Chronic Lymphocytic Leukemia Update, Issue 1, 2018 (Video Program)
Chronic Lymphocytic Leukemia Update, Issue 1, 2018
Proceedings from video interviews with Prof John G Gribben and Dr Jennifer R Brown on the treatment of chronic lymphocytic leukemia.
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Case: A 73-year-old woman who presents with fatigue and cervical lymphadenopathy receives ibrutinib as first-line therapy for chronic lymphocytic leukemia (CLL) DR GRIBBEN: So I guess in CLL, it was always an issue. This is a disease of the elderly, and the most efficacious treatments we used to have were always in clinical trials done for younger, fitter patients. The hugely attractive things about drugs like ibrutinib are how well tolerated they are. So clearly, these have opened up treatment approaches for more elderly people. So the case here is a very typical person. She’s in her seventies, she presents with early-stage disease picked up on a routine medical. She’s asymptomatic for a number of years and watched and waited. And her blood count goes up, hemoglobin starts to drop, platelets start to drop. And then the usual feature I see that most often drives me to start talking to patients about treatment is this feature of increasing fatigue that people talk about also. And, of course, for lots of women, the cervical lymphadenopathy, as occurred in this case, can often be an issue which some people worry about. So the whole question to me here is about, where do you reach the point where you do move from watch and wait to treat? I personally don’t like the idea that there’s a certain white count that you use to determine when you treat somebody or that there’s a particular size of lymph nodes. Some people find some lymph nodes not a problem. Other people find the idea of having a few lymph nodes really distressing. So it’s all about talking to the patient, finding how they’re coping with their symptoms. DR LOVE: What about this patient? You said she had some lymphadenopathy. Where was it ? DR GRIBBEN: She had some lymphadenopathy, mostly cervical. So for her, this was a big issue that there were big kind of cervical lymph nodes appearing that were increasing in size. She felt them to be very unsightly. She was very self-conscious about it. It made her kind of be aware in thinking about her disease a great deal more. And when she just had the lymphocytosis, she’d been coping with the disease much better. As soon as those lymph nodes started to increase in size and her friends started asking about her disease, she found that to be a feature that she found very, very uncomfortable. But I would say that accompanied with the lymph node swelling was the fatigue that was increasing that really made me start to talk to her about treatment options. DR LOVE: I wanted to ask you about that. Do you think that the fatigue goes beyond anemia? DR GRIBBEN: Yes, I’m very clear in my mind. What also I find fascinating about the CLL patients is how some patients can — I’ll talk a little bit later about the very opposite, about somebody profoundly anemic still bicycling into work every day — and how what looks like the same disease burden can have a very different impact on one individual than the other. I certainly am aware that I’ve got patients with still normal hemoglobins with a relatively modest lymphocytosis who can be very fatigued. And I’ve got other patients with white counts of 2,300 that I continue to watch, because they’re completely remaining asymptomatic. So what is it about the disease that impacts and causes this fatigue in some individuals more than in others with what look like exactly the same parameter? This is something I’ve thought about, and we don’t really know a great deal about why it is. But I kind of talk to my patients about that it’s basically about how your body reacts to having that CLL burden onboard. DR LOVE: I’ve actually — I heard or recall — I can’t remember — it was MD Anderson or maybe a few places that actually have fatigue clinics. DR GRIBBEN: Yes, absolutely. And the other thing, of course, to remember in this disease is that in this case, people have got the disease for years. And what I find is, you’ve got to really question these people quite closely, because people start to adapt. And you’re just saying, “Are you feeling fatigued”? And they answer, “Oh, no.” And then you go a little bit deeper, and you’re finding out they’re having a nap every afternoon. They’re going to bed earlier. They’ve stopped playing golf. They’re not complaining about it, but they’ve adapted their lifestyle. And what I invariably find is that people will often say once you start treatment and you get the disease under control and the fatigue goes away, is that they all almost invariably say, “Gosh, I didn’t realize how fatigued I had been until you started treating me and I got better.” Because they’d so slowly drifted down into that state of fatigue and got used to it. And a lot of people in this age group, also, a bit like myself, tend to kind of say, “It’s kind of usual that I’m a bit more tired as I get older.” So people kind of adapt for it, think it’s nothing to be concerned about. But this to me, it becomes a real feature that I don’t think we’ve been paying enough attention to in the past. Assessment of biomarkers to inform therapeutic decision-making for patients with CLL DR LOVE: Can you talk about what her biomarker workup showed and what you consider to be the essential workup for a patient with CLL? DR GRIBBEN: Sure. So when I’ve got a patient that needs to be treated with CLL, the features I’m concerned about that’s going to make me think about the treatments are going to be the FISH panel. So what’s the cytogenetic abnormalities that we’re seeing? And in particular, I’m looking for the presence or absence of a 17p deletion or a p53 mutation. Because that automatically to me rules out the option of considering chemotherapy at all. We’re going to talk in a minute about whether or not anybody should have chemotherapy at all in that kind of setting. I look for the mutational status of the immunoglobulin gene, whether it’s mutated or unmutated, because that also can have an impact both on the response to therapy and help you decide what’s the therapy you’re going to be using. There are an almost unlimited number of additional kind of biomarkers you could add in to kind of add to those features. But for me, the stage, the cytogenetics, the mutational status would be the most important factors that I would look at. DR LOVE: Could you just briefly comment on p53? We did a survey recently that suggested there’s not as much awareness of that as there is to 17p. Can you talk about the therapeutic implication and also the overlap of when — do you see p53 without 17p? DR GRIBBEN: Sure. So about 5% to 10% of patients who are previously untreated who require therapy are going to have a 17p deletion. And approximately the same number of patients will have a p53 mutation without a 17p deletion. So you could actually say they’re about equivalent numbers. Now, most patients with 17p deletions will also have a p53 mutation. So there are more patients with p53 mutations than there are with 17p deletions. But functionally, the results are the same. The impact in terms of the way in which the disease progresses, it’s a poor prognostic feature — not thinking about therapy but just thinking about the way the disease progresses. But where it stands out most is, both 17p deletions and p53 mutations show a really poor response to chemotherapy, as you would expect. Now, you raised an interesting concept here saying, at least in CLL, people think about 17p deletions. Of course, p53 mutations are something we see in lots of different cancers. We see it in lots of different B-cell malignancies. But funny enough, it’s only in CLL that it’s already changed the therapy that we’re doing. So rather than say I’m disappointed that people don’t know enough yet about p53 mutations, I’m actually heartened to say that actually, a lot of people already know about 17p deletions. Therefore, educationally to then be able to say — or a TP53 mutation. So I think you could be thinking about these as almost interchangeably. Everything you think and you know about 17p deletion applies to a patient with a p53 mutation. Perspective on watching and waiting versus treatment for patients with newly diagnosed CLL DR LOVE: Just 1 more issue about to treat or not. So I’m going to tell you about a case I just heard about — the general medical oncologist told me about. Patient with CLL who was I think in — he was in his fifties, late fifties — young and completely asymptomatic. She’s following him. His white count goes up, gets up to about, I think, 180,000, still asymptomatic. And the patient was very well informed. Read, walked in and said, “I would like ibrutinib. I really don’t like having this disease.” So first of all, how would you react? Have you had that happen to you? And this man, as it turned out, had great insurance. He wasn’t going to have to pay anything. How would you react if a patient said that to you? DR GRIBBEN: Sure. I think it actually is something that we see all the time. As you know, I worked in the States for a long time, and now I’m working back in Europe. And the funny thing is, it was always clear to me that the average American patient hates the concept of watch and worry, as they tend to call it. It’s not in the American psyche that you’ve got cancer and you do nothing about it. The European approach tends to be much more, “Oh, it’s great, I don’t need therapy.” It’s quite different how you see the 2 sides of the Atlantic viewing the same news in a slightly different way. But you’re absolutely right. There are some people in whom the concept of being treated is what they’re most afraid of. And there are other people in whom the concept of having the disease can be a real big issue for them. As much as possible, what I try to do is have a discussion and a dialog with somebody. Treating anyone with CLL is about this — there’s almost never a time when you say, “You have to be treated today.” So all we’re talking about now is the when. As always, the issue we have right now is, we still don’t have any data that tells us that earlier treatment is better than later treatment. CLL12: An ongoing Phase III