Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the current and future management of chronic lymphocytic leukemia with Dr Jennifer Brown, the CLL Center Director at Dana-Farber in Boston.

We have a great faculty for this series and later on, we’ll show you the results of a survey we did of the faculty of their usual treatment patterns. As always, if you have any questions or cases you’d like to run by Dr Brown, just type them into the chat room and we’ll talk about as many of these as we have time.

If you’re into audio programs, we know a lot of people end up listening to replays of these webinars, check out our podcast series, Oncology Today, including a recent program with Dr Hillmen. We do webinars all the time now. Next Monday, we’re going to be starting a series on targeted therapy of non-small cell with Dr Camidge. And, of course, we’ll be talking about ALK plus a lot more. And then on Thursday, April 28^th, we’ll start a 3-day hybrid symposia. We go every year to the Oncology Nursing Society meeting. We’re going out to Anaheim. We’re doing 10 symposia in 3 days. If you know any nurses who might want to come over there in the California area or the LA area, let them know about. We’re also going to do all of these online. So let your nurses and nurse practitioners know about this. A lot of content. We have 40 investigators, nurses and physicians there. This should be a great event. We’re really looking forward to it. We’re starting another series on upper GI cancers with Dr Janjigian from Memorial. And then, we’ll be going out to the AUA meeting, doing a program on both prostate cancer, we’ve got a lot of great stuff going on with PARP inhibitors, new trials, and then bladder cancer with 5 lines of therapy approved in metastatic disease.

But today, we’re here to talk about CLL. So interesting. I always love talking about CLL. So much going on. As always, we have some cases from docs in practice we’re going to run by Dr Brown and see what she thinks about it.

Here’s where we’re heading. We’re going to start out with some case presentations. Then, we’re going to get into a bunch of papers that Dr Brown has done. Then, we’ll show the survey. At the end of the slide deck, which you can access through the chat room, we have a bunch of appendix slides and we may refer to some of these as we go along.

But I just want to start out, Jennifer, this a paper about a month ago. I think it was really the first report of mechanisms of resistance to the noncovalent BTK inhibitors. Of course, pirtobrutinib, one getting a lot of attention. And I want to just take a minute before we start because this is something that really comes up a lot. I get a lot of questions about it. And I’d like you to imagine you’re kind of making rounds with a bunch of fellows. So no slides. I want you to really talk like we’re on rounds. And I’d like you to kind of chat a little bit about your vision about how BTK inhibitors work, what kind of resistance you see with the covalent BTK inhibitors and then what is now being reported with the noncovalent. This is a paper that you did that talks a little bit about this, starting out with B-cell receptor signaling. So maybe you can kind of walk us through your vision about how BTK inhibitors work and what we know about resistance mechanisms to the 2 types of BTK inhibitors.

DR BROWN: Sure. So BTK, of course, is the Bruton tyrosine kinase which was initially cloned as the gene that causes Bruton’s agammaglobulinemia, a disease in which patients have a lack of immunoglobulins, but actually very few other problems. And this suggested that BTK would be an excellent target potentially for treatment of B-cell diseases. It’s immediate downstream of the B-cell receptor and triggers the downstream signaling that leads to proliferation and survival of the B-cell. And this is true also of CLL, that BTK is the central survival pathway which is constitutively activated in most CLL.

So the first in class inhibitor of BTK, of course, is ibrutinib. And ibrutinib is a covalent inhibitor of BTK which it means it binds irreversibly to a particular cysteine residue, cysteine 481, in the active site of BTK. We now, of course, have additional covalent inhibitors that we’ll talk about later, I’m sure, acalabrutinib and zanubrutinib. And because these drugs bind specifically to this particular residue in BTK, the mechanism of resistance is mutation of that residue. And so we know that about 75% or so of patient mutate that cysteine to a serine or another amino acid that can’t bind the covalent drug. And sometimes this is accompanied by mutation of the immediate downstream target of BTK, PLCgamma2. PLCgamma2 mutation by itself is rare though. And then about 20%, we don’t know the mechanism of resistance.

And so the noncovalent BTK inhibitors, which have come on the scene in the last few years, were designed to target the CLLs that were resistant to the covalent BTK inhibitors in which cysteine 481 is mutated. And so pirtobrutinib is the one that has generated the most excitement. It has treated hundreds of patients in a Phase I study with a lot of activity in patients previously treated with covalent BTK inhibitors. And so this paper that came out about a month ago was looking at mechanisms of resistance to the noncovalent inhibitor, pirtobrutinib, which doesn’t require any specific residue to bind to. And here, you can see they had 9 patients whose disease had progressed on the Phase I study and they sequenced them and they found that essentially what we would call second site BTK mutations, other mutations in BTK, were popping up as the mechanism of resistance. These were all pretty much in the tyrosine kinase catalytic domain, however, and are predicted to potentially interfere with the binding of pirtobrutinib.

The interesting thing that we see with all BTK inhibitor resistance, both to the covalents and now also to the noncovalent, pirtobrutinib, is that it tends to be multiclonal. So we know that the cancer cells start out hopefully with one major clone that carries some mutations that are in all the cells, but then there are also subclones that develop over time with other mutations in only a subset of the cells. And so these mutations that cause resistance then develop within the subclones. And sometimes we get multiple of these subclones with the resistance mutations which really underscores, again, how much pressure we’re putting on BTK and how important that survival pathway is to the CLL cell, that the cells keep finding multiple ways to escape from it and cause resistance.

DR LOVE: Can you comment on these? I never saw graphics like these before, but they’re super cool. I guess as they go to the right, it’s with time. And what you’re looking at here is the clonal evolution? What are you looking at here?

DR BROWN: That’s right. It’s a pictorial of how the clonal evolution might be occurring. So we can see prior to treatment, this patient has the gray clone which is predominant in their disease and it carries that XPO1 mutation. And then during treatment on the inhibitor, it looks like they acquired a PCLgamma2 mutation and that’s actually in 2 separate clones again, one within the gray clone with XPO1 and then another one that’s separate. And then at subsequent relapse, we see acquisition of BTK mutations as well. And, again, that’s happening in 2 separate clones which we can tell by the pattern of mutations in the 2 blue, the light and dark blue, that are popping up on the right. And you can do these over a patient’s entire disease course from prior to therapy and then through multiple rounds of treatment. And you’ll see sometimes actually even adverse clones from early on disappear because the resistance mutation develops in a different subclone.

