New treatment paradigms in chronic lymphocytic leukemia (CLL) — John M Pagel, MD, PhD

DR PAGEL: I am excited to give you a presentation here today about new treatment paradigms in chronic lymphocytic leukemia. In particular, I’m going to focus on the frontline therapies where we’ve really had dramatic and game-changing treatments for patients with CLL. And it's still somewhat confusing about how to approach these patients. So, maybe we’ll talk a little bit about that through some cases as well towards the end.

But let’s get started and give a little bit of a course level setting for patients with CLL. Don’t forget that this is a disease of people who are a bit older, median age is 72. Very important to remember that these people also have comorbidities, and it's more common to happen in men than in women. And when we think about patients, as we diagnose them and approach them with CLL, we understand that that age, those comorbidities, and the fact that we really are providing palliative approaches for patients, not curative intent — these people are going to live for a long period of time no matter what we do — we want to be thinking about the best ways to treat specific individual patients to meet their needs. And obviously, their needs are to live as long as possible. I mean sign me up for that, right. And also to do it in a way that's extremely well tolerated. And that's really where the game has been changed dramatically as you’ll see and we talk about, we’re really getting dramatically, and have really gotten dramatically away from chemoimmunotherapy for patients who have CLL.

This is again, a disease for those types of patients, understanding, of course, that not all CLL patients are created equal, right. The vast majority of patients who have CLL will have genetic aberrations, we’ll talk a little bit more about that. And these CLL cells can be usually in a more indolent behaving biological fashion, but there also can be some more aggressive biologies as well as presentations with CLL.

One of the things that we’re learning and understanding is that we should really be assessing the mutational status of the immunoglobulin heavy chain gene to really help prognosticate for individual patients and how they’re going to do.

It's a one-time test. The results of the test don’t change. So it's good to know at some point, hopefully very early on, about somatic hypermutation status of the immunoglobulin heavy chain gene in each individual CLL patient.

And I’ll just remind you that it's actually, what I like to say, “good to be a mutant.” Remember, somatic hypermutation or gene rearrangement of immunoglobulin genes is a normal process. And as it happens through the germinal center, it leads to a more mature cell. And if the CLL cell or clone is developing in that more mature cell that's already undergone that mutational process, it's a more indolent disease. And you can see that on the curve here on the top. Those are the IGHV mutated patients. If a CLL cell has not yet undergone that gene rearrangement or mutational process, they're unmutated, they don’t do quite as well. Unfortunately, the majority of our patients have unmutated disease. But it's important to recognize, again, I think, that not all CLL is created equal and we have to look for that and understand that. And of course, we still don’t do enough FISH testing in this day and age.

So in 2020, it's really important to understand, despite the fact that we’re maybe going to approach patients in a relatively similar way now, what their genetic risk is. We have to know if they have any of these high-risk features, not just at the time of diagnosis, but at time of treatment encounter, and that might be multiple treatment encounters, looking for deletions of the short arm of chromosome 17 or 17p deletion, deletion of 11q — those are high-risk features, as well as having a TP53 aberration. It’s important to look for TP53 aberrations as well. It's recognized by the NCCN as something we should be looking for and, of course, complex karyotypes are associated with poor survival. And as you can see on right side of this slide, the graph there showing survival — if you’re on that green curve, a 17p deletion, albeit this is somewhat older data, you don’t do nearly as well as those people who have more favorable features such as a 13q abnormality as well.

We recognize, though, that there’s still unmet needs in CLL, not only in the upfront setting, but in the relapsed/refractory setting. So we have all these new therapies. It's great that we’re getting away from intensive therapies, especially for elderly patients, perhaps less fit patients, but we also need to continue to develop more favorable safety profiles for these patients that will really help benefit them from a quality of life standpoint, for long periods of time. And know even in the relapse setting, that is we get down into further and further treatment encounters, that remissions will become shorter and shorter. So we need more important targeted therapies, other agents with novel mechanisms of cell kill in those kinds of setting, that will kind of level set or reset, hopefully, the biology and allow people to continue to do well.

I think, despite the fact that we still have these unmet needs, we’re still moving the ball down the field. People are living, for the most part, full, good, outstanding lives and hopefully we're doing it in a way where they have an outstanding quality of life as well.

