Introduction: The Chronic Lymphocytic Leukemia (CLL) Experience — 2000 to 2025

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we focus on the management of chronic lymphocytic leukemia. We have a great faculty: Dr Jennifer Brown, the Direct of the CLL Center at Dana-Farber Cancer Institute in Boston and Dr Paolo Ghia from the Università Vita-Salute San Raffaele and the Director of the CLL Strategic Program, the IRCCS Ospedale San Raffaele in Milano, Italy. And sorry, Paolo, I know I didn’t get the pronunciation perfect, but I’ll work on it.

Today we’re here to talk about CLL, what’s been going on in the past year. And as we do in all of our programs, we just mention the fact that we will be talking about the use of non-FDA-approved agents and regimens, so check out the official prescribing information for more information.

As we do in all of our Year in Review programs, I met with the faculty in the last couple weeks to record a presentation reviewing many, many papers and presentations over the past year. These are actually in the chat room, and we’re going to send it out with this recording of this program tonight as well.

So this is really a 3-part program. And the 2 presentations, which are both excellent, really interesting content. They go through in detail a lot of papers. Here are the papers that they review. So to get into the data specifically and ups and positives with all these papers, check that out.

What we’re here to do today is I picked out a few of the slides from the presentation for further discussion, particularly in terms of clinical implications, so I can get both of the faculty’s point of view, and also research implications in terms of where we’re heading.

So we’re going to start out talking about BTK inhibitors, then venetoclax, and then of course one of the biggest stories in the history of CLL, the AMPLIFY presentation that Jennifer did at the ASH meeting, but other combinations, then we’ll talk about pirtobrutinib, and we’ll finish out with CAR-T and other novel agents.

But I just want to take a breath for a second before we get started, and this is a question that was kind of in my mind last night, Jennifer. I know you started the CLL Center at Dana-Farber in 2007 after you got there in 2004. The place is really an outstanding center now for research and patient care.

But what I was curious about is this is kind of my view of CLL, from our perspective, Research To Practice. So first of all, just to mention the fact that a quarter to a third of our audience has been in oncology less than 10 years, so when they came into oncology ibrutinib was already here, but for everybody else there was a long history, of course, with chemoimmunotherapy, BR, FCR, even rituximab alone. Then in 2013 ibrutinib was approved, ’17 acalabrutinib, ’23 zanubrutinib. In the middle of it, 2020, the pandemic started.

I always think about CLL when I think about webinars because the pandemic hit at the same time that CLL was really exploding. The whole issue of choice, which we still have today, choice of first-line therapy. We did a lot of webinars. We presented a lot of cases, issues about the pandemic, et cetera.

And then more recently we had pirtobrutinib approved, in ’23, CAR-T therapy with liso-cel in ’24, and then in December the AMPLIFY data.

And Jennifer, the question we actually asked the audience, I’m going to tell you in a second what they said, but I’m curious. I was kind of thinking about this and trying to think about like what have we really accomplished. I mean obviously the science of CLL has exploded. It’s just amazing how much stuff we have to talk about.

But I was kind of curious, from a patient point of view, particularly for these people new to oncology who don’t know the world before ibrutinib, Jennifer, kind of let’s say the face of CLL before novel therapy, before 2013, in terms of what patients’ experience, what their survival was. The question we asked was is the survival significantly longer? If it’s not, or even if it is, what about quality of life? Is that better for patients in terms of survival? I’m not exactly sure how many people actually die of CLL.

A lot of people die of transformation, but I’m not sure that’s different now than it was in 2013, so I’ll be curious what you think about that question. I would think that morbidity would be less without all these novel strategies, but again, particularly once you get beyond first-line therapy, Jennifer — I was actually flashing on one of the earlier patients we presented after the pandemic came in, it was a patient who actually had previously been diagnosed with CLL, and in order to — the patient had read about ibrutinib. The only way he could get ibrutinib was to go on a trial, so he went on a trial of FCR versus ibrutinib, the well-known — I think it was an intergroup study, and he got randomized to FCR, and he got cured. I mean, he has no more disease, but he’s had all kinds of problems from the FCR. He got cured by mistake because he really wanted ibrutinib.

But I’m just kind of curious, before we started getting into what happened in the past year, just to reflect back on what’s happened in the last 10 or 15 years, Jennifer, as you’ve seen it, people going through the CLL center. What’s your take on what we’ve done in terms of improving quality of life and duration of life/survival?

DR BROWN: I think we’ve improved both quality and duration of life, at least for the approximately half of CLL patients who have the more aggressive disease, and maybe even some of the others. Nowadays it’s hard for people to remember, we had patients with huge lymph nodes, bulky lymph nodes poking out, 8, 10 cm in their armpits, in their necks, groin, that we couldn’t shrink after their first or second round of therapy. And that doesn’t happen anymore, hardly at all. And I think transformation is actually less, too, probably because we have longer duration of benefit from therapy and more effective therapy. Certainly in the randomized trials we haven’t seen a lot of transformation even in 5- and 6-year follow-up, so that’s encouraging.

DR LOVE: That’s really interesting. That’s the first I’ve heard anybody say they thought transformation was less frequent. So Paolo, any thoughts, again, now versus 15 years ago, the CLL experience?

PROF GHIA: Thank for the question because we just published a manuscript where we actually we are revisiting the past 10 years, and we showed that in the era of ibrutinib, of continuous treatment with BTK inhibitors, patients indeed now have a life expectancy that is superimposable to that of age-matched, healthy individuals. So I think that’s the biggest accomplishment in the past 10 years in the era of novel therapies because not only in front line we have very effective treatment, but we can also rescue them at later stages and lines. So I think it is now the ground on which we have to improve and get to a final cure.