DR LOVE: Here’s another patient. How do you read this?

DR BROWN: Right. So this one has that FBXW7 and BIRC3 mutation in the big green clone and then they acquired a BTK C481S mutation. So that’s the mutation, again, associated with resistance to the covalent inhibitor. Then subsequently, there’s complete clonal shift. So the yellow goes away and then the blue pops up. There’s still an FBXW7 and a BIRC3 mutation, but they cysteine 481 is gone and now there’s a different BTK mutation that’s associated with the noncovalent resistance rather than the covalent resistance.

DR LOVE: So we’re always talking about we wonder how millennials must view diseases like CLL, if they think this is the way that it always was that we had these kinds of graphics to look at when we’re using BR and other, you know, FCR. So no, it’s different. It’s way, way different. It’s so exciting. Amazing. Anyhow.

Case: A man in his late 60s with chronic lymphocytic leukemia (CLL) on observation for 10 years who develops angioedema — G Richard Polkinghorn, MD

DR LOVE: Let’s go from the sort of sublime to the practical. This is actually, it turns out, a patient, I was interviewing Dr Polkinghorn this week. It turns out this patient was actually seen by you all at Dana-Farber. Really interesting case. I really didn’t hear much about this before. Angioedema as a problem with CLL. Here’s Dr Polkinghorn.

DR POLKINGHORN: He did not require any therapy until a couple of years ago when he developed angioedema.

DR LOVE: What actually did he describe in terms of what happened and what did he look like?

DR POLKINGHORN: So his face gets swollen, and then it slowly progresses. His tongue gets quite swollen, and then he develops difficulty breathing, comes into the emergency room with strider and feels like he’s going to stop breathing. So it’s pretty intense. And he was treated with fairly standard treatments for angioedema. However, the angioedema came back, and he sought consultation in Boston, at Dana-Farber, and they felt this complement-mediated angioedema was CLL related, and their recommendation was to start him on ibrutinib, which we did. And since then he has had absolutely no angioedema, which were life threatening, I point out. I would be interested in how often they see this complement-mediated angioedema associated with CLL and whether they think treatment, as in this case, is helpful.

DR LOVE: Of course, I’d be curious about the mechanisms of how this occurs. I don’t know if you want to give us your theory or what we know about that.

DR BROWN: Right. So I would say we see one of these every couple of years at the Farber. It's definitely not uncommon. And I do generally think that treatment helps. I view it as within the spectrum of autoimmunity that we see in CLL. It obviously may be a different mechanism than autoimmune hemolytic anemia or ITP, but I think in terms of how we might think about it, it’s a reasonable model. And as we know with autoimmunity in CLL, treating the disease usually puts it into remission. And I have cases from in the distant past where we treated with chemoimmunotherapy and the angioedema went into remission and then this patient responded well to ibrutinib. An interesting question that I think about in this context often is, does it matter if they’re continuously on therapy with a BTK inhibitor versus putting them into deep remission in terms of which will work better on the autoimmunity? And we don’t really have a good answer to that. I think at the moment, probably both strategies can work pretty well.

DR LOVE: That’s really interesting. So in patients who, a matter of fact, we have a couple patients who only have autoimmune phenomena, do you ever just hold the BTK after they respond?

DR BROWN: It depends. I would say if they had very, very little disease, I would probably choose a time-limited strategy rather than the BTK inhibitor. If they have a lot of progressive disease and they’re doing well on a BTK inhibitor, I would not be so inclined to stop, even if they are in a relatively low disease state.

DR LOVE: I was kind of surprised that you all, I know you didn’t see this patient, but I was kind of surprised you all recommended ibrutinib. I think it was a fairly recent case. In what situations are you using ibrutinib nowadays as opposed to acalabrutinib, for example?

DR BROWN: Right. I’m not using ibrutinib at all actually. I pretty much always use a second generation BTK inhibitor now that we have 2. Well we have randomized trials of 2 different second generation covalent BTK inhibitors showing at least equal efficacy and improved tolerability. And that, of course, is for acalabrutinib as well as for zanubrutinib. The latter not yet approved in CLL, but hopefully soon.

DR LOVE: Yeah. I didn’t know if there was more immune effect of ibrutinib or whatever, but I’m not hearing too much about ibrutinib anymore. So I don’t know whether it’s a coincidence or not —

DR BROWN: So —

DR LOVE: Sorry. Go ahead.

DR BROWN: I was just going to say that in theory, in the beginning, we thought there was more immunomodulatory effect of ibrutinib, but the data to date actually support that acalabrutinib is similarly immunomodulatory and I think that probably reflects that most of the immunomodulation is from disease control as well as putting the residual disease into a quiescent state.

DR LOVE: But it’s used in graft versus host disease. Has acalabrutinib been studied there?

DR BROWN: Not to my knowledge.

Case: A woman in her early 60s with small lymphocytic leukemia and BTK (Bruton tyrosine kinase)-related arthralgia — Rajni Sinha, MD, MRCP

DR LOVE: Interesting. So I was about to say, I don’t know if this is a coincidence or not, but this is the second case that we’ve had of a patient with CLL who got their pancreas removed sort of mistakenly, so to speak. I don’t know if you see that, but we’ve already had 2 cases in the last 2 months. But anyhow. Here’s Dr Sinha. She got this patient after that happened as a referral for a second opinion of this 60-year-old woman.

DR SINHA: This is a 60-year-old who actually came to me after having had a pancreaticoduodenectomy for a large pancreatic mass. The path was consistent with small lymphocytic lymphoma. She came to me from another institution, kind of unhappy that she was left with no pancreas. In January of 2022, she starts to develop constitutional symptoms, some weight loss, some night sweats. So we discussed treatment options. She really has no high-risk features. She opts for acalabrutinib. She calls a few times and she has severe joint pain. She’s tried all the over-the-counter medication, muscle relaxants, but elbows, joint pains. So my question would be, how would you manage this patient’s joint pains in relation to acalabrutinib?