placebo-controlled trial of ibrutinib versus watch and wait for previously untreated Binet Stage A CLL in patients at risk of disease progression DR GRIBBEN: There’s a great trial being done, the CLL12 trial, which took high-risk patients with CLL, giving them early treatment or watching and waiting them until the classical iwCLL criteria were achieved. That study’s fully accrued, but it will probably take years for it to actually read out for us to see the data. Until we see that data, we don’t yet know whether starting treatment is beneficial. So I would be having a discussion with your patient saying, “You’ve got to remember that — we certainly hope you’re going to have a very long duration of response, but there are mechanisms whereby you can become resistant. The sooner we start the drug, the sooner that process of resistance might start, and that you could end up 5, 6, 7, 8 years from now being in a worse position than you are.” Now, all of this will change if the CLL12 data tells us there is a benefit of giving somebody ibrutinib earlier. Now, going back to your scenario, if I have that discussion with that patient and he tells me that no, no, he hears all the information, he feels it, and he still wants to be treated, I’d be asking him, what is it about the disease that — what’s the feature for him that wants to be treated? And if I’m convinced that he’s now been educated about what the risks of doing that are, and for him that’s an indication for treatment, I as a clinician feel I’ve got to listen to my patients and not just acquiesce to what they want. But I could conceive of circumstances where I would treat that patient but I’d certainly be, personally at the moment, trying to talk him out of it. And if I couldn’t, I’d probably say, “Okay, let’s go with it.” DR LOVE: This CLL12 trial, when you say high risk, these are mainly 17p, p53 and it’s ibrutinib? DR GRIBBEN: No. No, so high risk was defined in a number of different ways. So included 11q mutational, so you added up the points. And if you were low risk, so you didn’t have any high-risk features, so if you were mutated, 13q deleted or normal karyotype mutated, you would not be treated. If you had 11q deletions, 17p deletions, mutated immunoglobulins and you had enough points accrued from each of those features and you’re considered high risk, you were randomized to receive immediate treatment versus continued watch and wait. So it’s not just the 17p-deleted patients that are in that trial. We’ll have a bigger population of other so-called higher-risk features incorporated within it. DR LOVE: But just to clarify, right now, in a not-common situation, but it does occur in the patient who’s 17p at diagnosis and needs to be treated and does not meet the usual criteria for symptoms or treatment, the 17p alone or p53 would not get you to treat? DR GRIBBEN: No, absolutely not. There are individual patients who will continue to have a very long period of time. I think overall, you’d say statistically these patients are much more likely to get treatment sooner. But, of course, it’s also the case that these are the group of patients in whom ibrutinib resistance itself is more likely to develop. So all the more reason to not be using up the drug time at a time the patient doesn’t need it. DR LOVE: So I’ve got a great ending to the story. And as I was listening to you, it has a different ending now — of this case I was telling you about. Because what happened — and this man didn’t lymphadenopathy, the patient, but he did have the high white count — so the doc gives the man ibrutinib. Goes into complete remission, not tolerability, he’s doing great, he’s super happy. But now that I think about it, when she told me about this case, she said, “One thing that was interesting: His hemoglobin was not that low. It was, like, in the twelves. But he said he had much more energy.” She said, “I don’t know if it was psychologic or whatever.” But it kind of reminded me of what you were just talking about fatigue, that maybe he had fatigue and didn’t realize it. DR GRIBBEN: Yea, I think that’s very, very likely. And also, of course, a lot of us seeing, when we’re giving patients ibrutinib, I’ve always assumed that it’s due to getting rid of the CLL. But you do wonder whether the ibrutinib itself is one of the side effects it has is kind of making people feel a little bit better on the drug. DR LOVE: Really? DR GRIBBEN: But it’s always a feat, because one of the issues is I’ve seen — you talk about the lymphocytosis going away, but, of course, when we start ibrutinib, we often see the opposite — the lymphocytosis really shooting up. And I’ve seen people start to feel better at a time when their blood counts are getting worse. But there’s something about the way that biologically this drug is working. My own personal view is that it’s probably working because of the biology of how it’s changing the CLL. But who knows exactly what the mechanisms might be. Case: A 49-year-old man with CLL with an IGHV mutation experiences profound fatigue and rash with fludarabine/cyclophosphamide/rituximab (FCR) as first-line therapy DR LOVE: You mentioned p53, 17p and IGVH mutation status. And I’ve been hearing that those are really the 3 things, these predictive factors that are really critical in making the decision. DR GRIBBEN: Yes, because they’re prognostic and predictive. DR LOVE: Right, okay. So here’s the one subset that I find interesting, which is 17p, p53-negative, IGVH mutated and a younger patient. And what I hear from investigators is FCR, for obvious reasons, try to throw them into long-term remission. And what I hear from docs in practice is, “We hate FCR, and we don’t want to use it.” Any thoughts about that conundrum? DR GRIBBEN: Yes, sure. I mean, I’ve got a case here. The 49-year-old guy here, which would be a very good way to illustrate exactly that issue. He is exactly this situation, doesn’t have a 17p deletion, doesn’t have a p53 mutation. But this time — he has mutated, so it’s the other way around. So the whole question of the idea of chemotherapy. So chemotherapy works well in the mutated patients. The concern you have, as we already know, the FCR works much less well in the unmutated patient. This is a young patient with a mutated immunoglobulin, and he tells me categorically, “I don’t want chemotherapy, I want ibrutinib.” DR LOVE: And what was his life situation? He was working? DR GRIBBEN: Yes. He’s a 49-year-old TV executive but looks and acts a lot younger than even that. Bicycling into work every day, hemoglobin of 6 when I’m seeing him and he’s going skiing. He’s bicycling into work. He’s going to the gym, very little in the way of kind of the opposite of what I talked about earlier about these people having really lots of fatigue. But he really wants to avoid chemotherapy. Now, I’m talking to him about, the fact is, this is the subset of patients in whom FCR has the potential to cure. Now, the C-word isn’t something we’ve been able to use in CLL before. But very clear data emerging that about 60% of patients that are mutated are going to have these very durable remissions, have eradication of MRD-detectable disease and, to all intents and purposes, probably cured. I had long chats with this guy about, “Look, if I were you, you’ve got a chance of going for cure with chemotherapy.” But this is a young, fit guy, and I gave him 6 cycles of FCR, and he struggled. He found it tough to get through 6 cycles of therapy. He got quite debilitated by the chemotherapy, and it’s taking him months after the chemotherapy to really feel he’s getting back on his feet. He happened to — got a very severe rash that probably was associated with cotrimoxazole rather than the chemotherapy that probably didn’t help him. But for those docs that you’re talking about that say “I don’t like giving FCR,” I hear what they mean. This is not an easy regimen to get somebody through. I use a lot of growth factor support for my patients to get them through it. But when I’m talking here about curative intent, the same way that I would with diffuse large B-cell lymphoma, where somebody’s starting to run into some problems, we want to keep pushing hard here, because I don’t want to just palliate your symptoms here. I’m going for cure. I really want to keep this dose intensity. I want to treat you every 28 days. I don’t want to dose reduce, because I don’t want to compromise the likelihood of being able to cure you. DR LOVE: And I see that he actually is MRD-negative. DR GRIBBEN: He is MRD-negative. Minimal residual disease (MRD) status and prognosis for patients with CLL DR LOVE: Could you comment a little bit about the use of MRD assays, what type of assay, and is it something that you think should be done in a nontrial setting? DR GRIBBEN: Yes. So I think there’s a huge amount of data now that becoming MRD-negative in this disease has huge prognostic significance, particularly after chemotherapy. The routine way that I do MRD in my patients is that — now, I did a bone marrow after the end of his therapy to look for the MRD question particularly. Nobody likes having bone marrows, and I certainly don’t routinely perform more bone marrows to look for MRD. How I do it is, I look in the peripheral blood. We look by flow assays, by multicolor flow. It’s a sensitive technique. And as long as a patient remains negative in their blood, I don’t then go on and look and do anything more than that. So I’m monitoring the patients routinely in their blood. You can do it by PCR, but I think it’s a good enough assay using the 6-color flow cytometry assay that we use kind of pretty routinely now to monitor patients’ blood. And I’m able to tell patients that they’re negative. To really tell a patient that they’ve had the best response, you really do need to have a bone marrow, because not everyone who’s negative in blood is going to be negative in bone marrow. It’s like going another level deeper. So in his case, where we were going for cure and I wanted to see how good the response was, I looked in his bone marrow and was able to tell him he was negative in his bone marrow. Now, lots of the clinical trials then go on and do more serial bone marrow biopsies. I don’t think that’s something that people are going to want to do in routine practice, and I don’t think it’s something my patients want to subject