a lot of dose reductions; 21% reduced pirto and 31% reduced venetoclax. This suggests that there could be potentially some pharmacokinetic interaction there, that the patients are seeing, a lot of drug.

So this is an MD Anderson trial. Very high rates of undetectable MRD, higher than we’ve seen even with the other 3-drug regimens, but at the price of high rates of heme tox and dose reductions. So again, like most of these single-center studies, it needs confirmation in a multicenter setting. And I have some hesitancy to use pirtobrutinib, the noncovalent inhibitor, before a covalent BTK inhibitor, because we still have very short follow-up with pirtobrutinib, whereas with covalent BTK inhibitors we know patients can get 8, 9, 10 years of benefit from them. And so for pirtobrutinib to be better it has to give the full benefit of the covalent BTK plus the extra couple of years it gives in patients who progressed on covalent BTK.

So this is really a pretty high bar, and so until we have more data longer term with pirtobrutinib, and until we understand a little bit better the mutation profile that might occur, that might result in resistance to the next line of therapy, I’m a little hesitant. I think part of the reason they were okay with it in this trial is that it’s time limited, so hopefully there won’t be the development of resistance mutations, but we don’t know.

Pirtobrutinib has also shown significant activity in Richter’s transformation. This is the largest prospective study in Richter’s transformation, with 80-odd patients enrolled. You can see in the waterfall plot that the response rate looked pretty good. The durability for the whole population, though, on the right, is not that great, where the median PFS is 4 months. Duration of response is about 7.4 months.

So again, the largest prospective trial in Richter’s. Overall response rate was 50%, complete responses 13%, which is somewhat unique. So high response but short durability, which is what we so commonly see with many drugs in Richter’s transformation. I think it looks like it’s probably somewhat better than we’ve seen, for example, with acalabrutinib or zanubrutinib or ibrutinib, but the data are limited with the other drugs, so it’s hard to tell. I think this does suggest that it may be a basis for combination therapy, which is certainly what we clearly need in Richter’s transformation.

So turning our attention to cellular therapy. We did about a year ago have the approval of liso-cel, the first CAR T-cell therapy for CLL, and we had an update of the survival curves from the TRANSCEND CLL 004 registration trial. The primary endpoint of that trial was the complete remission rate, which 20%, essentially.

And so the interesting aspect of these data. If you look at the top, we have the full population who are enrolled at the selected dose level, on the left. On the right, we have the selected cohort of the BTK progressor/venetoclax failure subset, which was the basis for the approval.

And the curves look really pretty similar. The progression-free survival is about 18 months, on the left, and 12 months, on the right, so a little bit worse. But it’s very dependent on depth of remission. So complete remission turns out to be the best predictor of outcome with the CAR-T therapy. The partial responders end up with an outcome a little bit better than the overall cohort, but not that much, and this is somewhat unusual because what we’ve seen with most studies recently is that undetectable MRD is a stronger predictor than response. But if you look at the curves on the bottom, that’s progression-free survival by rates of undetectable MRD, and undetectable MRD is not as good a predictor in this setting. This is probably because the partial responders, some of them, did have undetectable MRD in blood or bone marrow but still had lymph node disease, which was a predictor of worse outcome.

So CR is more predictive than undetectable MRD, and that’s only about 20%. So if you think about this patient population, where liso-cel and pirtobrutinib are approved, it’s likely that the ease of use of pirtobrutinib, as well as the PFS that’s similar or better, would likely lead you to use pirtobrutinib before CAR-T in most patients, except perhaps maybe some very young, fit ones who are hoping for more definitive therapy. The double-refractory population does have a worse outcome than the full population, similar to what we saw with pirtobrutinib. But again, a little bit hard to interpret whether that’s specific to the drug type that the patients have received or just what we’ve seen always, that the more prior therapies the harder it is to get disease response.

And we also heard a presentation at EHA last year that patients with 3 or fewer prior regimens who did not have bulky disease were more likely to achieve a response. And so even though this is an immune therapy, similar to all our other treatments, it’s better to have less disease when you get it to get a deep response.

And then we heard at ASH an update on the liso-cel with ibrutinib cohort, also a heavily pretreated population. But the data here looked a little bit better. The complete remission rate is 45% and the overall response rate 86%, and undetectable MRD is reaching 85 to 95%, so that looks quite good.