DR LOVE: So usually when you hear about arthralgia, this is about ibrutinib. So I’m not shocked to hear this. I am curious about your personal experience. Also, have you seen cases like this where people had their surgery mistakenly sort of?

DR BROWN: So I have seen cases of mistaken surgery, nothing as aggressive as a pancreaticoduodenectomy though. But we have seen some colectomies, for example, or partial colectomies. And that’s always unfortunate, obviously. Now in terms of the arthralgia issue —

DR LOVE: So — go ahead.

DR BROWN: So I have certainly seen it with acalabrutinib, but much less commonly than ibrutinib and usually not nearly as persistently. I would say usually with acalabrutinib, it may pop up for a few days here and there and then tend to go away over time whereas ibrutinib, some people just have it consistently every day constantly. So I’ve never had to really dose reduce or stop anyone on acalabrutinib for arthralgias. But with this person, you could try a Medrol pack, short course of steroids, see if it helps, but once you do that, usually it tends to come back when you stop it. You could try a dose reduction. You could try getting zanubrutinib which I do think has potentially even less arthralgia than acalabrutinib.

DR LOVE: Just before we started, we were chatting and I think I heard you say, it was the study where you were looking at T-cells and PI3 kinase inhibitors, but you mentioned something about a T-cell subset associated with autoimmunity. Are there specific kinds of T-cells that are associated with autoimmunity? And do you see more of them in people who have autoimmune problems?

DR BROWN: So that’s interesting. There is a category of T-cell called Th17 type cells which is relatively recently defined that is involved in autoimmune disorders. And it turns out that Barbara Sherry down in New York has looked at this in untreated CLL patients. And there is actually expansion of this population of cells in subsets of CLL patients although it’s actually more common in lower-risk IGVH mutated rather than unmutated patients. To my knowledge, no one’s actually looked at this in patients with and without autoimmunity. I’ve been interested in it, but it hasn’t risen to the point where we’ve been able to do it. One thing is that autoimmunity is more commonly associated with unmutated IGVH which is different from the PI3 kinase inhibitor activity autoimmunity which is actually more associated with mutated IGVH. Whenever there’s a simplistic explanation to the autoimmune problems of CLL, I usually view it skeptically because it seems like it’s a very complicated problem and we need a lot more research on it because it’s still not very well understood.

DR LOVE: Interesting. So you may have noticed that the theme of our ONS spectacular this year is What I Tell My Patients. We’re going to really try to, we’re curious how people explain things to patients. So we’ve got a little addendum here on this case from Dr Sinha and I want to know what you would say to this patient.

DR SINHA: The other question is, she’s now been on the medication for about 2 to 3 months. Her white cell count is still around 130,000. She’s extremely anxious. And what do I tell her in terms of how long it should take for her absolute lymphocyte count and/or her white cell count to gradually come to a level where everyone’s very comfortable? The big thing with her is she is a pilot. And she wants to know can she go back to work?

DR LOVE: So, what do you think?

DR SINHA: That makes me nervous in terms of allowing her to go back to work on acalabrutinib. I know that the risk of arrythmias, bleeding issues, may be “lower” but it makes me nervous.

DR LOVE: So any thoughts about these 2 issues? What do you say to the patient in terms of the white count not coming back down, what to expect?

DR BROWN: So I always warn the patients ahead of time that the white count may even go up for a while. It can even go up for the first 2 or 3 months before it starts to come down. And it may, in fact, never normalize in a subset of patients. In the frontline setting, we tend to see that a little bit less, but it can take a long time, and especially if this patient has a mutated IGVH. We know from the ibrutinib data that the median time to normalization is on the order of 14 months. So I would not be worried about that at all as long as the patient feels better in terms of her symptoms and her hemoglobin is recovering. And even the hemoglobin recovery can take 4 to 6 months sometimes. Then regarding the pilot issue —

DR LOVE: I have a feeling — I was just going to say, I have a feeling question 1, in a way, is related to question 2 that somehow maybe she’d feel better about going back to work if her white count was normal. And the other thing I’m curious about your thoughts on is, I kind of, as time has gone on, I’ve become more aware of the issue of ventricular arrythmias, mainly with ibrutinib and I wonder what your thoughts are about that and, again, just this practical question about being a pilot.

DR BROWN: Right. So I agree with your comment that I think if a person has been on acalabrutinib for a year or 2 and is stable and their disease is well controlled that that is a very different scenario than this current scenario for the patient. And the FAA actually has lists of drugs that people are and are not allowed to be on in terms of being a pilot. And so the last time I looked into this was a few years ago, but at that point, these drugs were not okay on that list. So I don’t know actually if that’s changed. So that’s obviously a point for the FAA evaluator.

DR LOVE: Yeah. Somebody in the chat room says, what’s the white count got to do with work? And I’m just saying psychologically maybe, not, obviously, of course, functionally, not an issue.

DR BROWN: Most of the most dangerous side effects of these drugs do tend to happen early. The higher rate of serious infections is in the first 6 months. The higher rate of atrial fibrillation, the relative risk of atrial fibrillation is much higher in the first 6 months. And, in general, once the disease is very well controlled in terms of tumor burden, then the likelihood, I think, of a severe event is less common.

Now you asked about ventricular arrythmias and that’s been a major interest and concern of mine on ibrutinib where we had seen quite a lot of ventricular arrythmias, in fact. Ibrutinib, I think, has multiple cardiac toxicities. We don’t have as extensive or as long experience with either acalabrutinib or zanubrutinib. But as yet, I have not seen any data to suggest that there is an increase in ventricular arrythmias with those drugs. In fact, in most of the randomized trials, there are a few events with ibrutinib and not a lack of events with acalabrutinib or zanubrutinib. So I’m hopeful that that risk may be less with the newer drugs.

Case: A man in his late 60s with CLL and hypertension, coronary artery disease, GERD and atrial fibrillation — Khuda Dad Khan, MD, PhD

DR LOVE: So speaking of choosing a BTK inhibitor and side effects with BTK inhibitors, we have a case from Dr Khan. What do you do when you have a patient who has a history of cardiac disease, but really wants to take oral therapy? Here’s Dr Khan.