themselves to. So I monitor the blood. And if the blood becomes positive, then you can start looking in a bit more detail. DR LOVE: So — and I see this man is now 18 months post-FCR, still MRD-negative. I don’t know if he’s asked you this, but if he did ask you statistically what the likelihood is at this point that he’s going to relapse, what would you say? In other words, what is the chance he’s cured at this point? DR GRIBBEN: When I started off treating him, I told him he had a 60% chance of being cured. Eighteen months’ MRD-negative rate, he’s already gone past about half of that risk of relapsing. So should say now he’s got an 80% plus chance of being cured at this point. DR LOVE: So what I’m really curious about is how this man feels about having gone through all of this. Is he glad he did, or did he wish he had ibrutinib? DR GRIBBEN: He’s certainly, as we’re getting further away from the treatment, he’s now glad he did. He was not giving me a good time — at the time, he was struggling through the FCR and thinking about, “I could have been having ibrutinib.” Now, of course, that he’s been off treatment for a year, he’s beginning to see the benefit of being off therapy rather than being on some continual therapy for the rest of your life. A very different conversation than having this woman, the first one, who’s now 75, and the concept for her of staying on therapy, she’s taking blood pressure medication and she’s taking ibrutinib. And she thinks of it in the same way. I take a tablet to control my blood pressure. I take a tablet to control my CLL. But giving somebody in their forties and fifties life-long therapy, it becomes quite a bigger implication. DR LOVE: So we’ll talk about whether or not maybe that might not be happening in the future. But I want to ask — and I don’t know if we really have a great answer to this, but I would imagine a well-read patient or maybe a health professional might ask this question, which is, you painted this picture for this particular subset — mutated, 17p and p53-negative — in terms of cure with FCR. If somebody were to say to you, “What about BR or obinutuzumab/bendamustine, do you see cures there?” DR GRIBBEN: Yes. But there are 2 things. The plateau is lower than it is with FCR, and the plateau’s shorter at the moment, because we don’t have the same duration of follow-up with the BR, and we certainly don’t have that data with the BO. The bendamustine/obinutuzumab combination is certainly a bit more toxic because of more neutropenia when you use the obinutuzumab compared to the rituximab. And so we’ll have to see what the longer-term follow-up is. But on the CLL10 study that compared FCR with BR and in the subset that are mutated, the same thing is true. The mutated patients do much better with BR or BO than the unmutated patients do. But I would argue that they still do less well than the FCR patients. Response to ibrutinib as front-line therapy for CLL DR LOVE: So this woman now has been on ibrutinib at 420 mg a day for the last 3 years. Can you talk about what happened when you started the ibrutinib, both in terms of the disease as well as tolerability? DR GRIBBEN: So the first thing she noted was that the lymph nodes shrunk very quickly, and that’s one of the features — it’s a kind of very positive, reassuring thing of the way this works. So one of the things that ibrutinib does is, it changes the adhesion properties of the CLL cells, so they leave the lymph nodes and go into the blood. Now, that gives the lymphocytosis. But, of course, the patients don’t see the lymphocytosis until you do the blood test. What they see are the lymph nodes shrinking, and she saw them shrinking very, very quickly. So when I saw her back for her first visit after starting ibrutinib, she was really excited. Because if you remember, the thing she was most concerned about were these unsightly nodes. And to her, she comes in, she goes, “Oh, John, look at this, this is incredible. The nodes have gone. The nodes have gone.” So the thing I think that’s most striking for patients you’re treating with ibrutinib is how fast these lymph nodes respond. With that, of course, comes that rise in lymphocytosis. And the important feature here is to remember that this is an expected side effect with this drug. The second thing is, people get very nervous about very high white counts — am I going to get leukostasis? Leukostasis is something that you see with CML and myeloid leukemias where the cells are sticky. CLL cells are much less sticky, and ibrutinib-treated CLL cells are less sticky again. That’s the whole feature. They’re not sticky. So I think the doctors get nervous about the lymphocytosis, but experts in the field don’t. And we are quite used to seeing the counts go very high. A concern that some people have is that, “Oh, I’m starting somebody with a white count of 200 plus, and they’ve got some lymph nodes. How high is the lymphocyte count going to go?” And I think what we can say is, “We have not seen any real risk, no matter how high that count goes.” And, of course, it’s also of short duration. Risk of ibrutinib-associated hypertension and bleeding DR LOVE: Now, I see this lady, who was hypertensive, well controlled prior to ibrutinib, required more antihypertensive medication. Is that something you see with ibrutinib? Do you see people developing hypertension who never had it? DR GRIBBEN: Yes, so probably hypertension’s the one side effect that increases in time with ibrutinib therapy. It’s not a big proportion, but it’s a proportion that increases. Many of the side effects with ibrutinib are quite transient, go away. I’ll tell a lot of people that things like the GI upset, mild rashes, some joint pains, those are things which can go away. The atrial fibrillation tends to occur really early or doesn’t. Hypertension is the one feature that I certainly see increasing in numbers and in severity of the patients. And one of the features with many of my ibrutinib patients is, of course, I’m not seeing them so often. I’m giving them a 3-month prescription at a time and sending them off. So I’m always telling my patients or general practitioners to monitor people’s blood pressure. Second reason, of course, is that it’s stressful for people to be coming into the cancer center. Monitoring their blood pressure every 3 months when somebody’s had to struggle to get into the cancer center and they find it all stressful isn’t the most ideal way of monitoring people’s blood pressure. So I kind of actively involve patients’ own practitioners in terms of saying, “Just be aware that this is a signal you’ve got to look for and think that you may have to increase the antihypertensive therapy.” DR LOVE: What’s the putative mechanism of the hypertension that you see? DR GRIBBEN: Nobody really is clear. It’s probably an off-target kinase effect. It’s probably not mediated by BTK itself. The issue is whether or not next-generation BTK inhibitors will have exactly the same features is something that we’ll have to see. But at the moment, it’s probably thought to be an off-target effect. DR LOVE: And this lady, any evidence of bleeding? One thing you hear about are people getting bruising on her arms. Did she have that? DR GRIBBEN: She’s certainly aware that if she knocks herself, or even kind of a little minor knock, she’ll notice some early bruising. That can be a concern for some people. This particular lady here, she’s just like, “Oh, yes, yes. Just sometimes I’m a bit clumsy. I just note it’s there. I know it doesn’t do me any harm.” But absolutely, this kind of easier bruising. And, of course, some of these elderly ladies have kind of thinner skins and tended to bruise more easily even without ibrutinib. So it can be an even bigger problem in this kind of patient population. DR LOVE: So she sounds kind of like — myeloma, they talk about the very elderly and the elderly, and she sounds like in pretty good shape, 75 years old. She had some other things. So what about chemoimmunotherapy? Did you discuss that with her? For example, one of the regimens that you use in older people is obinutuzumab/chlorambucil. What about that? And also the advantage, and how did she see it in terms of shorter therapy? DR GRIBBEN: Sure. So I always have a conversation with people in this kind of setting. About you’ve got 2 choices: You’ve got a fixed duration of therapy, or you’ve got the continuous therapy. And I guess in my own mind, I’m kind of pushing it a little bit less because what’s also clear, of course, is, we see much better results with ibrutinib front line than we see when we’re using it for relapse. So in patients like this, in whom the funding isn’t going to be an issue because she’s got good insurance that’s fully covering the drug and has full access to it, that doesn’t become a factor for her particular circumstance. And I’m kind of feeling more and more that for these patients, ibrutinib can really be the answer here. Selection and sequencing of treatment for CLL DR LOVE: And that kind of brings me to this algorithm that I kind of — as you know, we ask these questions, survey questions, we ask everybody kind of what they do in their practice. And as I’ve been asking these questions of first-line therapy, how it fires with biomarkers, I’m starting to see an algorithm, and I want to know to what extent you might agree with it. Which is for the patient who needs to be treated, you can identify the people who are 17p or p53, it’s going to be ibrutinib and venetoclax, assuming no other issue. But for 17p-negative and p53-negative, if they’re mutated, IGVH mutated, then we get into the whole argument about FCR that you went through. But for the remainder where, for example, BR was something that was often used in patients like that, what I’m hearing is ibrutinib followed by venetoclax/rituximab, period. What do you think? DR GRIBBEN: Yes, sure. So yes, the whole issue about using chlorambucil/obinutuzumab is that until we had ibrutinib, that was clearly a much more effective therapy for these patients in whom FCR was never going to be an option. So it was an advance. Unlike the FCR argument we had with our patient where I’m talking about potential cure, there isn’t a subgroup of patients in whom I think chlorambucil/obinutuzumab’s really going to cure you. I think the mutated patients are going to