DR LOVE: So that’s the second thing I was going to ask, is kind of what your thoughts are about the next 10 years or so, Jennifer, where you see overall the treatment strategy heading, where you see MRD. Do you see that’s going to become a part of daily practice, for example?

DR BROWN: I think we’re definitely moving toward time-limited combination therapy and deeper remissions, so patients can have breaks off treatment, and MRD-guided approaches will hopefully become more common. It’s hard to incorporate continuous MRD guidance, but we have trials that are looking at, for example, 1 or 2 evaluation timepoints in terms of duration of therapy, and so it’ll be interesting to see if that provides benefit compared to a fixed duration.

I’m also very interested in the potential for using immune therapies as consolidation or even in combination to potentially really deepen response and maybe get us that last bit toward cure.

DR LOVE: So actually I was going to say, our audience, the most common answer they gave was that they felt like both survival and quality of life were improved. The rest were split between one versus the other.

Again, Paolo, any thoughts about where we’re heading and what CLL’s going to look like in 5 or 10 years?

PROF GHIA: Yeah. I definitely think that MRD assessment will become part of many or any clinical trials in the future because hopefully it will also become an intermediate endpoint for clinical trials so that we can speed up the approval of new drugs.

In general practice it really depends on the results, on how feasible and easy it may become to assess MRD. And in particular we have probably years in front of us before we will know exactly what to do based on the MRD value that we obtain in our patients.

Current Therapy Options with Covalent Bruton Tyrosine Kinase (BTK) Inhibitors

DR LOVE: Alright. Well, let’s start getting into some of the papers that came out this past year and what they mean. We’re going to go back and forth between things that each one of you presented, and we’re going to start out talking about BTK inhibitors because we want both of your thoughts on this.

These are some of the related papers that we talked about. And Paolo, maybe you can comment a little bit on this paper, CLL12. We get a lot of questions about this issue of people 17p, high risk, who don’t really fit the criteria for treatment. Can you talk about what this trial looked at, what they saw, and what you think it means to docs in practice?

PROF GHIA: So this is a typical trial that comes every probably 10 years, where we really don’t believe somehow that we can wait until progression before starting treatment, so we want to try early approaches, early treatment, and that’s what has been explored in the CLL12 study with our German colleagues, ibrutinib versus observation in patients with high-risk disease.

So what we learned from this is definitely even with ibrutinib, even with BTK inhibitors, still we don’t see any advantage in terms — not in terms of progression-free survival, which is of course short and then prolonged if you start early the therapy, but in terms of the PFS2, so the second — the need of the second treatment, and in particular in terms of overall survival.

But what we learned, again very clearly, is that what we have still to understand how to identify really the patients who will suffer the most from CLL, from the leukemia, because in this study, again, they were selected based on the knowledge at that time, which is several years back, and still some of these patients did not progress or did not need treatment after many, many years in the control arm. So that’s where we have to refine our knowledge.

DR LOVE: So Jennifer, I beg your pardon for saying this, but I have to say things that come into my mind and talking to people in all kinds of oncology. In a weird kind of way it makes me think a little bit about smoldering myeloma. We work with your myeloma colleagues all the time on CME, and initially there wasn’t much happening, and now you see them talking about treating people who in the past they would never treat attempting to cure. And you brought up the possibility of immunotherapy or cure.

Do you think there’s going to become a time that we will be treating people who today we’re saying oh, you can be observed, a subset of these patients? And do you think there’s the hope that maybe treating earlier, theoretically, might potentially lead to greater long-term better outcomes?

DR BROWN: Well, I think we still have no evidence for that. CLL is a more indolent disease, and as Paolo said, it is hard to figure out who’s going to have the most rapid progression and the worst potential outcome, and until we understand that we don’t even really know who to target the trials to.

We also have to reduce the morbidity of the potential treatments. We know that a lot of clonal evolution, worsening of the disease, does happen under the influence of treatment, and so that potentially is accelerated by earlier treatment, and that’s a concern, I think, that we need to be cognizant of, and we’re potentially studying this.

DR LOVE: So I want to go to a couple —

DR BROWN: For now there’s no indication for early treatment.

DR LOVE: Well, as they say, the lack of evidence is not evidence of a lack, but whatever. Maybe we just need to find the right patients, so maybe not, too, as you were saying.

So again, I just picked out some of the papers you all went through, not so much to review all the details but get more of the bottom line. And Paolo, you talked about this, I don’t know if you’d call it a pooled analysis — not a meta-analysis, but a pooled analysis of a number of trials looking at acalabrutinib trying to get more strength in terms of efficacy, as well as tolerability. Any broad conclusions you have looking at acalabrutinib? And we’ll talk a little bit, of course, about zanubrutinib, as well, but in terms of this paper any thoughts? What was your takeaway from this, Paolo?

PROF GHIA: Yeah. This was a reassuring paper, as I would say, meaning that by pooling data from many different trials in front line and in relapsed/refractory setting, then we just confirmed, actually, the initial impression about acalabrutinib, the second-generation BTK inhibitor. And so we confirmed that — we were confirmed that this is a better tolerated drug, and it is also very effective in the long run in all categories and subsets of patients, including patients with deletion 17p or TP53 mutations and patients with unmutated immunoglobulin genes. And again what is also we learned already in the past years also with the other BTK inhibitors is that if you use it in earlier lines of course the progression-free survival and the control of the disease will be more prolonged than if you start using in second, third, or even more advanced lines of therapy.