So, let’s spend a few minutes talking about how we approach these patients in the front line. And in particular, I want to focus on Bruton’s tyrosine kinase inhibitors. Now this is not a new class of drugs. We’ve had ibrutinib for a while. But we’re still trying to figure out the best agent to use here, and there might be one agent that's more appealing in a specific patient as opposed to a different agent for a different patient, but putting the data together will help us figure out how to use these drugs. And I’m a very big fan of using BTK inhibitors in the front line. Remember, from the RESONATE 2 trial, we had the approval of ibrutinib for treatment naïve CLL patients. This was primarily for people who were a bit older. They could either get ibrutinib or they were randomized to single-agent chlorambucil. Hopefully, this is the last time we ever have a single- agent chlorambucil trial. But clearly, we’re looking at the primary endpoint of progression-free survival, shown on the left here. That was a dramatic improvement with ibrutinib compared to chlorambucil.

And actually, interestingly, that translated to a dramatic improvement in overall survival as well. There was almost around an 80% reduction in the risk of death if you received ibrutinib versus chlorambucil. Again, these are older people. I think it's very important to recognize that they don’t typically do really well with chemotherapy regimens and even regimens we like to think that are better tolerated, such as chlorambucil.

So, where do we take that data and move the ball down the field? Well, I think one of the ways we do is we try to improve on the tolerability of the drug, and in particular that's important with ibrutinib because we know lots of patients will have to come off of therapy due to an adverse event related to the ibrutinib.

We know that there are really 3 major things that I always look for to assess for major problems with ibrutinib: they’re hypertension, atrial fibrillation or major hemorrhage. So hypertension happens maybe 14% of time with ibrutinib in the real world. Now they’re needing an extra antihypertensive medication, maybe even 2. Those aren’t things that we want to see in our patients. I still think of hypertension as that silent killer and so we want to try to avoid that, maybe we can improve on that. Same with atrial fibrillation.

Atrial fibrillation is not benign. People can have symptoms. They may need to be on anticoagulation or antithrombotic agents. So that's been a problem that we see with ibrutinib. And in fact, in the real world, maybe up to, well more than 10% of the time, up to 15% of the time. And then also with major hemorrhage. So these can be very serious bleeding issues, things like GI bleeds or intracranial bleeds that we want to reduce the incidence of, and we do see those with ibrutinib as well.

The good news about BTK inhibitors and ibrutinib is that we have a tremendous understanding of the safety data with this agent. We have long-term follow up of patients treated with ibrutinib and know really what the safety signals are. So we recognize that, despite the fact that a significant number of patients may have to come off of ibrutinib due to an adverse event, this does go down over time. So the emergence of new safety signals doesn’t really happen. Most of the time if we’re going to have a problem it happens early. And as people get out further and further and staying on this oral therapy daily, indefinitely, they can do extremely well.

We like to of course, build on our therapies. We are never satisfied, and we shouldn’t be. And one of the ways it's important to advance the use of a BTK inhibitor perhaps, is by adding an anti-CD20 antibody, in particular obinutuzumab. And that was looked at in the trial comparing it with ibrutinib to a regimen of obinutuzumab and chlorambucil. This is clear here that you can see in this iLLUMINATE trial that the progression-free survival in an intent-to-treat population for ibrutinib and obinutuzumab was significantly better than what we saw with chlorambucil-based regimen with the anti-CD20 antibody. And that held true as well in a very high-risk patient population. These are people with 17p deletions, 11q deletions, TP53 aberrations.

So, clearly, chlorambucil as a single agent, now in combination with a really outstanding second-generation Type 2 glycosylated antibody, obinutuzumab, we know that again the regimen, ibrutinib/obinutuzumab is superior. So we’ve really fallen out of favor of using chlorambucil-based regimens for those types of reasons.

Now, of course, you know, and it's important to recognize, that chlorambucil is kind of a strawman when we have it in these trials; it's relatively easy to knock over. We don’t use a lot of it and haven’t historically, even for older patients. We’ve used a regimen such as bendamustine and rituximab. So the Alliance trial that now has been published, we presented this at ASH a couple of years ago, Jen Woyach led that, really looked at the comparison of ibrutinib or ibrutinib and rituximab in a randomized 3-arm trial to bendamustine and rituximab. Again, these are people who are a bit older. They’re one’s that we think could tolerate bendamustine and rituximab. It's for people that are over the age of 65. And again, they had this 3-arm randomization. You can see on the bottom left there that the progression-free survival was significantly improved with ibrutinib or ibrutinib and rituximab over bendamustine and rituximab. And this held true for all the different subgroups.