DR KHAN: Very pleasant Scottish gentleman, a very beautiful accent, nice man. He is a mason, he does this brickwork, and it became difficult for him. He was taking frequent breaks and even needing a nap. He was also having night sweats. He also has underlying coronary artery disease. In fact, he has a history of atrial fibrillation, and he was on anticoagulation. He also had gastroesophageal reflux disorder, and he was on omeprazole. His preference was to take oral treatment at home. He did not want to come to the office frequently. So then the question was which BTK inhibitor to use, and I was inclined against ibrutinib. Then I was concerned about acalabrutinib because of his PPI. But his insurance would not approve zanubrutinib. And then the other question also is with zanubrutinib whether you need an anti-CD20 partner or you use single-agent zanubrutinib?

DR LOVE: I told you they can ask a lot of questions in 50 seconds. So any thoughts about this case? I’m sure you’ve seen plenty of people like that. Would you put them on BR or something?

DR BROWN: No. I’m comfortable using a second generation covalent inhibitor in a patient like this, either acalabrutinib or zanubrutinib. As noted, sometimes it’s hard to get zanubrutinib at present unless the patient has previously failed another one of the inhibitors. You don’t need to use a CD20 with zanubrutinib. It’s been developed as a single agent in CLL. I would note that acalabrutinib is actually coming out with a formulation that will still be absorbed even in patients on PPIs. So that issue may improve significantly moving forward.

DR LOVE: Yeah. We saw that at ASH. Any problems that you see with it? Or are you expecting that this issue is going to go away? Because I hear a lot of cases like this of people on PPIs. Do you think that’s going to happen fairly soon?

DR BROWN: I think it is supposed to happen fairly soon. I would also say that I tend to stop the PPI when the patient starts on acalabrutinib while you’re trying to get good disease control, but many times if the patient has refractory symptoms a few months in, they tend to go back on and it doesn’t seem to cause a problem.

DR LOVE: That makes sense. And interesting too. Question in the chat room about using combination BTK and venetoclax. We’ll get there in a second. We’re heading in that direction.

Case: A man in his mid 60s with CLL who receives obinutuzumab and venetoclax — Raman Sood, MD

DR LOVE: But first, let’s see another case here. And we’ve been talking a lot about the issue of complications, side effects with BTK inhibitors. This is a patient who is on obinutuzumab/venetoclax and he also mentions another interesting case that he had with a patient on venetoclax. Here’s Dr Sood.

DR SOOD: Mid-60s, Hispanic guy. He came to me about a year ago with pretty bulky adenopathy. The white count was like mid-40s, not anemic. So we were kind of watching him and recently we noticed that his white count is less than 6-month doubling time, and his nodes are getting pretty bulky. We decided to go ahead with the treatment at this point. And we decided to go with the venetoclax and obinutuzumab combination because he liked the finite duration of treatment. Actually pretty dramatic effect the first dose of obinutuzumab. The next day he came back, the white count had already dropped from 60,000 down to 10,000 within a day actually, and the lymph nodes were starting to melt down. I did have a patient who had delayed cytopenia a year later, mid-80s. Had a CR to CLL therapy, but a year later she had just dropped her white count. And we did a marrow. There was nothing there. So she required growth factor support for a while for severe neutropenia, but now, over the last 2 years, has finally recovered.

DR LOVE: So I want to use this as an opportunity to ask you some of the questions that people always bring up about using venetoclax. But what about that second case he was talking about where a year later, the patient developed cytopenia, had to give growth factors for a while? Have you seen that happen? And what’s going on do you think?

DR BROWN: I’ve certainly seen plenty of residual neutropenia shortly after venetoclax. I can’t say that I’ve seen people who stop and then it recurs or comes back a year later. That’s a little unusual and always a little bit concerning. I’m glad this patient recovered. I would say there’s a possibility it could be autoimmune actually. We have seen more autoimmunity with venetoclax than we used to. And there’s also a report from Italy suggesting that there’s more emergent autoimmunity with venetoclax than with BTK or PI3 kinase inhibitors. It could also have been related —

DR LOVE: Autoimmunity from the disease or from the venetoclax? The disease I’d assume.

DR BROWN: Well probably not the venetoclax a year later I wouldn’t think unless it somehow altered the patient’s milieu. We sometimes used to see that with chemoimmunotherapy, right? With FCR, patients in remission and then like 4 or 5 months later sometimes would come up with autoimmunity ITP. And that tended to be felt to be related to the FCR. So I wouldn’t rule it out completely with the venetoclax. But it’s also possible the patient’s disease was starting to recur and that that could have been why.

DR LOVE: So no matter how many times we go through CLL, it’s always interesting to me because everybody has different takes on some of the key questions. And you heard him describe what happened when he gave the patient obinutuzumab. We hear that all the time now. We were talking about a trial where the control arm had rituximab in it. I was like, why are they using rituximab? You said because MURANO, et cetera. But I am kind of curious in real-life, so to speak, what kind of CD20 strategy you use. Which agent? And how do you sequence it in recurrent disease?

DR BROWN: Right. I do tend usually to use obinutuzumab even in the relapsed setting and that’s partly because it’s just a much more potent agent than rituximab in CLL and partly also because I prefer the schedule. I’d rather debulk the patient with the obinutuzumab than the venetoclax. And you can’t really debulk a relapsed patient all that well with rituximab. Even if you gave it before the venetoclax, it doesn’t work all that well. So overall, I tend to prefer the obinutuzumab.

DR LOVE: People feel a lot of relief when they decrease the risk status for TLS by using CD20 or obinutuzumab. But I’ve also heard a couple cases of people getting TLS from the anti-CD20. Do you kind of, what do you do preventatively when you’re going to give the obinutuzumab to somebody with a high white count or big nodes?

DR BROWN: Yeah. So you definitely can see TLS. I actually pretty much always give patients steroids and diphenhydramine starting the night before and the morning of in addition to what I give in clinic that day. And I check pre tumor lysis labs. I usually give at least a couple liters IV fluid. I check post first infusion tumor lysis labs. And then I recheck the labs the following morning on the second day. If all the labs have been normal to that point, then I don’t necessarily check post on the second day. And then, obviously, they’ve been on allopurinol for at least a few days before starting as well. The thing about it I would say though is that the CD20 type TLS is much more predictable. It’s like chemo TLS. It’s what we understand. Whereas venetoclax TLS can be random and stochastic and that’s why it’s very scary. The potassium can just take a big jump in the matter or 2 hours. And that doesn’t tend to happen with the obinutuzumab. You kind of know what you’re dealing with. So that’s part of the reason I like it better.