DR LOVE: So Jennifer, I’m also curious. Paolo talked about another paper from the ASH meeting. I’m always curious about this issue in all cancers, the very elderly and particularly frail, elderly patients. This was a study looking at acalabrutinib in elderly patients. Any comments on this data? And also your clinical experience and your approach to older patients. It was interesting, too, looking at what happened to these patients in terms of their frailty once they started on treatment, in this case acalabrutinib. Any comments about how you think through the very elderly? We have a case tomorrow of a 98-year-old we’re going to present, but that’s getting very extreme there. But anything you want to say about this paper and your thoughts about the frail elderly, Jennifer?

DR BROWN: I think it does underscore that with the advent of the second-generation and later-generation BTK inhibitors there is almost not really a patient who I wouldn’t consider treating if they really needed treatment for their CLL. My experience has been that with acalabrutinib and zanubrutinib one can actually use them successfully even in somewhat frail, elderly patients. And so that is actually revolutionary compared to before. And it’s also very easy to give these drugs, typically. The monitoring and visits to the clinic are not as great, and that makes it feasible.

DR LOVE: So I want to bring up another paper. A lot of times we bring up these papers to alert the audience that these are really good papers to read, and this is one of them. This is a review of topic we’ve talked about many times in the last few years, BTK-related cardiovascular toxicity. I mean, I actually have this paper right here printed out. It’s 10 pages, very comprehensive. Paolo went through a lot of the details of it.

But I just want to use this as a way to get into some of the issues and how you think about them. I want to start out, Paolo, with the issue of bleeding. How do you approach the patient who’s already on anticoagulation, based on the type of anticoagulation, the scenario? Any comments about the issue of bleeding with BTK inhibitors, and also the difference between first-, second- and third-generation BTKis?

PROF GHIA: Yes. I would like to give 1 first general message, which is what we learned and what is also suggested strongly in this paper, is that we have to do thorough cardiovascular assessment in all our patients before starting BTK inhibitors, and I would even say without starting any therapy in CLL. Because most of our patients are old, they have comorbidities, they have cardiac comorbidities, so we want to be aware, fully informed of their baseline situation, so that whatever happens during the therapy we are ready to intervene.

Having said that, the bleeding is one of the most common, in particular minor bleeding, fortunately. Minor bleeding is probably one of the most frequent adverse events that patients complain about on the BTKi. There is an advantage in particular with acalabrutinib in terms of minor bleeding, which is decreased compared to ibrutinib, for example, something that we didn’t see exactly with zanubrutinib compared to ibrutinib.

And it’s something that you have to keep in mind, and whenever the patient needs to start anticoagulation, like for example when developing atrial fibrillation, still we start anticoagulation as in any other individuals, and then we try to play with the dose based on what happens to the patient. And nowadays we know that we can play either with dose of the anticoagulant or also, for example, in the case of ibrutinib, the dose of the BTKi, so it’s to find the right balance in each patient.

DR LOVE: So Jennifer, I was mentioning to you that everything we do at RTP is based on rounds, so any clinical pearls you have that you want to add to what Paolo just said about bleeding. But I’m also interested in your comments on atrial fibrillation, obviously the issue of what do you do when somebody develops atrial fibrillation on a BTK inhibitor. But also, even more challenging, I think, is the patient who has already had atrial fibrillation how you think them through in terms of potential BTK. A lot of people avoid it, and yet others maybe don’t.

DR BROWN: Right. Just to remind people, in terms of the bleeding, we really don’t use warfarin anticoagulation concomitant with BTK inhibitors. We most commonly use DOACs. One can also use enoxaparin sodium. There are data for that. And I also do worry about dual antiplatelet therapy with clopidogrel, as well as aspirin, for example, although we’re getting a little bit more experience, but that’s essentially 3 antiplatelet drugs, and so be very cautious there.

With respect to the atrial fibrillation, I think we’ve gotten pretty comfortable managing it. If a patient is well controlled with their chronic atrial fibrillation, and they’re on, say a DOAC, I don’t really worry too much about using a second-generation BTKi. They tend to stay stable, and we just are a little bit more careful about evaluating any bleeding or bruising risk.

And patients who do develop atrial fibrillation, sometimes it’s an incidental finding in the office, and they’re not even really symptomatic. So those patients, I don’t even really stop the BTK. I just, if they need some rate control I start that, and I start some anticoagulation and usually continue.

Now patients who have a more acute presentation I will usually hold the BTK until we get control of the rhythm, hopefully the rhythm, at least the rate, and start anticoagulation. But I will usually rechallenge once people are controlled, and most patients are able to continue and just manage through the atrial fibrillation.

DR LOVE: So Paolo, anything you want to add to that in terms of atrial fibrillation? But I also want to bring up another issue brought up in this paper, ventricular arrhythmias. Not too often that you see potentially Grade 5 toxicity from a treatment in CLL, but you can obviously die from ventricular arrhythmias. I’ve heard about cases of people on ibrutinib. I’m not sure exactly what we know about the second-general acala and zanu in terms of ventricular arrhythmias. I’m curious what your thoughts are, Paolo. And do you bring this up to a patient? It’s a pretty scary side effect to bring up to a patient. I’m curious if you bring that up.

PROF GHIA: Yeah. First thing on atrial fibrillation, I mean as my cardiologist taught me it’s really when they already have atrial fibrillation nothing worse can happen, it’s not going to get worse, so this is definitely not a contraindication for starting a BTK inhibitor in case you believe that’s the best therapy for your patient.