I also want to point out here that there was really no benefit to the addition of rituximab to ibrutinib in this study.

So, we like the idea of getting away from chemotherapy. There’s not a real significant role now based on this kind of data for bendamustine and rituximab. It's really targeted therapies in the front line. And while obinutuzumab may be valuable in the front line, we have this trial and actually other randomized trials that have shown us that rituximab in combination with a BTK inhibitor is portably not a major advance.

But even in these patients through the Alliance trial, we still see these adverse events that can be problematic. You can see here these adverse events of Grade 3 or higher for the 3 different arms. Again, a lot of myelosuppression with bendamustine and rituximab, those hematologic adverse events. But, a significant number of Grade 3 or greater non-hematologic adverse events with ibrutinib or ibrutinib and rituximab, almost three-quarters of patients having a Grade 3 or greater non-hem adverse event. And some of those actually were Grade 5 adverse events, which is concerning, to me at least, in a front-line setting. You can see there that there were patients who had fatal events and, in fact, even 11 patients with unexplained or unwitnessed deaths in the ibrutinib arm.

Now, it's not exactly clear what the contribution of ibrutinib was or not, but it does give some pause to say maybe adverse events can be very significant in some small subsets of patients and we need to be careful and so some more investigation and figure out better ways to approach patients, even with targeted therapies.

Now that was for older patients with bendamustine/rituximab being a comparator that was appropriate. In younger patients, the gold standard has always been FCR, as you know. Certainly, FCR is something that has provided long-term survival benefit in patients with very, very favorable risk disease. Those are the IGHV mutated patients. Again, remember, it's good to be a mutant. They really can have long-term functional cures or survivals in about up top 60% of patients. But, otherwise, FCR has been controversial, even in younger, fit patients. So, the idea of comparing a targeted therapy to FCR in that patient population.

Here’s the ECOG trial, patients under the age of 70, who were able to get either ibrutinib and rituximab or FCR. And the progression-free survival was significantly better. There was a 65% reduction in the risk of progression or death if you got ibrutinib and rituximab compared to FCR. And actually, interestingly, there was an overall survival benefit as well, which is seen on that graph down there on the middle right. That, of course, suggests to us that there are very few people, even younger and fit, who won’t benefit from targeted therapy. And maybe we move the ball further by getting away from toxic chemotherapy, again in even younger, fit patients.

I’ll come back to the idea as well, about mutated patients who might do really well with FCR. That might be the one area where we still have a significant role, potential role for chemoimmunotherapy, FCR, but I would also point out that the early data suggests that the ibrutinib/rituximab patients are doing well there and tracking along, although we don’t have nearly as much follow up.

But again, even in the ECOG trial, we had a fair number of patients with Grade 3/4 treatment-related adverse events. We had of course, less neutropenia with IR compared to FCR, but infections still can be a problem. And we need to, of course, continue to do better in the development of our therapies. And in particular, remember it has to be cognizant of the patient population.

So these are people that have comorbidities, as I’ve mentioned. Nine out of 10 patients with CLL will have at least one comorbidity and actually, half of the patients will have at least one major comorbidity. That can be like COPD. Coronary artery disease. Significant renal insufficiency. So these are people that we really have to tailor our therapies to and figure out how best to treat them.

I would argue that one advance might be the second-generation BTK inhibitor acalabrutinib. Acalabrutinib targets BTK in exactly the same way ibrutinib does, binds to the same epitopes in the BTK binding pocket, but it's a different drug. And you can see that looking at this kinome maps. The way it's a different drug is it's a cleaner kinase. There are fewer red dots on the acalabrutinib kinome map than there are on the ibrutinib map. Those red dots represent the off-target kinases that each agent interacts with. So, there’s about 6 or 7 off-target kinases that acalabrutinib will interact with. More than 40 or so with ibrutinib.

And you can see some of those depicted at least in the table there on the right, the kinase inhibition data. You can see, that about half-way down, acalabrutinib doesn’t hit a kinase, as an example, EGFR. Ibrutinib has strong interaction with EGFR. And that's why we see likely more rashes and diarrhea with ibrutinib that we don’t see with acalabrutinib.