DR LOVE: Interesting. It makes complete sense although I’ve never heard anybody actually make that point. I think it’s really a helpful point. Another very common question all docs are asking us is about MRD assays. We have a paper, I don’t know if we’re going to get to it, a consensus statement on MRD. But first of all, do you think MRD is reasonable for a doc in practice to use outside of trial setting, for example, after a year of first line therapy? And of course, the big question, what do you do if they’re MRD positive? Do you do according to the trial and stop therapy or do you keep going?

DR BROWN: Right. So it’s still the recommendation that we don’t alter therapy based on the MRD results. And, in fact, I don’t. With the frontline ven/obin regimen, I will check the MRD because I’m interested in knowing what it is and because it’s prognostically important. But I don’t change what I’m doing based on it. The one possible exception to that in my practice would be if I’m using venetoclax/obinutuzumab in a 17p deleted patient which I would tend not to. I favor BTK inhibitor more. But if I were doing it for some reason and the patient were still MRD positive, I might consider extending that patient’s therapy somewhat. But that’s not a recommendation. And so there’s not really any need for docs in practice to check MRD, but if it’s of interest prognostically or because the patient is interested, it’s not unreasonable. But if they’re MRD positive, for the majority of patients, I would still stop. There’s still 73% of patients in remission 4 years later regardless of MRD.

DR LOVE: So a couple of great questions in the chat room, one from Dr McKenna. Can you use obinutuzumab-based therapy in a patient who progresses after ven/rituximab 1 year later?

DR BROWN: So I would say that 1 year after time-limited venetoclax is a little bit borderline for retreatment and we don’t have data on it, but you could consider it. If you’re talking about venetoclax/obinutuzumab, that would probably be what I would do. Obinutuzumab by itself, like most CD20 antibodies in CLL, doesn’t have a huge response rate on its own, but it really works synergistically with our other drugs like chemotherapy or like venetoclax. And so it would be reasonable to try that. If the patient had a 17p deletion or very high-risk markers or very bulky disease, I might be a little less inclined to do it and more inclined to do BTK inhibitor. But just be aware that the 1-year interval of relapse is a little short in terms of what you’d be looking for for likelihood of a really good response again.

DR LOVE: All right. So here’s a really interesting one from Charles. 89-year-old patient with Stage 0 CLL on observation develops Stage I non-small cell lung cancer and gets localized SBRT and then over the next 3 months, the white count goes from 110,000 down to 13,000. Abscopal effect? Any thoughts about this wild one?

DR BROWN: Well I can say that we see it a lot although usually, it’s with less targeted radiation and radiation at least covers a little bit of bone marrow. But I’ve had lots of patients normalize their white counts after radiation for breast cancer. At least a few —

DR LOVE: Really?

DR BROWN: Yeah. At least a few after prostate cancer.

DR LOVE: Wow.

DR BROWN: There, you might be getting a little bit of pelvis in terms of marrow. But yeah. We see it. I think it is probably related.

DR LOVE: But you think it’s an abscopal effect or you’re just hitting the marrow?

DR BROWN: Well I think we’re not hitting enough marrow in at least some of the cases that I know of, so it must be an abscopal effect.

DR LOVE: That is so interesting. I’d be really curious if anybody in the audience has ever seen that in any of their patients. So interesting.

Case: A man in his early 70s with IGHV-mutated CLL — Gurveen Kaur, MD

DR LOVE: Okay. Well this one is specifically for you. I thought you would find this next one very interesting. 70-year-old man with IGVH mutated disease. Here’s Dr Kaur.

DR KAUR: Unfortunately for the patient and family, his wife was also battling with ovarian cancer and undergoing treatment. So that was also dictating how management of this patient will play out. He was having all these unexplained fevers, fatigue, night sweats and weight loss. So he was wanting to go on treatment and, of course, met all the indications. Not in the best shape when I saw him, ECOG kind of fluctuating between 1 and 2. And then, given that he’s the sole caregiver for the wife, he wanted to be on a treatment which is not going to make him terribly sick. So, based on all these factors, we came up with the discussion, and then decided to start treatment with venetoclax and obinutuzumab. So the patient did tolerate the treatment really well. He continues to be in complete response and remission at this point.

DR LOVE: What would you have been thinking if he were younger?

DR KAUR: I would have definitely wanted him to go on the chemoimmunotherapy with FCR.

DR LOVE: So before you comment, Jennifer, let’s see what the audience thinks. Audience, I want to know, in general, you’ve got a younger patient with IGVH mutant disease, no del(17p) or TP53, in general, how are you going to approach therapy for a patient like that? And let me see here. Hold on. I’ve got the wrong one pulled up. Oh here it is. Okay. So before you comment, I just want to show the audience this. This is from our faculty survey. And there you are with FCR. And I was saying to her, well supposed I showed you a bunch of data where 95% of people are not using FCR, would that change your mind? She said no. But anyhow. She’s got you on her side. So what are you thinking? And let me see what the audience says. Actually, 21% of the audience says FCR. So they’re not too FCR oriented.

DR BROWN: I remain quite compelled by the long-term data with the 55% long-term progression free survival with all those patients with undetectable MRD. I have to say, it’s been a long time since I’ve given FCR though. And 60 is a borderline age. The younger the patient, the more I’d be inclined toward it. And I usually do ibrutinib/FCR according to the study that we did here. We now have 3 studies combining ibrutinib with FC and a CD20 antibody, all of which now have at least 3 to 4-year follow-up in progression free survival in excess of 95% and undetectable MRD in excess of 75%. So they’re the most effective regimens we have. And then this unmet need issue also concerns me. If you’ve got a 50-year-old, you’re not going to get them to their natural lifespan with BTK inhibitor and BCL2 inhibitor. You’re giving up a really effective regimen for the majority of CLL patients, not the very high-risk disease, but the intermediate to lower-risk disease, you can get 10 years. Even unmutated patients, you can get 10 years out of an FCR or like an ibrutinib/FCR regimen. So that is a lot of my thinking.