In terms of ventricular arrhythmia, again, it has been reported, though fortunately, very, very, very rare, in particular with ibrutinib, a first-generation BTK inhibitor, and that’s why many doctors are then tending to use second-generation BTK inhibitors, where there has been a number of studies. Of course you have less follow-up, so the situation is less clear, but we have also to distinguish between the possibility of ventricular arrhythmias and a fatal outcome, which is definitely much rarer.

It's something that we may discuss with our patient, but again, it very often is associated to a pre-existing cardiac situation, again, which leads us to the concept, as I said before, where we should really do a thorough cardiologic workup before starting so that if there is anything that is not really convincing you from a cardiology point of view then you might choose another therapy. But of course it’s a risk that may happen, and we cannot do much against it, but it’s definitely very rare. I don’t remember in my practice seeing one.

DR LOVE: So we could spend the whole hour just talking about this topic. Just one other question. And you see, Jennifer, there the topic of hypertension. I’m curious how closely you follow blood pressure in your patients. If they start out normotensive do you have them check their blood pressure? Do you have any preferences — hypertension, for example, difficult to control hypertension, make you sway in your decision about which BTK inhibitor to use? And do you think hypertension might in some way contribute to atrial fibrillation?

DR BROWN: Right. So in terms of hypertension, we do discuss it with patients. It tends to be a longer-term side effect rather than say the first few weeks, so you usually don’t talk to them too much about it when they’re first starting. But we monitor them in clinic, which we see them a few times in the first 3 months and then usually every 3 months, so we do pay attention in clinic, and if there’s any signs of it going up then we can get them starting to monitor it once they’re kind of settled on therapy.

In looking at the trial data, clearly with acalabrutinib hypertension is reduced compared to ibrutinib. The head-to-head trial for zanubrutinib had fairly comparable rates of hypertension between zanubrutinib and ibrutinib, although the degree of increase with zanubrutinib was less than ibrutinib.

I have to say, in my practice I don’t feel like I’ve really noticed this difference between acalabrutinib and zanubrutinib, and so I haven’t tended to make decisions about which drug to use based on that. I consider it a fairly significant class effect over time.

DR LOVE: And here’s some great graphics from this paper. There’s a lot of great — there’s a really cool algorithm I’m not going to get into today, but it’s a great paper to read.

Paolo, any other final comments about this topic?

PROF GHIA: No. As Jennifer properly said, the occurrence of hypertension or the worsening of hypertension occurs late from the start of the therapy, so it’s something that is then even difficult to understand how much is due to the drug and due instead to the aging of the patient that remains on therapy. So we are checking the blood pressure. Patients are checking the blood pressure because they are — most of them are already old, so it’s something that we do. But it’s definitely — though we mention about it, because we will do the check, but it’s not something that is really driving my decision in any way. It’s definitely something we don’t put so much weight in.

Role of Venetoclax in the Treatment of CLL

DR LOVE: So a couple words about venetoclax. I have to say, as soon as I saw the abstract for the AMPLIFY trial came out I was like really couldn’t wait to do this program. And I’m really looking — I already have so many questions in the chat room about AMPLIFY. They’re chomping at the bit.

I think it’s instructive to also look at what’s going on with venetoclax or venetoclax/obinutuzumab because in terms of time-limited therapy of course this is the current option that people are turning to. And Paolo, you talked about the long-term — longer-term 6-year follow-up on the CLL14 study of venetoclax/obinutuzumab. Anything you want to comment on there? I was talking before about the patient who was cured with FCR, and I’m curious whether or not in either of these venetoclax trials or ibrutinib trials we’re seeing anything that looks like a plateau on the curve.

PROF GHIA: Yeah. So that’s the point, in fact. I mean, besides all the good news that we learned from the CLL14 study, the study that compared venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab, we all looking forward to see long-term follow-up in order to see a plateau, and now after 6 years, in particular for the patients with mutated immunoglobulin genes, and unfortunately we don’t — which is the plot in the middle, we don’t see that. So this is somehow disappointing, but of course it’s a completely different mechanism compared to mono chemotherapy. These are treatments that can be given again, so a completely different story. So if we don’t reach a plateau we can always retreat the patient with obinutuzumab-based treatment, so it is not worrying us at all.

Of course ven/obi somehow paved the way to fixed-duration treatment, and in particular we learned how good it could be to have an all-oral therapy, as we will see with a BTKi plus venetoclax combination, rather than to have the issue of infusion with obinutuzumab, the infusion reaction and so on.

We also learned that with ven/obi, in particular patients with unmutated immunoglobulin genes, and definitely patients with p53 aberrations, are not probably benefiting the most from this therapy.

DR LOVE: Jennifer, any other comments you want to add to the issue of venetoclax/obinutuzumab?

DR BROWN: Well, I’ll just comment on this slide that clearly the patients with undetectable MRD do better than the ones with detectable MRD, but underscoring this issue that we’re not seeing a plateau or potential cure, less than 10% of patients still had undetectable MRD at the 5- to 6-year follow-up. So we are seeing a steady recurrence, but we can use it again.

DR LOVE: I was mentioning that we’re doing this program at AUA on AKT inhibitors, and I was talking to Dan George from Duke, who’s going to be the moderator for that, and he was — I was telling him we were having this — telling him about the AMPLIFY trial and the fact that we’re doing this thing, and he was saying it kind of reminds him a little bit of prostate cancer, where they’re doing intermittent therapy. They treat with intensive hormonal therapy and then stop and see what happens. And maybe someday — you get a long disease-free interval when you use ven/obi. Maybe you’ll have some kind of sequential strategy in the future.