Another example is TEC — T-E-C – kinase. You can see that with ibrutinib there is significant interaction with TEC, less with acalabrutinib. TEC is actually in platelets. And that's why we see significant problems with bleeding with ibrutinib and perhaps less with acalabrutinib. Again, I would argue strongly that when you don’t have the platelet dysfunction through TEC inhibition and you don’t have that inability of platelets aggregate to collagen — again, in acalabrutinib you’re going to have less bleeding. So, perhaps, potentially important advance as well for patients.

Well, acalabrutinib is also available now for patients in the front line. You can see, here’s a randomized trial, the ELEVATE TN trial that we presented just last December at the ASH meeting. I should say at the ASH meeting in 2019. You can see that there it is a randomization between acalabrutinib, acalabrutinib with obinutuzumab, and the comparator arm in an older patient population being that old standby of chlorambucil and obinutuzumab.

This data led to the approval of acalabrutinib in the front line for patients who either got the single-agent monotherapy acalabrutinib, or they could get the anti-CD20 antibody as well.

Here’s the data that led to that approval. There was at least an 80% reduction in the risk of progression or death if you got acalabrutinib versus chlorambucil and obinutuzumab. And actually, even better if you added the obinutuzumab to acalabrutinib. Of course, as I’ll show you briefly, there are some more adverse events that go with the addition of the obinutuzumab to the acalabrutinib regimen.

So very improved progression-free survival that held true for all of the different subgroups looking at this forest plot, even for patients who were a little bit older. Patients who have advanced stage disease. You can see of course, as well, benefits for high-risk 17p deletions, those with 11q. The unmutated IGHV patients, complex karyotype. And even patients with bulky disease, albeit the numbers were small. We recognize that oral targeted therapies can help in patients as well with bulky disease.

And where I think acalabrutinib really has a major advance is, coming back to that cleaner kinome map, cleaner kinase of acalabrutinib, that you have a very well tolerated therapy. So relatively low rates of Grade 3/4 adverse events. You don’t see much in the way of arthralgias. You don’t see much in the way of rashes, which aren’t even listed here. A lot of those things that we consider very problematic with ibrutinib are certainly less in clinical practice and in the real world with acalabrutinib.

One thing that is unique with acalabrutinib to know about is that there is a headache that can be associated with it. Four out of 10 patients will have a headache. It's Grade 1, Grade 2. Rarely significant. But you can see that it can happen. And if it does happen, people will usually have a very self-limited early on headache and it's very responsive to caffeine as well, if that is needed.

There are very few discontinuations with acalabrutinib, maybe on the order of about 10% or so, either monotherapy or with obinutuzumab. That’s again, I think, appearing to be less in the 25% or so discontinuation rates we have with ibrutinib in the real world. And as we see in this trial and early Phase II trials, the vast majority of patients are able to stay on acalabrutinib for relatively long periods of time and do very well. So a very, very well tolerated therapy.

I’ll just briefly mention these agents in relapsed/refractory disease. Just for the sake of time I won’t say a lot because really, in fact, we’re using these BTK inhibitors earlier rather than later. So certainly, ibrutinib was approved in the relapsed setting compared to that second-generation antibody, ofatumumab. WE don’t use it a lot anymore, but certainly a valid comparison. You can see significant improvements in progression-free survival there.

We also, of course, have acalabrutinib now approved in relapsed patients, based on the ASCEND trial, where we randomized relapsed patients to acalabrutinib as a monotherapy, or either idelalisib, that PI3 kinase inhibitor, with rituximab, or in a smaller number of patients, bendamustine and rituximab. And what was seen there again, not surprisingly, that the single agent acalabrutinib had a superior progression-free survival compared to either the idelalisib and rituximab patients or the bendamustine and rituximab patients. About a 70% reduction in the risk of relapse, progression or death with acalabrutinib versus those other regimens.

And that is shown here for the entire cohort and the comparator arm lumped together, idelalisib and rituximab and bendamustine/rituximab.

And in the relapsed setting, again a very well tolerated treatment. So we don’t see significant problems that are usually dose limiting.

And I’ll also point out that in the relapsed, as well as the front-line setting, with acalabrutinib we have relatively low rates of atrial fibrillation, maybe on the order of about 4% atrial fibrillation with acalabrutinib. We have low rates of major hemorrhage, on the order of about 3%. And we have very low rates of hypertension, about 4 or 5%.