DR LOVE: So it looks like the chat room is starting to respond to your thought. I don’t know what’s less popular, bleomycin or FCR, but I know docs do not like FCR. But as you point out, there are potential advantages to it. This is — I want to go back and jump into a few of the papers that you’ve written that get into some other topics. This is a paper that you were part of talking about unmet need in specifically people resistant to both BTK and venetoclax which I think we’re seeing more and more. We’re going to talk about the GLOW study and the idea of — the many other studies looking at combinations. I like this graphic here. It really sort of outlines what the issue is. Can you talk a little bit about that and sort of where things like pirtobrutinib and CAR T and other strategies fit in here?

DR BROWN: Right. So this is just outlining the idea that patients whose disease progresses on continuous BTK inhibitor and then progresses on a venetoclax regimen or after, but then too soon where retreatment won’t work, those patients have become a real unmet need. We have PI3 kinase inhibitors, but we don’t know about their activity in that setting because they haven’t been tested in that setting. We have pirtobrutinib, but it’s not yet FDA approved. We have CAR T-cells, but they’re not yet FDA approved for CLL. So this is really a tough scenario now. And then if we think about using both BTK and venetoclax together frontline, the hope is maybe we could retreat with the same combination after or give one or the other of the drugs subsequently, but we don’t have any data on that yet. And so that’s why it’s highlighted here as a potential unmet need.

DR LOVE: Let me ask you something. I don’t know, of course, whether we’re going to see an approval and I guess there’s a possibility, maybe even a likelihood, if there is one, it’s going to be ibrutinib plus venetoclax. I don’t know how it’s going to be in terms of regulatory issues, but would you be comfortable putting another BTK inhibitor in there or you would stick with ibrutinib? And will you even use that?

DR BROWN: I would be comfortable switching. I would not use ibrutinib/venetoclax. I really don’t like ibrutinib because of the cardiac toxicity and particularly, I’ve lost quite a few patients to ventricular arrythmias, far more than I’ve ever lost to MDS after FCR, honestly. So this is a concern of mine. But I would be willing to substitute acalabrutinib into that regimen if I could get it paid for which is a possible issue. I remain unconvinced though that we should use the 2 drugs together upfront in most patients. We don’t have proof that it’s better than venetoclax/obinutuzumab. I don’t want to lose the CD20 because CD20s are really very potent in CLL. They were our first drug that increased overall survival in a randomized trial. And so keeping the venetoclax/obinutuzumab there and saving the BTK for later seems, to me, still a reasonable strategy. And I think that was underscored by the CLL13 data that we saw at ASH where the undetectable MRD rates were actually very similar for venetoclax/obinutuzumab as for the ibrutinib/venetoclax/obinutuzumab arms.

DR LOVE: Yeah. That was what surprised me that they didn’t see higher MRD. It didn’t look like it was that much more than the venetoclax combinations. You mentioned CD20 and, again, very common question in what situations you’ll add CD20. People seem more impressed with acalabrutinib data on CD20, but are you using it with BTK, with any BTK?

DR BROWN: I use it sometimes with acalabrutinib. With ibrutinib, I would never use rituximab. We have 2 negative randomized trials. And I don’t use obinutuzumab with ibrutinib unless I really need it for cytoreduction. But as I said, I don’t use ibrutinib anymore, so it’s become kind of irrelevant. I think the reason people are most potentially impressed with acalabrutinib is because we actually have a randomized trial, not powered to look at it, but did find a 9% at 4-year improvement in progression free survival with the addition of obinutuzumab to acalabrutinib compared to acalabrutinib alone. We also know that there is some rationale for potential better synergy with acalabrutinib compared to ibrutinib because ibrutinib inhibitors ITK which can inhibitor ADCC. Acalabrutinib doesn’t inhibit it. So I will sometimes add it with acalabrutinib. The issue that arises though, as we heard in some of the cases earlier, a lot of times the patients who are choosing a continuous BTK inhibitor are doing so because they don’t want to come to clinic. And so adding obinutuzumab pulls them into clinic more than they want to. So even if I suggest that it may have this benefit, many of the patients don’t really want to do it because it’s too much work relative to the perceived benefit.

DR LOVE: So we worked a lot with your colleague, Matt Smith, in prostate cancer. And, of course, we just saw the approval of lutetium. And I was hearing from these investigators for quite a while that they wanted to use it, they thought it was the best option in many clinical situations, but it wasn’t approved. Finally, it got approved. Is that kind of the situation that you see pirtobrutinib in, that it’s really, I hear investigators wanting to use it, they’re ready to use it, it’s just not approved? Is that the way you see it?

DR BROWN: I think we have plenty of data for using it in this relapsed refractory unmet need setting after covalent BTK inhibitor. In fact, for patients on the clinical trial in which we were very active participants, I often used it after covalent BTK inhibitor before venetoclax because I had it on trial, then the patient could get it and venetoclax is approved.

DR LOVE: Wow.

DR BROWN: So I can save venetoclax for later. I think the standard approach would be to use it after covalent BTK and venetoclax. And I think we’re definitely ready to do that. We have hundreds of patients treated on the Phase I, expanded into a Phase II study. What I would hesitate to do though is I would not use it before a covalent BTK inhibitor because we don’t understand enough about the sequencing and the mechanisms of resistance. And we have much longer follow-up also with the covalent BTK inhibitors which you don’t want to risk losing that long-term benefit of the covalent inhibitor by using the less proven drug first.

DR LOVE: I’m trying to remember when ibrutinib actually was approved in CLL. It wasn’t like 100 years ago. It wasn’t really that long ago. I can remember before that when we were presenting cases and we had a first line case and we’d say, well what do you want to do or what would you do with a patient like that? And the whole panel would go, I want to give them ibrutinib, but it’s not approved. So I don’t know if pirtobrutinib is quite in that situation. What about tolerability issues? We’ve been talking about arthralgias, cardiac, et cetera. What about pirtobrutinib? What’s been seen with the data and what have you seen clinically?