have a longer duration of response. They may have an increased likelihood of becoming MRD-negative, but I’m still not talking cure. So I’m still talking about, you’re going to give them the therapy and they’re going to get ibrutinib at some point in the future. The median time to relapse after chlorambucil/obinutuzumab in the CLL11 trial’s getting up towards 3 years. So you’re not talking about these very, very long durations of response that you see with FCR. So I guess probably what you’re seeing in the field is more and more clinicians moving right up front to ibrutinib. And, of course, the clinical trial data supports it. The randomized trials that have looked at ibrutinib versus chlorambucil clearly demonstrate superiority of ibrutinib. Inside the clinical trials, even the crossover going back to allow the patients to cross over to ibrutinib still had an inferior outcome. Now, that’s a clinical trial vagary that people have to be aware of. The criteria in a clinical trial to crossover is a much higher threshold than we would use in our clinical practice to re-treat a patient. So you had to have an independent review committee say that they had progressed above where they were before to do that crossover. So that’s a difficult point. But there’s no doubt in my mind that ibrutinib is a superior treatment up front than chlorambucil/obinutuzumab. And I guess the other issue was — you already kind of alluded to it — is part of the reason why before I might have considered chlorambucil/obinutuzumab more is that then I had ibrutinib as a salvage. And if ibrutinib was all I had, I wouldn’t want to go from ibrutinib and when the patient relapsed think about chlorambucil/obinutuzumab, because that’s not where I’d think about it. So when I didn’t have a next option, I’d consider chlorambucil/obinutuzumab, then ibrutinib. But now that I’ve got venetoclax or venetoclax plus rituximab, my algorithm then becomes ibrutinib, then venetoclax. So I’ve got a fallback circumstance. So I guess like many other of my colleagues, increasingly comfortable of using ibrutinib front line. I’ve got a salvage second line for those patients in whom it doesn’t work or a patient who really gets a complication of the treatment and has to come off it. Results of the Phase III MURANO trial evaluating venetoclax/rituximab versus bendamustine/rituximab for relapsed/refractory CLL DR LOVE: So I want to ask you, actually, about your 64-year-old man who ended up getting venetoclax, who was also del(17p) and p53-negative. But before I do, can you talk a little bit about the data? I mean, the data was presented at ASH, and almost immediately we saw investigators changing what they did. I mean, you heard them talk about practice changing. I call that practice changing because we asked them what they did, and they started doing it. So first of all, can you talk a little bit about the data? This is the MURANO trial. DR GRIBBEN: Sure. So the MURANO trial was — it’s a very interesting trial for a number of reasons. So as you’ve already alluded to, it’s venetoclax/rituximab versus, in that trial, bendamustine/rituximab. Why it’s an important trial is, it’s one of the first trials in which a standard chemoimmunotherapy approach — so BR was our standard second-line therapy. So, if you like, our best chemotherapy went against a modern targeted therapy, the Bcl-2 inhibitor. So it’s the first trial in which these drugs went up against not the chlorambucil that nobody uses anymore but went against our very best treatment. The second thing that’s really interesting about the MURANO trial is this fixed duration of therapy that they chose to do. So that trial gave people venetoclax. They gave 6 months of rituximab, and they gave 2 years of venetoclax and then stopped. And it wasn’t an MRD-driven stop point. It wasn’t like saying, “Let’s stop the drug in those people who are already MRD-negative.” It was, “Let’s give everyone the drug for 2 years and then stop.” The results very clearly demonstrated that venetoclax and rituximab was completely superior to BR. And why I think this is practice changing is that means that, to my mind, there is no role for chemoimmunotherapy second line anymore. We’ve done a head-to-head trial with our best treatment, and chemotherapy lost wholeheartedly. So to me, that’s my rationale for saying, “I no longer consider chemoimmunotherapy second line for my patients. There are better options out there.” DR LOVE: Yes, I mean, the difference in those curves and the hazard rate was — I think it was less than 0.2 — were shocking. DR GRIBBEN: And, of course, there’s also the vagary of that trial is that there is what you and I would call an overall survival advantage. DR LOVE: Right. DR GRIBBEN: And then we’ve all got used to now thinking about this thing called an alpha spend, which none of us knew very much about before, that just meant that because of the statistical plan, the company can’t say that’s an overall survival advantage. But I think every clinician would say, “That curve is an overall survival advantage, and I know which curve I want to be on.” Assessing the risk of tumor lysis syndrome (TLS) with venetoclax DR LOVE: So one of the issues, of course, with venetoclax — it’s been out there ever since we first started hearing about it — is tumor lysis syndrome. And it’s interesting, because I see that this 64-year-old man that you gave this combination to actually had bulky lymph nodes and was at high risk for tumor lysis syndrome. Can you talk a little bit about what his status was when you started the regimen and how you approach preventing TLS in him? DR GRIBBEN: Sure. So one of the features — I mean, remember when the first patients that went onto some of the earlier clinical trials of venetoclax, there were deaths from tumor lysis syndrome. And, certainly, the company, very appropriately under those circumstances, put up their hands in almost horror. But every clinician I knew was kind of excited. I mean, very sorry for the patients, but the issue is, you’re getting tumor lysis syndrome because the drug is so effective. Prevention and management of venetoclax-associated TLS DR GRIBBEN: There’s a very good plan in place, which we have now in terms of saying what is the risk for tumor lysis syndrome and what you should do. DR LOVE: And that’s actually in the package insert. DR GRIBBEN: It’s in the package insert. Not many of us look at the package insert, but this is the part of the package insert you should look at. DR LOVE: This all-time package insert was that table. But the thing that was interesting is, it really comes down to lymph node size and white count, right? DR GRIBBEN: Yes, absolutely. So you fall into low-risk category, intermediate risk, and high risk. And irrespective of what risk you are, the important thing to take away for venetoclax is, you do this ramp-up. You start at that 20-mg dose and you, over the next 5 weeks, build up the dose to the 400 mg. I should say that more carefully. You build it up over 5 weeks if you don’t hit the parameter that says you should stop and go a little bit more slowly. The issue with managing tumor lysis syndrome is to think about it and plan for it. This is not a circumstance you react to. This is one you proactively try to manage these patients with. So you give the patient the 20-mg dose. You have done their bloods before you start. You look at other features like the renal function, like other biochemical abnormalities that may be there, and you repeat the bloods 8 hours later, and you look to make sure there’s no biochemical evidence of tumor lysis syndrome. And what I’m looking for, in particular, is the potassium going up. And what I like to do is, I use the plot feature on the labs and plot. Because what I’m looking for isn’t just whether the potassium’s gone out of the normal range, but is there any change at all in terms of do I have to consider other features in this? And for a high-risk patient like this, I admit for the first 2 weeks. I actually admit the patient. I’m giving lots of fluids. I gave rasburicase to this particular patient because he was high risk, and I monitored very carefully, and I’ll repeat the labs the next morning. And you certainly want to make sure you’ve seen the lab before you even give the next dose of drug to make sure that it’s safe to escalate at all. The feature that we see here is that with the implementation of this more modern tumor lysis syndrome approach — that is, giving the dose escalations, thinking about the risk factors and thinking about the appropriate measures to prevent tumor lysis syndrome, there haven’t been subsequent deaths from tumor lysis syndrome. And, in fact, what we are seeing now is even biochemical tumor lysis syndromes becoming a thing that we don’t see as much as we used to. I guess that people have to be aware of — you’ve got to be cautious about it, and you can’t get into being complacent about it. And although we admit this patient for the 20- and 50-mg dose, you still at the third and the fourth week as you’re going up in doses can’t be complacent about just sending that patient away. I made sure that I had the 8-hour labs, and I looked at them carefully and that I knew that it was safe for him to continue that dose and go off. But I have to say, once I get a patient onto the 400-mg dose, tumor lysis syndrome isn’t something that I have to be concerned about that anymore. It’s only a feature as I’m dose escalating the patient up to the dose. By the time I get to the 400-mg dose, the tumor bulk has almost invariably decreased enough that even high-risk patients aren’t high risk anymore, particularly when you’re then also adding in rituximab, as we did in MURANO. DR LOVE: I was curious that you gave this man rasburicase. I’m not sure how clear the package insert is about that. Now, he was high risk, he had a white count of 60,000, nodes as big as 11 centimeters in the abdomen. And you said he was in the hospital for 2 weeks? Because I thought these patients were — DR GRIBBEN: No, no, no I just — he’s in hospital on the day of the dose escalation. DR LOVE: Just the day. DR GRIBBEN: Just the day. I’m bringing him in, doing labs in the morning, giving him his venetoclax, doing an 8-hour lab and a 24-hour lab. And then I discharged him, and then I readmitted him the next week. DR LOVE: Got