And also, just 1 other issue I was just kind of curious about, which is this a paper from the Lancet, but also something I’ve heard about on and off over the years, which is venetoclax without anti-CD20, Paolo. What do we know about the efficacy and tolerability of venetoclax by itself?

PROF GHIA: That remains actually one of the unsolved mysteries of CLL, and we remain like that because in the relapsed/refractory setting, the investigators switched almost immediately from venetoclax alone to fixed-duration venetoclax plus cetuximab and so on and so forth in combination treatment. So we are really missing data.

The general impression, and also in the VENICE-1 trial, is that monotherapy is — the continuous therapy with venetoclax monotherapy is not like continuous therapy with BTKi. So the BTKi has a rationale in using it continuously, also because we don’t achieve deep responses. With venetoclax it’s really probably stratifying patients based on those who have very nice and deep responses, even achieving undetectable MRD, even with the monotherapy, and those who can even remain for a long time on the therapy, but then they will not benefit as long as you might expect from a continuous treatment with BTKi.

DR LOVE: So I want to get into AMPLIFY, but anything, Jennifer, you want to say about venetoclax monotherapy? Any situations in your practice outside a trial where you use venetoclax by itself?

DR BROWN: Not anymore. I always use an antibody, almost always obinutuzumab since we know it’s better than rituximab from other data, comparative data.

AMPLIFY Trial and Other Novel BTK Inhibitor and Bcl-2 Inhibitor Combination Strategies

DR LOVE: So that leads into the discussion of the AMPLIFY trial. I’m going to ask Jennifer to talk about it. And these are the papers that — on AMPLIFY, as well as other related papers.

But before we get into the actual AMPLIFY data, just to take a step back, and we’ll get into this in a second, Jennifer. We’ve had a couple questions in the chat room about the issue of COVID deaths that occur. And when I saw that abstract that was the first thing that got my attention because I guess you did the — a lot of the patients on the AMPLIFY trial went on during the pandemic, before the vaccine was — and you had quite a few deaths there.

Now that we’ve at least gotten past that stage of the COVID, when you put it all together, Jennifer, what’s your take on COVID and CLL? Anti-CD20? How concerned are you? What was going on when you had all these deaths? Were they mostly unvaccinated patients?

DR BROWN: Yeah. So not only were patients going on early in the — they were actually, many of them, 75% of patients had started treatment and were actively on treatment when the pandemic started, before the vaccines were available. The deaths were almost entirely in unvaccinated patients, and it was the early era of COVID when the strain was more aggressive.

I think we’ve seen an evolution on several levels. This includes that now we have repeated vaccination, which even in many patients who don’t respond initially we can start to see some response to vaccine after repeated vaccination. We also have probably weakening of the strains and general herd immunity.

And so I think it’s become much less of an issue than it was. AMPLIFY, does I think, underscore that the CD20 antibody is a critical component in the COVID risk because we saw the deaths primarily in the arms with the antibody. But I do think nowadays it’s manageable, and it’s a tradeoff that one has to consider in the context of any specific patient.

We also actually, in patients on long-term BTK inhibitors, still see difficulty with clearing COVID, where we sometimes have to do prolonged or extra courses of nirmatrelvir/ritonavir or remdesivir.

And so particularly those 2 populations, people with current CD20, are on long-term, ongoing BTK inhibitors, I will worry about COVID. But we’re not really worrying about death anymore. These patients aren’t even in the hospital, most of them, when we’re giving them their prolonged courses to get over it. They just have an upper respiratory tract infection or bronchitis.

DR LOVE: So it’s interesting you bring up BTK inhibitors because I remember at one point early in the pandemic people were talking about BTK inhibitors to treat COVID. I was all excited about it. Because of course at that point everybody was panicked in general, before the vaccine came out.

Paolo, anything you want to add to this discussion, before we get into the AMPLIFY data, about COVID, CLL and anti-CD20 antibodies nowadays?

PROF GHIA: Yeah. I’m going to actually share what Jennifer said, so COVID is probably not a priority anymore. I think it’s a lesson learned in that as we also see in GAIA study, CLL13, where there was a triplet with ibrutinib/venetoclax/obinutuzumab, also there, there was increasing infections in general. So that’s probably what we have to keep in mind without being scared of any drugs.

I mean, we have to know that drugs and know how to use them, but we have to be aware, definitely, that whenever you add an anti-CD20 antibody you add an increased risk of infection in general, probably viral. Also because we learned during the pandemic, and thanks to COVID, that the antibody at the end of the day lasts for up to 12 months, not shorter, as we thought before. So the immune suppression can really last for long, and again, it can interfere also with vaccination. So one has really to plan.

As Jennifer mentioned, vaccination is fundamental. We have to vaccinate our patients definitely before starting therapy. I always say even at diagnosis already, so when the immune system is at the highest.

DR BROWN: I agree with that.

DR LOVE: So let’s get to — go ahead.

DR BROWN: I wanted to mention that in the AMPLIFY data we actually published, before the unblinding, that patients who were vaccinated during therapy, at a time when people think they’re getting treatments that are going to inhibit the response, had a better survival. So you should get them at diagnosis, you should get them before therapy, but if you don’t you should still vaccinate them on treatment because in AMPLIFY we saw a benefit.

PROF GHIA: Yeah. Yeah.