DR BROWN: Right. Pirtobrutinib is extraordinarily well tolerated. There hasn’t been any cardiac events problem, any bleeding problem. There are almost no Grade 3 or 4 adverse events in the total of over 600 patients treated. The most common one is neutropenia which I think was about 10% in the latest ASH update. And I can tell you that this is real. Our patients really complain of nothing when they’re on pirtobrutinib. So that’s another big plus for the drug.

DR LOVE: So I’m liking that story a lot. And, of course, the obvious question is first line either monotherapy, you can tell me what kind of trials, are there trials looking at it? And then here, what you were involved with just this week presented at ACR combining it with venetoclax/rituximab. This is the trial we were talking about that had rituximab in it. Anyhow. Where do you see — where is it being studied and where do you see it landing in the next few years?

DR BROWN: Right. So they’re opening a large Phase III program. This recently reported abstract was pirtobrutinib with venetoclax/rituximab in the relapsed setting and that served as the basis for one of the Phase III trials which is venetoclax/rituximab +/- pirtobrutinib in the relapsed setting. And, again, the reason they’re using venetoclax/rituximab there is based on the MURANO trial and the fact that we have good baseline data for how that regimen would work. They also have a frontline trial, a couple actually, that I believe are in process. And there’s another relapsed trial comparing pirtobrutinib to investigator choice of idela-r or BR, I believe. So there will be a large Phase III program soon, so stay tuned. They are mostly looking at pirtobrutinib as a single agent except for that pirtobrutinib/venetoclax/rituximab study.

DR LOVE: So I know there are other noncovalent BTKis that are being looked at and you’ve looked at including this one, vecabrutinib. But this didn’t look as effective, I guess, as pirtobrutinib. I guess they’re not all the same. What’s the difference in the drug itself?

DR BROWN: Right. So they all have different structures. Pirtobrutinib actually has a fairly unique structure. I think that the reason we didn’t see as much activity with vecabrutinib actually does relate to some of the so-called drug-like properties like the absorption, distribution, how well it accesses its target, how long it stays on the target because some patients did have pretty good benefit while others had much less benefit. Vecabrutinib is not moving forward in CLL as a result of that study, but is being studied in other indications.

The other noncovalent inhibitor which is actually still in trials in CLL and being most aggressively studied is the former ArQule compound which is now owned by Merck. And we had an update on that data at ASH. And that also has a quite nice response rate on the order of 65% or so in relapsed refractory CLL patients. It looked like it had more toxicity. So that’ll be something to keep our eyes on. They are actually trying to escalate the dose a bit more currently.

DR LOVE: Interesting.

Case: A man in his early 70s with CLL, thrombocytopenia and possible underlying plasma cell dyscrasia — Bhavana (Tina) Bhatnagar, DO

DR LOVE: So, again, I don’t know if it’s just coincidence or not, but we’ve had, I think, several cases of people with concomitant plasma cell disorders and CLL. And interesting to try to dissect those out. Here’s another one. This is a 70-year-old man who is a patient of Dr Bhatnagar. Here’s the case.

DR BHATNAGAR: So this patient is an active 70-year-old gentleman. He’d been on watchful waiting since his original diagnosis. And then over the past 2 years, his platelet count started dropping. He didn’t respond to any ITP-based therapies. The patient himself wants to hold off for as long as possible before starting anything. In addition to the CLL, he was found to have a 1.8 g/dL M-spike. The rest of his labs looked okay. So I repeated his bone marrow biopsy, which showed a low-grade B-cell lymphoma. I assumed that was the CLL. But he only had less than 5% plasma cells. So there appeared to be 2 different things going on here, with the CLL and possibly with underlying plasma cell dyscrasia, and I’d be curious to know if that’s something that we see frequently in patients with CLL, and if so how do we manage this?

DR LOVE: Any thoughts?

DR BROWN: Right. So my first thought is that I’m not sure it’s a separate disease. I believe this patient had an IgM. And we see both IgM and IgG sometimes made by CLL that has a small fraction with plasmocytic differentiation. And so that would be what I would be most concerned about or thinking about in this particular patient. I have patients who even go back and forth between a more Waldenström’s type phenotype and a more CLL type phenotype in the setting of an IgM monoclonal gammopathy. I think having a full blown definitive multiple myeloma type picture in combination with CLL is relatively rare. We’ve had a few cases, but not that many. And obviously, IgM myeloma is vanishingly rare.

DR LOVE: Any other thoughts about this case?

Sounds like not. Let’s talk a little bit about zanubrutinib. We saw this press release, I think, it was yesterday or in the last couple days. We had seen the ALPINE studies it seems like 5 years ago, but I guess, was it last summer, comparing zanubrutinib to ibrutinib. And the GLOW study was also presented at the EHA meeting. And we saw this press release, I guess, more follow-up from the ALPINE trial. Any thoughts about that? One of the things that was interesting and controversial about that study was they initially reported a PFS advantage, nobody knew whether that was because of how they did the trial, it had never been seen before. Now, they’re reporting, I guess, about to report response rate. Just gets into the issue, is one better than the other? And if it is, is it because it’s better tolerated or because it’s actually more effective? Any thoughts, in general, about that question with zanubrutinib and specifically the ALPINE study?

DR BROWN: Right. That’s an interesting question. I think ALPINE study did use overall response rate as its primary endpoint and is meeting it here. The progression free survival benefit is something that we’re seeing at 1 year of follow-up and I think it’s extremely interesting whether or not it will continue to persist at later follow-up. Obviously, with the comparison between acalabrutinib and ibrutinib, there was an early favoring of acalabrutinib on the PFS that then shifted and became equal after a couple of years. And so I think we’re waiting on longer follow-up with the zanubrutinib. But it’s certainly not worse, at present anyway.

DR LOVE: That’s interesting. I didn’t realize that was seen with acalabrutinib. That’s really interesting. What about —

DR BROWN: Yeah. That’s the shape of the curve.

DR LOVE: That’s interesting. You also reported more data on zanubrutinib at ASH, one trial comparing it to BR. It kind of looks similar to the ibrutinib study. Also, now combined with venetoclax in patients with del(17p). Can you talk about those 2 datasets and also kind of where you see some of the critical trials in zanubrutinib over the next few years?