it, okay. And it looks like he did great. And now he’s just on venetoclax? DR GRIBBEN: Now he’s on single-agent venetoclax. He’s finished his rituximab period. And for him, of course, it was particularly attractive. He did not like the concept of continuous therapy for the rest of his life. He personally likes the concept of the 2-year point. Now, one of the big issues that we have here is, we don’t have a huge number of patients on MURANO that have yet been reported that are off that 2-year time point. The New England Journal paper was reassuring in that line still looked pretty steady, but we’re going to see at ASH the next update of MURANO to see, are those patients going to fall off the curve and is the concept of a 2-year fixed duration the right thing to do or should we be doing something different? Lots of clinical trials using this approach use an MRD endpoint to say, if you’re MRD-negative, you can stop, and if you’re MRD-positive, you continue on therapy. That isn’t what MURANO did. And they didn’t do it that way, because the company felt that MRD monitoring isn’t quite ready and in prime time anymore. So would people kind of feel comfortable about using it? But we might, depending on what we see with the MURANO data, we might be going back to be talking about: There are patients that can stop, but maybe there are other patients that should continue. DR LOVE: So agree or disagree? Once you get the patient on venetoclax through the tumor lysis risk, their quality of life and the problems they run into are substantially less than you see with ibrutinib. DR GRIBBEN: Yes, I think that would be my sense. That the toxicity profile of people on venetoclax, once they’re on that 400-mg dose, is really very tolerable. I mean, I’ve had a lot of patients I’ve treated on clinical trials on the ibrutinib/venetoclax combination where I really was concerned about, now you’re getting people taking 8 tablets a day and what was the toxicity profile going to be like? And all of those patients, also, did very well on the combination. But my sense is yes, the kind of little niggly things that ibrutinib patients start to complain about. They don’t complain about it when their lymph nodes are shrinking, but when somebody’s been on the drug a little bit longer, little things that preserve can become a real nuisance. And I’d certainly see less of that on venetoclax than I do on ibrutinib. Benefits and risks of the venetoclax/ibrutinib combination as potential up-front therapy for CLL DR LOVE: And that kind of leads into the issue of tolerability/toxicity with BTK inhibitors and also the issue of acalabrutinib. But before we get into that, you mentioned ibrutinib/venetoclax, and certainly there seems like a gigantic excitement about that. After I hear them talking, I’m like, why aren’t we using this now? But can you just kind of talk about what we know about that combination, including what was presented at ASCO and whether you think this is kind of where we’re going to land maybe in a couple of years? DR GRIBBEN: Sure. So the original trials were in the relapsed setting, and people got really excited when we saw the ibrutinib/venetoclax combination had really, really high response rates. And probably even more excitingly drove people to MRD negativity at high rates. And in those studies, you could actually get people off the drug altogether. So, of course, for many people the concern is, you’ve got 1 very expensive drug. You’ve got another very expensive drug. Why should they add them together? If you can add them together and get people to stop after a couple of years, that has become a cheaper combination than giving 1 drug continuously. The second issue then moved to the up-front trials, and we’ve seen data now presented at both ASH and now at ASCO of groups of previously untreated patients receiving, as their first therapy, ibrutinib/venetoclax combination. Truly spectacular response rates. And again, getting people off the drug. I guess 1 concern and 1 little caveat that people still have in the back of their mind is, we have to see the long-term follow-up. There’s always the risk if you’ve used — remember I talked about earlier, I was happier to use ibrutinib when I knew I had a fallback. If you’ve used your 2 best drugs together and then the patient relapses, do you treat with ibrutinib and then venetoclax? Do you go back to the combination? What’s the response rate when you retry? We don’t know that yet. And the reason we don’t know that is because the patients treated with the ibrutinib/venetoclax combination have done so well, we haven’t got a cohort of patients that we’ve had to re-treat yet. So we just don’t know. The second thing would be that if, let’s say, somebody was going to get 10 years with ibrutinib and then get another 7 years with venetoclax if you used it continuously. That potentially means 17 years of duration of response that you could be adding. We haven’t treated anyone with ibrutinib/venetoclax in whom we can say, “I know what your outcome’s going to be like 17 years from now.” So we still have to see how durable those responses are. But I’ve got to say, so far, like everybody else, I’m really excited about that combination. This could be the answer we’ve been waiting for to really see very high response rates and potential eradication of disease in many of these patients. DR LOVE: What’s the schedule of the combination of ibrutinib and venetoclax, and do you use the ibrutinib to debulk the patient first to lower the risk of TLS? DR GRIBBEN: So all the clinical trials that use the combinations start with ibrutinib monotherapy. Little fine tuning to look at is different trials use different durations of doing that. But you’re absolutely right. The issue here is, you are looking to debulk the patient before you start. Now, on those clinical trials, when we first started doing them, we were admitting the patients for tumor lysis monitoring. But I have to say, patients that have had that run-in with ibrutinib first that start the venetoclax, I won’t say you can relax, because you still have to think about tumor lysis syndrome, but by the time you’ve got into that pre-run-in with ibrutinib, usually for about 6 to 8 weeks on the different clinical trials, it looks very safe to be able to add in venetoclax at that time point. You still do the ramp-up. You don’t go in at a 400-mg dose. You go that 20, 50, 100, 200, 400 ramp-up that you would normally do. And, certainly, all the patients I’ve treated on that combination, I haven’t seen any real problems in being able to add in the venetoclax when you’ve already done that. Case: A 65-year-old man with FCR-refractory CLL who has a history of poorly controlled atrial fibrillation receives acalabrutinib on a clinical trial DR LOVE: So let’s finish out talking about the issue of tolerability issues with BTK inhibitors and also the potential of using other BTK inhibitors besides ibrutinib. And, obviously, at least in the United States, acalabrutinib is now approved in mantle cell. It’s been studied in CLL. Maybe to get into that, we can hear about your patient. I don’t think it says the age of the patient. DR GRIBBEN: Oh, sorry, that patient was in his sixties, yes. It was a man. For him, the big issue here was, he was truly refractory to FCR chemotherapy. So he was in his early sixties. We treated him with FCR and had no response whatsoever. Now, this is the data that this sort of patient that before we had these BTK inhibitors around, this is the kind of patient that Michael Keating had published from the MD Anderson, would have a median survival of less than a year. This is a group of patients who are going to, historically, do extremely poorly. And, of course, along comes ibrutinib. And we’re able to say, “Now we’ve got a good therapy for a previously completely unmet need.” Use of acalabrutinib in patients with preexisting, poorly controlled atrial fibrillation DR GRIBBEN: One of them with ibrutinib is this signal of atrial fibrillation. And we’ve got this patient here whose atrial fibrillation is already poorly controlled. DR LOVE: So he actually had ablations done. DR GRIBBEN: He had had ablations done. And even with ablations, he still had recurrence of his atrial fibrillation. So if he’d been ablated and his atrial fibrillation was now treated by the ablation, I wouldn’t have a concern about using ibrutinib. But this patient came along and we had, at that time, a clinical trial open with acalabrutinib, which, at the time, struck us as being a potential use of this agent. And, of course, we’ve got trials ongoing right now, head-to-head acalabrutinib versus ibrutinib. We’ve certainly got data suggesting that the risk of atrial fibrillation with acalabrutinib looks lower than it is with ibrutinib. I think that has to be fully substantiated, but certainly the data that’s emerged doesn’t say that atrial fibrillation doesn’t occur with acalabrutinib. But it does clearly appear to occur at a lower frequency than we see with ibrutinib. As always, when you’re using a drug like this, that potentially you’re using to minimize one side effect. Acalabrutinib-associated headaches DR GRIBBEN: The one side effect we do see with acalabrutinib that we don’t see with ibrutinib are these headaches, which are a feature of getting these patients — so and in some of these patients, it can be quite severe. But again, it’s a case of reassuring a patient that whatever the mechanism is, they seem to settle down over time. So if people can manage the headaches during that first usually 6- to 8-week periods — but usually that’s kind of the outer end — those headaches will eventually decrease. DR LOVE: And that happened with this man. What did he actually describe to you? DR GRIBBEN: Yes, he said, “I’ve just got this kind of feeling of fuzziness in my head the whole time, and at times my head’s just pounding.” So that kind of stress headache is what people kind of describe. Not a migraine but a kind of bilateral stress-type headache that just wouldn’t quite go away. DR LOVE: And now that went away eventually? DR GRIBBEN: Yes, that settled down. And again, it’s a little bit about handholding and reassuring somebody saying, like, “I promise you this will go away. Just keep persevering, keep taking the analgesia with the drug, meantime.” And for him, I think in about 4 weeks