DR LOVE: That’s a really great point.

Alright. Let’s talk about AMPLIFY. I was mentioning, we don’t use a lot of slides here because a lot of people end up listening to our webinars while they’re shoveling snow or raking the leaves or whatever. But Jennifer, can you just describe the design of the AMPLIFY study and specifically particularly for the AVO arm exactly when people get treated, what patients go through?

DR BROWN: Right, exactly. So this, of course, is a Phase III randomized trial, registrational, in fit CLL patients without 17p deletion who were randomized between acalabrutinib/venetoclax, acalabrutinib/venetoclax/obinutuzumab or chemoimmunotherapy where FCR was restricted to people with adequate renal function, under 65 years of age, and BR was given to fit patients who are older or with lesser renal function.

The primary endpoint compared AV to chemoimmunotherapy, and then the next — first secondary endpoint was AVO to chemoimmunotherapy. And so both of those were highly positive for progression-free survival favoring AV and AVO.

Now, the AVO regimen — so both AV and AVO start with a month of acalabrutinib first, and then on the AVO arm obinutuzumab comes in at month 2. And according to the package insert, and the way we give it in ven/obin, you do days 1 and 2, day 8 and 15 in month 2, then they get a week off, and then in month 3 they start their venetoclax ramp up, again according to the package insert. And the patients on the AV arm just do the 2 months of A and then do the venetoclax in month 3. So then the obinutuzumab will continue with the monthly infusions for the 5 additional doses, and the AV together, after the venetoclax ramp up, will continue together to complete 14 months.

And so it’s a little bit intensive in months 2 and 3 for the patients, but then it gets easier with monthly infusions, and then once those are done just with the 2 oral drugs.

DR LOVE: So before you get into more about the results, Paolo, any comments about what happens to these patients as they go through this process? And particularly one of the things we see with ven/obi is that by the time the patient gets to venetoclax they’re often debulked, and so the risks for TLS is decreased. Do you see debulking with the BTK, with the acalabrutinib, and then by the time they get to the obin are they less bulky? What actually happens?

PROF GHIA: No, no. That’s in fact — that’s the point, and that’s the whole rationale behind the design of the treatment, because again, with a couple of months of BTKi we all know how effective they are in debulking patients, in bringing patients probably to normal level or almost normal level of hemoglobin. That … can almost disappear. So besides the increase in tumor lysis syndrome risk when you add venetoclax, it’s really the fact that you have immediate control of the disease like is typical of a BTKi, and so when you get to venetoclax you feel, the patient and the doctor feel much more relaxed. You have already controlled the disease, and then you can now improve the quality of the response.

DR LOVE: Anything else you want to say, Jennifer, about the data, both efficacy? You note here the fact it looks like they had good outcomes whether they’re mutated or not. Anything else you want to say about tolerability? And in particular, of course, the question everyone wants to know is do you think this is a good option for patients, and if so, which patients would you be thinking about AV, and what patients would you be thinking about AVO? As always, people bring up young, fit, higher-risk patients. I wonder, too, about older, fit, higher-risk patients.

But from a clinical point of view where do you — we went through, again, once the BTK was out there, ven/obi, 3, 4 years, people are trying to sort out how you present it to patients, what kind of patient like this, what kind of patient looks like this. Hopefully now we’re going to have another really different option on the table here, particularly because it’s all oral. A lot of people aren’t huge fans of obinutuzumab and the experience people have receiving it.

Jennifer, how do you see this settling out in clinical practice? Do you think you could use another BTK inhibitor instead of acala, zanu for example, with this? You talked in your talk about all the trials looking at zanu. Any thoughts?

DR BROWN: So there’s no planned comparison in AMPLIFY between the AV and the AVO, but it does, as we saw in the PFS curves, look like the AVO is achieving a longer 3-year PFS at 83%. The AV is 76%. And this also correlates with the rates of undetectable MRD, which were very high on the AVO arm, and we’re about 40-ish percent on the AV arm, which is not dissimilar from other BTK/BCL2 combinations.

I think the AV arm was really very well tolerated. There was only a 10% rate of Grade 3 infections, which is lower than almost any of our other therapies in trials that we’ve seen. And again, it’s all oral.

In the mutated patients, essentially AV and AVO were doing pretty equivalently at 3 years, and so especially for the lower to intermediate-risk patients that’s a very easy and safe option. The AVO was still very well tolerated.

I should say there was very little cardiac or hypertension toxicity on this trial on either acalabrutinib-containing arm, possibly because it’s only 14 months of therapy, but that was very reassuring.

But there were more infections, in particular, on the AVO arm, and somewhat more neutropenia. And so that’s where one just has to balance that somewhat increased infection risk versus the fact that there was an extremely high rate of undetectable MRD.

If you actually censor for COVID the 3-year PFS is 91% in the AVO arm. And also in the AVO arm we saw that the unmutated patients did as well as the mutated patients at 3 years, so we are really reversing that worsened outcome that we see in the unmutated patients with the obinutuzumab. And so it seemed like really the unmutated patients, as well as the 17p-deleted patients, which we saw in the parallel trial that we did at Dana-Farber led by my colleague Matt Davids, seemed to benefit in particular from the obinutuzumab.

And you asked about older patients, as well as younger, fit patients. I think I’d be perfectly comfortable doing the 3-drug regimen for older patients, ess if they had bad disease, as long as they were reasonably fit.

DR LOVE: Yeah. I skipped through that paper that you all had with AVO with (del)17p, obviously very important.