DR BROWN: Right. So the SEQUOIA study at ASH was the frontline registration trial for zanubrutinib in non-17p patients and that met its primary endpoint also of a significant improvement in progression free survival by about 16% over BR. And I agree with you, it does look actually quite similar to, for example, the ALLIANCE study that compared ibrutinib or ibrutinib/rituximab to BR in terms of where the data are at about 2 years. And so we have 2 randomized trials supporting the approval of zanubrutinib in CLL. And it is very well tolerated. In fact, it has the lowest rates of atrial fibrillation in its studies compared to even acalabrutinib. The zanubrutinib/venetoclax is an arm of SEQUOIA which is still very early in terms of the data, mostly establishing safety and a very high response rate. So we’ll see how that evolves over time, but there’s obviously interest in that. The other arm of SEQUOIA is the largest prospective frontline study in del(17p) CLL of a BTK inhibitor which is single agent zanubrutinib. And that actually has extremely promising data as well with like a 30-month PFS of about 89%. So I think the evolution of those trials in 17p, the zanubrutinib and the zanubrutinib/venetoclax, will be extremely interesting to follow-up as well as the longer-term follow-up of ALPINE. And then hopefully, we’ll see an approval soon.

DR LOVE: Yeah. Again, fortunately, we have alternatives. But, again, you look at these data and you wonder when it’s going to get approved. In terms of del(17p), do you consider, outside of trial setting, do you generally use a BTK inhibitor? Which one? And also, if a patient wants time-limited therapy, they have 17p, are you okay with using venetoclax/obinutuzumab?

DR BROWN: Right. So I do generally use a BTK inhibitor. I’ve generally used acalabrutinib because that’s easy to get. I think that the data actually are strongest for zanubrutinib, but it might be hard to get in the frontline setting when it’s not yet approved for CLL, but it would be reasonable to try to get it, I think, for this patient population.

My view about whether I’d be willing to use venetoclax/obinutuzumab is very nuanced. We do a lot of other prognostication in these patients looking at the complexity of their karyotype, how many other genetic abnormalities they have, how many other driver mutations they have, do they also have a p53 mutation or is it just 17p deletion or is it just a p53 mutation, how bulky is their disease, how long is their time to treatment, do they have a mutated or unmutated IGVH? Anyway. All these things kind of nuance my view of how risky the 17p patient is. And so the ones that are on the risky end of that scale, like they show up in your office with big, bulky adenopathy, very symptomatic at their initial diagnosis, they have a complex karyotype, they have both alleles down, those patients I’m really going to favor the BTK inhibitor. But if it’s a much lesser disease burden patient who maybe has been able to be watched for a while, that sort of person, or maybe an isolated p53 mutation, which in my experience has not been as bad as patients with 17p and 17p, p53 together, those patients I would consider the venetoclax/obinutuzumab. It’s not that I’m opposed to the venetoclax/obinutuzumab, but I do worry a little bit about time-limited therapy because I think these patients have very proliferative clones and they need that sort of constant break on the growth of the cells. Clinical trials of time-limited therapy where people are monitoring closely for MRD recurrence and treating early for MRD recurrence, those I think are very interesting in the 17p setting because I think if time-limited therapy becomes widespread for those patients, that’s probably what we’d be looking at doing.

DR LOVE: So your colleague in breast cancer, Hal Burstein, is always joking with me that I come up with these scenarios that he never sees. But I’m going to give you a scenario. I don’t know how likely it is. But here’s the scenario. Zanubrutinib is approved, you can access it just as easily as you can acalabrutinib, and acalabrutinib the new formulation has come out and you can give it to people who are on PPIs. So which one would you choose?

DR BROWN: Yeah. This is a hard question. I haven’t completely decided. Some of it — so right now, I feel like the Afib rates are favoring zanubrutinib a little bit over acala, but the hypertension is favoring acala over zanu and so I’m kind of interested to see how that plays out. I’m also interested to see how the longer-term follow-up of ALPINE plays out. If there’s still a PFS benefit for zanu over ibrutinib, that would make me tend to favor zanu. The trial is different from the trial with acala/ibrutinib and it may be that they didn’t see — if there is a benefit we see in the zanu trial, that doesn’t mean there might not be one with acala in that type of trial, but the trial that was done was different, they didn’t see one. So we kind of only have the data that we have. But I think right now, I haven’t completely decided. I might try and get — I have experience with zanubrutinib, but not nearly as much as acala. So I might try and get a little more experience with zanu as well early on to help decide.

DR LOVE: Interesting. So one more topic. You have this paper coming out this week. I don’t know. You maybe already presented it at ACR on what looks to me like genomics of transformation. I didn’t even understand all the stuff you all presented, but I know it was looking at the biology of transformation. So I’m just going to ask you for your view of what actually is going on with transformed disease biologically, how it differs from garden-variety diffuse large B-cell, for example.

DR BROWN: Right. Well so it is, Richter’s syndrome DLBCL is its own unique disease. It’s distinct from both ABC and GCB DLBCL. And it’s particularly associated with p53 aberrancy. A subset has CDKN2A deletions. Another subset has notch mutation with trisomy 12. And so I tend to think of it in those buckets. We know that the p53 aberrant Richter’s is the worst. That paper you just highlighted is a big effort being led by Cathy Wu at our place where she’s accumulated a very large number of Richter’s that we’re studying along also with the pre-existing CLL to try and see exactly how the pre-existing CLL evolves to the Richter’s, whether there’s something we could identify early there or intervene on because right now, we still, obviously, have a lot of trouble treating Richter’s and I think catching it early is probably one of our best bets for trying to understand it as well as who should we monitor? What are the main risk factors?

DR LOVE: So, Jennifer, sometimes I think about CLL like the Talmud, you can just keep talking about it, it’s never the same, it’s always interesting and particularly interesting to talk to you today. Thank you so much for joining us. Audience, thank you for joining us. Come on back on Monday. You want to hear what Dr Camidge has to say about targeted therapy, not only ALK, MET exon 14, HER2, you know, the whole scenario. Be safe, stay well and have a great night. Thanks so much, Jennifer.