the headaches had just disappeared. DR LOVE: And his disease responded? DR GRIBBEN: His disease responded very well. And he remains on therapy, and he remains on therapy because, of course, the clinical trial is continuous. So he remains on therapy. DR LOVE: How long has he been on treatment now? DR GRIBBEN: He’s been on treatment now for coming up to 4 years, I think, now. DR LOVE: Wow, 4 years. Wow, interesting. Going back, though, to that decision on — this man really seemed like he had a serious problem, but others maybe not quite as serious, or maybe they’re anticoagulated. Perspective on the use of venetoclax/rituximab as second-line therapy DR LOVE: What about using venetoclax/rituximab in this situation rather than a BTK inhibitor? DR GRIBBEN: Yes, it’s a very, very good point. So I should say that if I hadn’t been able to get this patient onto the clinical trial with acalabrutinib, given his circumstances and risk of CLL versus the risk of atrial fibrillation, I would have treated him with ibrutinib anyway. And, of course, now I’d also have the choice, although I didn’t have it at the time we treated him with acalabrutinib, of going straight to venetoclax/rituximab. For a patient who’s relapsed who hasn’t had either rituximab or venetoclax before, you have now in the relapsed setting got a choice of using ibrutinib versus venetoclax and rituximab. And again, that it becomes an issue of which one do you choose first, and which one are you going to go second? I guess in many people’s mind, the algorithm still kind of automatically sits of ibrutinib with venetoclax afterwards, because we’ve got more experience. Because ibrutinib came along first, we’ve got more experience of treating ibrutinib-resistant patients with venetoclax. There’s more and more data emerging about doing it the other way around, and people are becoming more comfortable. So now you really have a choice. And then it’s going to be about sitting down. And as we had with chemotherapy, you’re talking about a fixed duration of therapy versus indefinite therapy as 1 issue to consider. And also to start taking into consideration other comorbidities. So is there a relative contraindication to doing this? I’ve got a patient who’s got an absolute contraindication to BTK inhibitors in terms of having a real bleeding risk in whom it’s very clear that venetoclax would be the preferred — is, in fact, the preferred option. With anticoagulation and BTK inhibitors, it’s not an absolute contraindication. You think about the bleeding risk, but the data is overall — there’s a bleeding risk there, but it’s safe. But it’s certainly one of the factors that I would bring into consideration and talk to a patient about in terms of thinking, are you, personally, a better candidate for venetoclax rather than ibrutinib, as would be a history of atrial fibrillation? Risk of bleeding with Bruton tyrosine kinase (BTK) inhibitors and use for patients receiving anticoagulants DR LOVE: What about the issue of bleeding risk with acalabrutinib? And chemically or biochemically, what’s the difference between acalabrutinib and ibrutinib? And what, presumably, would be the mechanism of different or less toxicity with acalabrutinib? DR GRIBBEN: Whereas I’m quite convinced, at the moment, that it looks like there’s less atrial fibrillation, I don’t think of acalabrutinib and ibrutinib of having any different risk in terms of the antiplatelet action and the way in which the drugs work. And, therefore, no difference in the potential bleeding risk. Now, clearly that’s to be confirmed in a clinical trial. But, certainly, my experience has been that on acalabrutinib patients have bruising also. DR LOVE: If a patient is on anticoagulation, how do you approach the issue of BTK inhibitors? And to what extent does it depend on the type of anticoagulation? DR GRIBBEN: Sure. The whole history of this is that there was the knowledge that these drugs had antiplatelet activity. And there were a couple of reported intracranial bleeds in patients on warfarin. So the early clinical trials of ibrutinib excluded patients on warfarin. So — and in fact, the European label, but not US label, has a relative contraindication to use of warfarin with BTK inhibitors. So almost paradoxically, our approach, therefore, is to take patients off warfarin and put them on a novel –– so a DOAC. And it’s kind of counterintuitive to say, “What’s the relative of risk?” Because what’s come out is that the risk of bleeding on an anticoagulant isn’t really that high. The real risk, for these patients, of bleeding is the patients on antiplatelet agents and, in particular, those patients on dual antiplatelet agents. So for me, the issue is if somebody’s got coronary artery disease and the cardiologist has them on dual antiplatelet therapy and then you add in a BTK inhibitor. That’s where the risk of bleeding goes up. And if they’re on a dual antiplatelet activity plus an anticoagulant and the cardiologist is not happy with you substituting one of those antiplatelet agents with the ibrutinib or acalabrutinib, that, for me, would be a real indication to move to venetoclax rather than using a BTK inhibitor. Role of allogeneic transplant in the treatment of CLL DR LOVE: I think you know that one of my favorite things in medicine is the How I Treat series in Blood. And I know you have a paper there on “How and when I do allogeneic transplant in CLL.” So I recommend everybody read the paper. But maybe you can give us the bottom line of what you were trying to get across. DR GRIBBEN: So allogeneic stem cell transplant for CLL used to be the only curative approach, and it was the only approach we had for patients like those with 17p deletions. What we’ve been talking about here is, there are now 3 or 4 very good drugs out there, which have activity in that disease setting. And what’s very clear is that since these drugs have become available, the number of allogeneic stem cell transplants that are being offered has just plummeted. So you could argue right now that ibrutinib and venetoclax have done to transplant in CLL what imatinib did to transplants in CML 20 years ago. Whether or not there’s a later resurgence as these people become resistant I don’t know. But what looks very clear is, allogeneic stem cell transplant was a high-risk procedure for these more elderly patients with CLL. And we were doing it because we’d no choice. Now we’ve got a choice. We’re able to offer patients much better treatment approaches. And allogeneic stem cell transplant, at the very least, has been pushed right back into the treatment algorithm compared to where it was just a few years ago. DR LOVE: So you have a 56-year-old man with Von Willebrand disease with CLL who you gave idelalisib to. He got pneumonitis. Now he’s on venetoclax. You’re thinking about allo in this patient. How come? DR GRIBBEN: Because he has an absolute contraindication to receiving ibrutinib or acalabrutinib. He has already had idelalisib, and, of course, I used that because venetoclax wasn’t available at the time that he needed it, and he got a period of time from it. And he’s now still a young man on potentially his — so what I’m doing with him is, I’m working him up for a transplant for a rainy day, so to speak. If he starts to progress through venetoclax, I don’t have another option for him. And under that circumstance, allogeneic stem cell transplant then becomes the only game I have in town. And what I don’t want to do is find out that I missed the window of him relapsing from venetoclax and then start thinking about an allogeneic transplant. And by the time I find him a donor, his disease already escaped because I’ve got nothing to re-treat him back into that state. So for me, it’s kind of back to where I was with that first patient. I’ve always liked to have 1 more option available to me after the one I’m treating now. And, fortunately, the field’s gone along over the last few years that — as we just had ibrutinib, now we’ve got ibrutinib/venetoclax. Now we’ve got other BTK inhibitors. Now we’re talking about combinations. We’ve always got that next line becoming available. But when you come to the end of those lines, that’s when you have to start thinking about going back to what else we’ve got. And what we’ve got for a young patient is a potentially curative approach that we shouldn’t completely throw away. But it’s going to be for these more niche patients that you might have to think about those other reasons why they’re going to fail. DR LOVE: Have you heard the term CLL is the new CML? DR GRIBBEN: Yes, I think what’s very clear is that for a lot of us, ibrutinib, wonderful as it is, was never an imatinib. Is ibrutinib/venetoclax imatinib? Maybe. Maybe it’s even better, because 20 years later we still don’t know who to stop imatinib for, and we’re already stopping patients with the ibrutinib/venetoclax combination. So are either of those drugs alone an equivalent of imatinib? I would argue no. But maybe that combination together is going to do it. Clinical presentation and management of hairy cell leukemia DR LOVE: Can we chat a little bit about hairy cell leukemia, as if — let’s say you’re reviewing it for a fellow or a doc who’s just come into practice in terms of kind of what we know about the disease and what’s new. DR GRIBBEN: Sure. So, I mean, it’s a very rare disease, so it’s something that you’ve got to really think about in the first place. It usually presents with relative pancytopenia, and the patients have usually got splenomegaly. I guess the most often symptom I’d see a patient complaining about would be tiredness, and, of course, the differential when you see these sorts of patients can be fairly wide. Clearly, the blood film itself can be very diagnostic. But everyone’s seen those pictures and remembers those pictures from your medical school textbooks. But, of course, it’s not often quite so straightforward there. But the immunophenotypic pattern is very, very characteristic. So once you kind of think about it in your differential, it’s not a hard diagnosis to make. The issue, of course, is also, the age distribution is such that I think I’ve pretty much seen patients at every age group from teenagers all the way to very elderly individuals often presenting in exactly the same way. And, of course, the other big feature about