Also, you presented a bunch of trials looking at zanubrutinib with venetoclax, as well as with a new BCL2 inhibitor, sonrotoclax, so hopefully we’re likely going to be seeing data there. They’re going to have to end up indirectly comparing to the AMPLIFY trial.

Again, Paolo, any comments on where you see the AMPLIFY strategy fitting in today? If you could use anything you wanted to use, how would you integrate this data into your practice? Can you describe a patient where you wouldn’t use either AV or AVO?

PROF GHIA: Actually, in Europe we have the luck that we have already starting using the combination —

DR LOVE: Right.

PROF GHIA: — between ibrutinib and venetoclax. And what we realized is, again, it’s so easy to use an all-oral combination then it’s easy to switch from any other treatment to this one in particular, because I think the future will be fixed-duration. So now, the way how we think when we see any patient who needs treatment, is why not fixed duration, so fixed duration is the first option. And then the fact that it’s all oral, and in particular having acalabrutinib is also well tolerated in the elderly patients, it makes probably the combination the first option to propose to the patient. And then, based on maybe patient preference, is then you discuss other treatment.

I agree fully with Jennifer that the option of AVO is something that instead you have to consider in a particular subgroup of patients where you want to be more effective, you want to have longer control of the disease, but of course you have to balance that out with higher risk of infection.

DR LOVE: Yeah, I know. When the data first came out people were saying, well, for those patients who would like limited-duration treatment and all-oral regimen. I’m like, well, who wouldn’t want that, theoretically, assuming you get the same long-term outcome.

Noncovalent BTK Inhibitor Pirtobrutinib

DR LOVE: Let’s talk a little bit about pirtobrutinib as well. I mean, we talk about the future, and I’m pretty sure it’s going to be including pirtobrutinib. And Jennifer, it already is here, so to speak. We saw this paper at the ASH meeting comparing pirtobrutinib to idelalisib/R or BR, which interesting it looked like it had pretty decent — it wasn’t as effective as pirtobrutinib, by far, but it still had some efficacy.

Any thoughts about these data, Jennifer, and kind of what it means to clinical practice?

DR BROWN: So this is the first randomized trial with pirtobrutinib, also the first randomized trial in patients who have all been exposed to covalent BTK inhibitor beforehand, and so in that sense it’s a novel population that we’re not used to looking at. And so I think that’s why some of the efficacy overall may be a little less than we thought, but pirtobrutinib had a PFS of about 14 months. And then in terms of the data here, which is time to next treatment or death in patients who are venetoclax naïve, it’s 30 months, in venetoclax treated it’s 20 months.

And so this is very encouraging. Pirtobrutinib is really our go-to in the patients who have progressed on covalent BTK inhibitor and venetoclax because it’s a very easy to give, very well tolerated BTK inhibitor. And as you noted, I think we also learned from this trial that idelalisib/rituximab also has activity in this patient population, with about a year of benefit. And so that’s also an option that we can use in these patients who at this point have fewer options.

DR LOVE: So Paolo, it’s been a while since we’ve talked about idelalisib in CLL, but here it is and looking pretty good. Anything you want to say about that? Also pirtobrutinib? And also tolerability issues with idelalisib, if any?

PROF GHIA: Of course. I mean, I was involved in the design of the BRUIN-321 study, and in fact the design was with idelalisib plus rituximab as a control arm plus — or bendamustine/rituximab because in Europe we were still using it at that time as third-line therapy, idelalisib plus rituximab. And I have to say that the PFS that you see now at 9 months, between 7 and 9 months depending on the … exactly what we learned and we knew already by using it in real-world setting, meaning that when you fail a BTKi and venetoclax you can still rescue the patient, so it was not a surprise for us, and therefore we enrolled very well in the study because it was very ethical from us. It was the real control that we would use in general practice. And therefore we are somehow reassured by the fact, as underscored by Jennifer, that at the end of the day the time to next treatment, which is the most relevant parameter for a clinician, is really around 2 years, and that’s exactly what we — the experience that we had in the study.

Because it’s not progression because at the end you keep the patient on pirtobrutinib even if the patient starts progressing, like we do with all BTK inhibitors. So we keep on treating the patient. We still have a benefit that is prolonged up to 2 years. So that I think is a very good — obviously not the final solution, of course, but it’s definitely giving us another couple of years where we can do something for our patients.

DR LOVE: So Jennifer, it’s always a challenge in oncology, I feel like no matter what tumor type we’re talking about this comes up of indirect comparison of agents that are a very similar class of agents, but yet you don’t have any data directly comparing them. You hear people talk about pirtobrutinib looking like maybe it’s even — clearly maybe going to be safer than ibrutinib, just like acala and zanu, but maybe even safer than acala or zanu.

I’m curious, Jennifer, what you think you would see if there was a trial that will never happen, a 3-arm randomized trial of monotherapy of acala versus zanu versus pirtobrutinib in terms of efficacy, but particularly in terms of tolerability. Do you think you could see a difference between pirto and zanu and acala in terms of tolerability?

DR BROWN: I think it’s possible. My impression is that the cardiac side effects of pirto are more limited. The more recent data with pirto has actually shown a pretty high rate of infection, as we would expect in these heavily pretreated, sick patients, which looks pretty comparable to acala and zanu, and also a little bit more bleeding than had been seen in the Phase I. And so that may be similar, but it still seems like — and also, thinking of my clinical practice, the cardiac toxicity may be less.