And on the right we can see that for all patients the PFS is about 31 months compared to about 18 months with the other regimen. So again, not a head-to-head trial, parallel cohorts, but perhaps a suggestion that the addition of ibrutinib may be helping the outcomes with liso-cel. And of course we believe that this may be due to normalization of the T cells in the period before CAR-T — normalization of the immune system to also be able to respond to the T-cells.

So again, heavily pretreated cohort, CR rate looks higher than liso-cel alone, but it’s hard to compare patient populations across studies. There are the issues of ibrutinib side effects. There’s a brain hemorrhage on this trial. In 2 prior studies that combined ibrutinib with CAR-T there were 2 cardiac arrests during the period of cytokine release syndrome. And still 59% of patients with the ibrutinib needed steroids or toci for CRS. So personally I think it would be of interest to study second-generation BTK inhibitors or beyond in the context of CAR-T to hopefully reduce some of these ibrutinib side effects, particularly the cardiac ones.

The data from ex vivo experiments, mass experiments suggest that the second-generation BTK inhibitors can also normalize T-cell function, which suggests that it’s not due to the kinase inhibitor profile of the drug as much as it is due to the inhibition of disease and disease reduction that we see.

And then epcoritamab is the bispecific antibody that’s been best studied in CLL, where we’ve heard data before. And at ASH this year we heard about the cycle 1 optimization cohort. So in the prior expansion cohort the CRS prophylaxis was only prednisone, with 2 step-up doses before the first full dose.

So in this optimization cohort they used dexamethasone prophylaxis with hydration and added an extra step-up dose before the first full dose, and this is because the rate of CRS was really still pretty high in the expansion cohort. You can see on the right at the top, CRS incidence is highest and worst at the first full dose, and there were still 18% of Grade 3 events with the epcoritamab in the expansion cohort. But with the additional step-up dose and prophylaxis, shown at the bottom, there were no Grade 3 events, there were overall lower rates, and most of it was Grade 1. So I think they did make some significant progress here in terms of improving the toxicity to make this a more usable therapy.

CRS is still most common with the first full dose, but there’s no Grade 3 and mostly Grade 1. And in these heavily pretreated patients the overall response rate was 61%, regardless of high-risk features, such as unmutated IGVH or 17p deletion. And the complete remission rate of 39% was particularly encouraging, as well as undetectable MRD in 75% of responders. And the median progression-free survival looks to be about a year from this cohort. So this study is continuing to accrue, and I think it will be of interest to design combinations or consolidation strategies for patients who still have detectable MRD in earlier lines of therapy.

And finally I’d like to conclude with 2 novel BTK degraders. And so these are molecules that bind to BTK and hook them up with the ubiquitin ligase, and so target BTK for degradation. And there are 2 of particular interest in the clinic, which we heard about at both EHA and ASH, and these are the data from ASH.

NX-5948 is shown here. And on the left you can see how heavily pretreated most of these patients are. Pretty much all of them had chemoimmunotherapy, covalent BTK and BCL2 inhibitor, and several have had noncovalent BTK inhibitor as well. The overall response rate has been 76% across all dose levels. This is just in the CLL patients, although there’s also ongoing work in non-Hodgkin lymphoma.

The median duration of treatment is still very short at only 4 months, but you can see from the green arrows on the graph that most patients are still on therapy. So this looks quite encouraging.

And then the other drug is BGB-16673. Again on the left, all the patients have had covalent BTK and BCL2 inhibitor, and a smattering have also had noncovalent BTK. The overall response rate’s almost exactly the same at 78% across all dose levels, which I think is really remarkable and suggests that we are seeing real activity of this class of drugs that’s potentially very promising. And the follow-up here is 11 months, but still many patients are still on drug, as shown by the arrows on the plot.

So we have 2 Phase I studies of distinct molecules in heavily pretreated patients, most of whom have had prior BTK and BCL2 inhibitor exposure, and both studies are showing a very nice overall response rate of approximately 76%. Follow-up is short but very encouraging. And mechanisms of resistance are still to emerge, but will be very important. Right now I think we have a sequence of patients going from covalent BTK inhibitor to noncovalent BTK inhibitor to BTK degrader, and we see different patterns of BTK mutations with the covalent and noncovalent. And we don’t know yet what types of mutations may confer resistance to BTK degraders, but there likely will be some because the drugs to have to bind to BTK. And so that may affect the sequencing of the drugs over time, and if the BTK degraders are less likely to develop resistance, then that may move them to an earlier line of therapy.

So very exciting times for our CLL patients now. Thank you for your attention.