hairy cell leukemia is how well it can respond to therapy. So you’re going into it with the expectation that you’re going to see a very good response and often very durable. But, of course, as with many of these other diseases, that also can lead to some of your own problems in that your patients so then expect to do very well, and then when they do relapse, they’re quite disappointed because they’ve been led to expect it’s not something that’s going to happen. I guess, then, we’re still talking about — for the vast majority of patients, they’ll respond very quickly to second-line therapies. There are brand new things coming along that look really quite good and quite exciting. The issue with any new drug that comes along for a disease like hairy cell leukemia that is rare and is even rarer in terms of relapse is how long it can take to accrue sufficient numbers of patients. And, of course, if the regulatory authorities start wanting kind of randomized trials, they’re just never going to happen in this kind of disease. So the kind of the regulatory pathway to getting a new drug, in itself, can be quite difficult. And the expertise that any 1 individual would have and some of the new therapies for hairy cell leukemia is pretty rare, because every individual only usually sees a handful of these patients, even in the big cancer centers. Obviously, there are a couple of places that really have a kind of major interest in accruing those sorts of patients, and usually those are the sorts of places that go ahead and develop the new drugs like the immunoconjugates that came out from NCI and from Scripps in the past. There’s been big interest in these kinds of diseases. But as always, it’s about thinking, how can you use your experience of managing other B-cell malignancies to help those patients through once you’ve kind of thought about and made the diagnosis? BRAF V600 mutations in hairy cell leukemia DR LOVE: Can you talk a little bit about what’s new in terms of understanding the pathophysiology of the disease, the pathogenesis? I was curious about the alterations that are seen in terms of BRAF mutations. DR GRIBBEN: Sure, absolutely. And, of course, that’s highly relevant in terms of there being BRAF inhibitors that can be used and another example where you can use a drug designed for other indications once you understand the pathophysiology and you have access to inhibitors that are able to hit particular pathways. It’s very commonly affected but, of course, not invariably affected. So again, you have to know if you’re going to use those sorts of inhibitors that the patient has that mutation for it to be able to respond. DR LOVE: And is this the same V600E mutation that’s seen in melanoma and lung cancer, for example? DR GRIBBEN: Yes, it’s very similar, but the place in which the mutations can occur, they largely cluster, but they can be outside that area. So it’s about making sure you’ve got the assay that incorporates where the mutation is likely to be but also to incorporate some of the other exons where mutations might be and be thinking about, is a patient going to have that mutation to be able to target it? First-line therapy for patients with hairy cell leukemia DR LOVE: What’s your typical first-line therapy for patients? And what kinds of issues do you run into? You were talking about cytopenias. DR GRIBBEN: Sure. So deoxycoformycin or pentostatin can be used. Most people would like to use rituximab with it, so a chemoimmunotherapy-type approach. The issue is, of course, both those agents do cause, in the short term, worsening of the cytopenias. The issue of how much benefit you add from rituximab — my own experience has been, I tend to look to use it. I can hardly think of B-cell malignancies where I don’t find the addition of an anti-CD20 monoclonal antibody as beneficial. And again, you’ve got some individuals that say, “Where’s the hard and fast clinical trial data?” And we’ve already talked about the fact that in these very rare diseases, that data can often be missing. But I tend to think that I’m looking to get a one-off approach to maximize the cure rate as much as possible, so I do use an anti-CD20 monoclonal antibody with it. DR LOVE: And in general, what do you see as the cure rate? And in people who relapse, at what point do you generally see them relapse? DR GRIBBEN: Sure. So, I mean, I’d be talking to a patient expecting to see — 80% to 90% of the patients are not going to relapse. The relapses can occur almost at any time, and one of the issues you do sometimes see is these very late relapses occurring in individuals who, of course, think they’ve put the disease behind them and think they’re already cured and it’s not going to come back. And we have talked about the fact that sometimes these people do find it very disappointing to find the disease that’s behind them is possible. Those patients who relapse earlier often can then have a shorter duration of response to just moving or repeating the first-line therapy as you’d see in any other B-cell malignancy. And it’s those sorts of patients in whom you’re looking for a more novel approach — either immunotoxins or looking for BRAF mutations to see whether or not you can add in other agents for that. The other group of patients you think about there are people who’ve gone through this multiply relapsing pattern where, clearly, they’ve acquired mechanisms of chemotherapy drug resistance. Approach to therapy for patients with relapsed hairy cell leukemia DR LOVE: And what are some of the options that are in consideration in terms of second-line therapy? And what are the clinical data that we have to support their use? Maybe starting out with the obvious, which would be BRAF inhibitors or BRAF MEK, as is used in other diseases. DR GRIBBEN: Sure. So if you have a BRAF mutation, the likelihood, in hairy cell leukemia, of responding to that inhibitor is actually very high. As always, we’re a little bit lacking durations of responses in that they haven’t been tested for that long. And certainly when I go to ASH and ASCO, those are the sorts of sessions I like to go along to, to see, what’s the longer-term follow-up of those groups of patients? You tend to see the publications arising in the papers with a very, very short follow-up, so you see very high response rates. But the big question, as you were kind of already alluding to, is, what’s the duration of response, and how really durable are those? The data that I’ve seen suggests that in some individuals it can be very durable, indeed. So the big question, of course, is, why are some patients relapsing more quickly than others, and are they developing additional mutations that bypass the BRAF pathway itself? That’s kind of much more poorly understood. DR LOVE: What are some of the other alternatives, both clinically as well as in research, that are considered with relapsed disease? What about BTK inhibitors, ibrutinib? DR GRIBBEN: There’s relatively little data out there on the BTK inhibitors in this setting. As always, there’s a handful of these sorts of patients that are within clinical trials, and you tend to hear about the anecdotal cases that respond well to it. And you hear about them. What you’d never know in those circumstances is, what was the denominator? That is, how many people tried the drug and didn’t respond? So I’d say that yes, there’s a possibility that patients could respond, but identifying who is and who isn’t going to respond is something, I think, we lack at the present time. Mechanism of action, efficacy and tolerability of the antibody-drug conjugate moxetumomab pasudotox for hairy cell leukemia DR LOVE: So you mentioned this, I guess it’s an antibody-drug conjugate, moxetumomab pasudotox. Can you talk a little bit about what that is and what we know about it in hairy cell? DR GRIBBEN: What you’re talking about here, of course, is an antibody that has with it a toxin, which is internalized inside the cell. It’s a very attractive proposition to be saying that you’re taking a poison just to the cells that you’re looking to target. And, of course, it’s a receptor that isn’t present in normal B cells, so you’re not looking to immune deplete the patient the way you do with other antibodies. So it’s all of these issues that the immunotoxins are attractive. It’s particularly attractive in hairy cell leukemia, because you’re talking here about a disease where you’re looking to treat the patient once and have a high response rate. One of the big problems with immunotoxins is that they are themselves immunogenic. And when you go back and look to be trying to re-treat patients at the later timepoints, people can have antibodies against the compound itself. So by using it in a way in which you’re treating a disease where a one-off type treatment is going to lead to long-term eradication, a big problem with immunotoxins is where you might have to consider going back and re-treating in the future. DR LOVE: Now, when you say immunotoxin, is it essentially a similar mechanism, the drug that we’re very familiar with, brentuximab vedotin? DR GRIBBEN: Yes, so the same principle, different toxin, but it’s a very similar principle, yes. DR LOVE: But this idea — I have never heard anybody say that about B vedotin. Do you see this immune thing that you’re talking — DR GRIBBEN: No, you don’t tend to see it the same way, but certainly lots of the original immunotoxin compounds people were using, using them again in the future was more difficult. I think also, a lot of probably the earlier technology, there was much more a concern about the release of the compound off the antibody. The linker technology is such that these toxins are much more stably bound to the antibody, and maybe that explains why you’re getting less free toxin released to become immunogenic. But you’re right, I haven’t seen patients with brentuximab having problems with antibody responses against the immunotoxin at later time points. DR LOVE: What about tolerability or toxicity issues? Obviously with B vedotin, we hear about peripheral neuropathy. What about with this agent? DR GRIBBEN: Yes, I haven’t. Certainly, again, I’ve got very limited experience of using it. But in the patients that I have seen with it, there was not issues with peripheral neuropathy. It was very well tolerated, which is one of the issues