So I think those improvements in those major adverse events with acalabrutinib might be differentiating and important for specific patients moving forward for improving their adverse event profile and maybe translating to improved quality of life with less arthralgias, rash and other types of problems in that regard.

Now just to close, to be comprehensive and to make sure we understand that other agents are also reasonable for targeted therapies, and in particular that's the B-cell inhibitor — Bcl-2 inhibitor venetoclax for these patients. That's also approved for frontline use and has significant appeal based on the CLL14 trial that took older, treatment naïve patients with comorbidities and randomized them to get venetoclax or obinutuzumab compared with chlorambucil and obinutuzumab. And one of the beauties of this regimen is that it’s what we call finite therapy. Some people like to call it time-limited treatment. Essentially, this is one year of treatment and then you stop. That's nice. It's nice for a younger, perhaps more fit patient. Somebody who doesn’t like the idea of being on therapy for prolonged periods of time.

It does appear to be a viable strategy for those patients based on this data. You can see that there was significant improvement in progression-free survival for those patients getting ven/obinutuzumab compared to chlorambucil and obinutuzumab. And again, it's one year of therapy. And you can see the majority of those people on that top curve after a year are still maintaining their outstanding progression-free survival status.

I do want to point out that data is emerging that suggests to us that if you have very high-risk disease, once you stop at a year you might actually have an early relapse. Fortunately, most people don’t have high-risk disease in the front line. But if you do, those might be people that we need to think about alternative treatments or ongoing and not stopping therapy. Perhaps even considering single-agent ongoing BTK inhibitor therapy as opposed to stopping treatment. Again, in those high-risk patients.

You can see nonetheless, the 24-month estimates of PFS for venetoclax and obinutuzumab, at 88%, again at 2 years, versus obinutuzumab and chlorambucil. Over 20% less from a progression-free survival standpoint. Let’s then recognize just, lastly, that venetoclax is also approved in the relapsed setting based on the MURANO data. I like using venetoclax after BTK inhibitors because of this data. While this data actually randomized venetoclax and rituximab to bendamustine/rituximab in relapsed patients, not surprising, again dramatic improvement in progression-free survival for venetoclax and rituximab. And that held true in all of the high-risk patients as well.

So we still had opportunities, improvements that need to be made. Clearly, we have to think about the important treatment parameters from tolerability for each individual patient. But we're doing well there. We need to continue to improve, of course. We do want to develop important therapies that are more meaningful, even for the highest risk patients. Those are the 17p deletions, the TP53 mutations of course, and 11q’s. And I think these novel therapies still have room for improvement. We’re moving the ball down the field. And we’ll learn a lot more about these next-generation — I should say third-generation BTK inhibitors as well now coming along, even second-generation Bcl-2 inhibitors, in the relatively near future.

Case: A man in his late 50s with treatment-naïve CLL and a history of hypertension and deep vein thrombosis

DR PAGEL: So let’s put this into context then about some cases. Who these patients are? And we’ll perhaps have a little discussion about how they might be approached.

Here’s our first. This is a 58-year-old gentleman with treatment naïve CLL. He’s very active. He’s an attorney in town. Plays a lot of golf. Was diagnosed in 2016 on a routine blood draw. We see this all the time, with a little bit of lymphocytosis.

He was followed, and you can see the blood counts there. He had a very favorable sole abnormality of a 13q deletion. He was IGHV unmutated, but just had active surveillance. And then, just this summer, started showing disease progression.

Now the absolute lymphocyte count is elevated, a little bit anemia. Platelets are around 100,000. And he has having symptoms with some significant fatigue.

Imaging shows him to have a couple of centimeter disease around, but, also, at least 1 lesion more than 4 cm.

So here’s a guy, he has hypertension, as you can see, as well as a history of a DVT. So he’s on apixaban, so he’s on antithrombotic agent. And he wants to maintain his quality of life. And I would argue strongly that this is a patient where we’re going to want to be thinking about targeted therapies. And I love the idea, in this patient with those comorbidities of trying to get away from any additional bleeding risk and giving him finite therapy. In a low-risk patient, such as the regimen I showed you just a few minutes ago of venetoclax and obinutuzumab.

Remember, you give the obinutuzumab first. Give it for at least a month, maybe even a couple of months to reduce the disease burden and that will reduce the risk for tumor lysis with venetoclax once you introduce it at that point. And then again, it's a year of therapy. It's finite treatment. That's very valuable for someone, perhaps young, active, doing well. Also with risk for bleeding.