I’m not sure I’m going to take on the question of efficacy. It’s really hard to know. We don’t really have any proper data. It turns out that it seems like an indirect comparison. You can make either acala or zanu win, depending on how you set your parameters, so that’s not completely fair.

And I would not yet consider moving pirto before them because we don’t have any long-term follow-up. We have 7-, 8-, 9-year follow-up with covalent BTK inhibitors showing how efficacious they are. In pirtobrutinib we just don’t have that, we only have a couple of years, and we don’t fully understand what the resistance profile, if used in earlier line, would be. And so trials are ongoing assessing pirtobrutinib in earlier line, and I’ll certainly be interested to see the outcomes of those, as well as the long-term follow-up of those. But for now I think it’s premature for practice for sure.

DR LOVE: Paolo, anything you want to add to that? And also, if you have a patient who’s not eligible for CAR-T who progresses on pirtobrutinib do you see responses to idela in a patient like that? Or would you use idela in a patient like that?

PROF GHIA: The first thing I wanted to say is that indeed we have a direct comparison because there is a Phase III comparing pirto to ibrutinib. So somehow we’ll be able to compare to have some data, direct data.

In terms of use of idela after pirtobrutinib, I have to say that we never tried it because in Italy and in Europe we have the possibility to use pirto in compassionate use only after being exposed also to idela, so what we call double refractory. So we don’t have that.

DR LOVE: So it’s starting to sound a little like ibrutinib is the new chlorambucil. You put these new BTK inhibitors because you know they’re going to beat them up, but you don’t look at the second line.

But also curious about the issue of pirto in transformed disease, Jennifer. If you could comment on that. And also your strategy in a younger patient with double-refractory disease. Are you thinking about pirtobrutinib as a bridge to CAR-T, for example? Where do you think bispecifics are going to fit in?

DR BROWN: So in terms of younger patients with double-refractory disease my first goal is to prevent them from becoming double refractory, and some of that is by time-limited options, where we stop and then hopefully they progress much later, and we can reuse the drugs. Also we’ve had a strategy of always using clinical trials intermixed and potentially saving standard regimens for later if we have an available trial at the time.

And I would say pirto as a bridge to CAR-T would probably be a good approach in those patients who’ve reached that point. It actually hasn’t come up for me recently, since the CAR-T approval, but that’s probably what I would do.

And then in terms of pirtobrutinib in transformed disease, we have a large prospective cohort of the Phase I Bruin trial that looked at pirto in Richter’s transformation. The response rate was about 50%, which is actually really pretty good in a large population. But the PFS is still a little bit short, as it is with so many of our single agents. And so I think it’s a good backbone to potentially build or try combinations on in Richter’s.

And then regarding bispecifics, so that would be another option to mix in there after double-refractory patients. And at the moment I would probably consider trying it before CAR, it’s a conversation with the patient, but just because CAR as it is only has about a 20% complete remission rate, and those are the patients who have the most benefit. For the others it’s only about a 2-year benefit, 2 and a half year benefit, which is not that different than pirto or the other options we’re talking about. Of course we don’t know what the benefit is with bispecifics, but it’s a little analogous to adding in drugs from clinical trials and saving what’s available until later.

CAR T-Cell Therapy; Novel Agents

DR LOVE: Any final comments on the double-refractory patient, Paolo? Also, we reviewed papers, I was mentioning, looking at venetoclax combinations with pirtobrutinib, and there are a number of trials that are being looked at. It looks very promising in terms of MRD, et cetera. Where do you see that heading? And any other comments, Paolo, about double-refractory disease?

PROF GHIA: No. Double refractory, now probably we have to talk about triple refractory, meaning that pirtobrutinib is definitely entering the scene, and so we will use it even before venetoclax or after venetoclax, but it will definitely be part, probably, of the standard treatment nowadays. And so thinking that we can salvage the patient after they’re so-called triple refractory.

I also share the enthusiasm — Jennifer’s enthusiasm for BTK degraders and for bispecifics that look really like promising drugs in the future.

With pirto in front line, I mean the data is very impressive, I mean 100% undetectable MRD, pirto/venetoclax/obinutuzumab. Of course we should really also collect data on what’s next, meaning that we don’t know what type of resistance really occurs after pirto. Can we use all the other BTK inhibitors after, or do we lose the entire class of drugs? And so those are the questions that probably we need to answer before we move pirto to front line.

DR LOVE: So a final comment from Jennifer. I feel like I’m talking to your breast cancer colleagues every day about estrogen receptor degraders. Now I’m starting to hear androgen receptor degraders in prostate cancer. And lo and behold, here we have BTK inhibitor — BTK degraders. How do these agents work and how does it play out clinically in terms of risks and benefits, Jennifer?

DR BROWN: Right. Well, so they have a multipronged molecule that binds to BTK on the one side, and on the other side brings in a ubiquitin ligase and triggers the proteasome to degrade BTK. And Paolo was mentioning triple-refractory. So there are a lot of triple-refractory patients on these trials, Phase I studies, at last double and some triple refractory, and we’re seeing very nice response rates, up on the order of 75%. Follow-up is still short, but I think the response rates and the fact that they’re similar between 2 different molecules in 2 different trials are very encouraging, suggesting that this is real, and so that hopefully we’ll get another line of BTK inhibitor therapy.

DR LOVE: Paolo and Jennifer, thank you so much. I know we all learned so much tonight. Audience, thank you for attending. Be safe, stay well and have a great evening. Thanks so much, Jennifer. Thanks so much, Paolo.

PROF GHIA: Thank you. Thank you all.

DR BROWN: Thank you.