Case: A man in his mid-70s with treatment-naïve CLL harboring del(17p) and unmutated IGHV and a history of mild chronic kidney disease

DR PAGEL: Our second patient is a little on the other end of the scale, older now, 75. Diagnosed a couple of years ago with kind of classic CLL; just this summer now having progressive disease with an enlarged spleen. Someone with some adenopathy. You can see the labs again, now with some cytopenias of significance, including a platelet count of 90,000. This was actually significantly different in what we saw just a handful of months ago, 9 months ago. So the disease is progressing relatively quickly. Adenopathy of significance, in fact even a little bit of bulky disease. Fortunately, the PET scan doesn’t suggest that this is a more aggressive disease. Clearly needs treatment. Had some chronic kidney disease, but doesn’t have any cardiac disease. Normal liver function. Is on a lipid lowering agent.

Here’s a great example of a patient who’s going to really likely benefit from single-agent targeted Bruton’s tyrosine kinase therapy. I’d lean that way over venetoclax for this patient. I like the idea of, in an older patient, keeping venetoclax in my back pocket where I can use it based on that MURANO data, if and when the patient relapses. But I also know that this patient’s going to tolerate the BTK inhibitor extremely well. You can see here those features that are not suggesting to me that the patient has comorbidities or anything that are going to limit the tolerability of the BTK inhibitor. It's probably a very good reasonable option for that patient.

Case: A man in his late 70s with multiple comorbidities is diagnosed with CLL with a TP53 mutation

DR PAGEL: Similarly, just know that there are older patients, as in this case, who have other comorbidities and can present in a very ill fashion. This patient’s with a pneumonia presentation, adenopathy and extensive disease. Confirmed to have CLL. But the blood counts are very good.

I would argue that this patient’s probably someone that we’re going to want to be able to treat sooner, rather than later, and in particular because that TP53 aberration that's down below.

And the purpose of this case is, say, especially for those people with high-risk features, 17p or TP53 aberration, targeted therapy is the way to go. I think venetoclax/obinutuzumab would be reasonable here, but if you did that, I’d be very reluctant to stop therapy at a year given that TP53 aberration. And it might be very reasonable to use a BTK inhibitor in the front line for this type of patient.

Well, that's the presentation on kind of a whirlwind tour.

Thanks so much for that opportunity. Happy to have a discussion, of course, now.

DR LOVE: That was really great. Let me ask you. These 3 patients, these are actual patients you took care of?

DR PAGEL: Absolutely.

DR LOVE: Not scenarios? And what’s the current status of each of the patients right now?

DR PAGEL: So that first guy I treated with venetoclax and obinutuzumab. That's a guy where I had this classic conversation to say, hey, you got these 2 different options. For you, you could choose a BTK inhibitor. It's just 1 pill. You take it daily. But we’re going to take it indefinitely. We’re going to take it until either your disease progresses or we’re going to take it until you have some intolerance. Or you can take this other therapy where we’re going to try and stop treatment at a year. And likely, you’re going to have a very deep remission if you do that. You’re going to be in an undetectable minimal residual disease state, which I haven’t mentioned, but we could talk about. And we’re actually likely going to be able to be off of therapy for some prolonged period of time. But know there’s an infusion with that. Early on there’s certainly more clinic visits. And when you’re knocking out B lymphocytes within an anti-CD20 antibody, there’s some additional risk for neutropenia and the like.

So it comes down to that individual conversation for each. That attorney who played a lot of golf, he was very interested in getting his disease under control and kind of going back to the life that he had without having to be thinking about his CLL and taking that pill every day.

The second patient, I had that conversation with that patient I definitely remember, but I really directed that patient much more towards the use of acalabrutinib. I think older people do well with those therapies. And again, I explained that while we could use venetoclax upfront, I like the idea of knowing I’m going to be able to rescue them almost always, if and when they have disease progression, or even if it progressed in a more aggressive fashion.

So that patient has been on acalabrutinib for over 6-9 months now, I suppose. About 6 months. And is in a very good remission, a partial remission. And that patient is doing very well.

The last patient is also on acalabrutinib and that patient has that TP53 aberration. And also, I would say, tolerating therapy, managing the disease well. And likely will have relapse, but if, in fact, when that happens, we have other agents such as venetoclax.