that made it an attractive option. DR LOVE: And what about efficacy? DR GRIBBEN: Yes, it’s very highly efficacious. As always, when you see the results of the clinical trials, you’re never quite sure what the selection criteria is in terms of how selected were those patients that went on to the clinical trials. But no, very highly efficacious. And as always, of course, the clinical trials have been in the relapsed and refractory patient population. You always wonder about how much more efficacious these agents could be if you took it much earlier in the treatment. DR LOVE: And is this agent used indefinitely until toxicity or progression, or you just give it and stop? DR GRIBBEN: You give it and stop. Yes, because you look like you’re — again, you eradicate the disease clone fairly readily, yes. Viewpoint on observation versus initiation of treatment for patients with newly diagnosed CLL DR BROWN: My approach to watch and wait really hasn’t changed. I’m a very big believer in not starting therapy before it’s necessary, until we have definitive evidence that it’s beneficial. Because we know that whenever you start therapy on a CLL patient, there’s an increased risk of complications usually in the first period on treatment, and that applies to ibrutinib as well as all the other therapies. And so I hesitate to. I also have a theoretical concern that most of the clonal evolution — the evolution of adverse karyotypes and adverse genetics — tends to happen under the influence of therapy, and it’s much more rare prior to therapy. And there’s evidence that many of those abnormalities are preexisting in tiny subclones in the CLL population. And so I have the concern that if we initiate therapy sooner, we may allow those to grow out sooner. Whereas while one’s not treating the disease, many times there is a more benign clone that may be occupying the microenvironmental niche that helps keep the small clones at bay. And so I really do stick to the iwCLL criteria for therapy still. DR LOVE: The other person I interviewed for this program is John Gribben. And he brought up something I kind of hadn’t thought about too much, which is subclinical fatigue. That he feels that there may be patients who don’t — they’re not anemic. They don’t fit the criteria for treatment, but if you question them closely, you hear about fatigue — maybe it’s not that evident if the person’s very active — that goes away when you treat. Do you think there’s a phenomena like that yourself? DR BROWN: I do think there’s definitely a phenomenon of subclinical fatigue. For example, say in the era of FCR, many times we’d wait, delay therapy and then you treat patients. And 6 months after therapy, they say, “I haven’t felt this well in 10 years.” And I think that’s because they probably had slowly progressive fatigue and symptoms associated with the disease that because it was slowly progressive, they just adapted. The problem is that I have many patients, even on novel agents, who still have fatigue and sometimes have emergent fatigue on the novel agents. And, unfortunately, we don’t know who that will be ahead of time. Some people feel terrific on ibrutinib. Some people feel worse than they did before. And until we know who that is, or until we get a next-generation, more specific inhibitor that may not cause that as much, I still hesitate to treat people for fatigue unless it’s definitely very evident. DR LOVE: And it’s so hard to tease these things out. Kind of almost gets more anecdotal. Comparison of efficacy and tolerability among BTK inhibitors DR LOVE: John was also talking about the idea that he thinks some patients somehow feel better on ibrutinib. I know you’ve had some experience with acalabrutinib. Can you discern any quality of life or qualitative differences between those two BTK inhibitors? DR BROWN: I do think that much of what we’re discussing here — the subclinical fatigue or malaise that some patients get on ibrutinib — I have not seen as much with acalabrutinib. The basis for it molecularly is very unclear. And my experience with acalabrutinib is still much more limited than my experience with ibrutinib. But that is my impression. DR LOVE: As long as you bring it up — and we’ll get into it maybe more a little bit later, but I’m kind of curious how you visualize or how you go through with your fellows the difference in spectrum of, I guess, kinases that are affected not just by these two BTK inhibitors but maybe others in development. Is there a big difference? DR BROWN: Right. So I think there is quite a substantial difference. As you know, ibrutinib is pretty nonspecific. It inhibits 19 kinases other than BTK, with an IC-50 less than 100 nanomolar. And that includes EGFR, which may contribute to rash and diarrhea, as well as quite a number of Src kinases — Tec and Itk. In the development of the next-generation covalent inhibitors, there’s been quite a focus on Tec and Itk. Tec because of the fact that dual inhibition of BTK, and Tec probably contributes to the platelet dysfunction. And so if you remove Tec inhibition, you may have less platelet dysfunction. And so that’s one of the developments that was employed with acalabrutinib. Zanubrutinib does actually inhibit Tec as potentially as ibrutinib, though. Neither of them inhibit EGFR or the Src kinases, and so there’s a lot more specificity there. And then the other actually very interesting kinase is Itk, because it’s thought that some of the favorable immunomodulation that may occur with ibrutinib may be mediated through Itk and that that may even — some people believe that may even contribute to the efficacy. And that was edited out of both acalabrutinib and zanubrutinib because of the concern that it would inhibit the activity of anti-CD20 antibodies, which was demonstrated in vitro, that inhibiting Itk and NK cells would inhibit ADCC. And ibrutinib does that, but acalabrutinib and zanubrutinib less so. DR LOVE: That’s really interesting. I haven’t heard about the EGFR thing. Because when I’ve heard the rash described with ibrutinib — I mean, is it like the EGFR rash? DR BROWN: It’s actually very variable. It’s not that consistent, and so I think it’s multifactorial. We get some very minor on-and-off rashes that are easily managed with a bit of topical steroid, and then we get very severe rashes, including erythema nodosum, erythema multiforme, even bordering on Stevens-Johnson syndrome, which we can’t manage and lead to discontinuation. And so it is really all over the map. DR LOVE: As long as we’re talking about mechanisms and kinases, what about atrial fibrillation? And what do you think the actual mechanism is? DR BROWN: Right. I do think it is related to kinase inhibition in the heart. And I do think atrial fibrillation is the tip of the iceberg. We reported also on risk of ventricular arrhythmias, including sudden death. And we’re working on assembling a series of heart block patients. I’ve had quite a number of patients require pacemakers after going on ibrutinib, as well as intermittently congestive heart failure. But the target kinase is really unknown. DR LOVE: So that’s interesting. So it’s thought to be a kinase, but nobody knows what it is. DR BROWN: No, and it may even be multiple kinases. BTK and Tec are both expressed in the heart. HER2 is also, obviously, expressed in the heart, and ibrutinib has activity against HER2. DR LOVE: HER2, wow, interesting. Okay. Effects of deletion 17p and TP53 mutations on response to therapy DR LOVE: Let’s get back to first-line therapy and particularly how biomarkers drive decisions. For years, we’ve heard about so many different prognostic biomarkers. But now, kind of — it seems like things are coalescing around predictive markers, and there’re not that many of them, from what I can see. But from a point of view of a general oncologist in community-based practice, what are the critical biomarkers that you think need to be evaluated in somebody who’s requiring treatment? DR BROWN: Right. So absolutely, 17p deletion and TP53 mutation. Evaluation for somatic mutation of TP53 has not been that widespread, but there are, increasingly, next-generation sequencing panels commercially available, and so this can be done just on peripheral blood at the same time as FISH for 17p. And those are both very critical, because we automatically triage any patient with either of those toward novel agent therapy. DR LOVE: Before you go on, can you talk a little bit about the genetics of what 17p is and the p53 gene? And also, I mean, we see this in many different cancers, but somehow it seems different here. DR BROWN: Right. So 17p deletion is a recurrent abnormality in CLL that can range in size and is often actually cytogenetically cryptic and is thought to focus primarily on deleting one copy of the TP53 gene, although there are also other genes in the region of deletion which may also be involved, and that’s been a topic of interest, research wise. Most patients who have 17p deletion will also have a somatic mutation of the other TP53 allele, and many of these are some of the hotspot DNA binding domain mutations that are well described in TP53 in a variety of cancers. There are some data, including from our group, that having both copies of p53 down in this way — 1 through deletion and 1 through mutation — is worse clinically than having just 1 abnormality. And isolated TP53 mutation is the least common. We do see isolated 17p relatively commonly. But isolated p53 mutation is probably only a few percent at diagnosis, although it goes up significantly later. DR LOVE: At a pathophysiologic level, I mean, maybe — how do you explain to your fellows why, for example, a patient with either 17p or p53 doesn’t respond to chemoimmunotherapy and will respond to novel agents? At a genomic level, is there any logic to it? DR BROWN: This is not extremely well known, but I think it may have to do with the fact that chemoimmunotherapy tends to need to induce apoptosis to kill cells. And so p53 is often required for the cells to kill themselves off in response to whatever therapy is inducing DNA damage. The novel agents, as we know from what you see in vitro — at least the kinase inhibitors, this doesn’t apply to venetoclax — actually don’t kill the cells very potently in vitro. And, in fact, a significant amount of how they work may be through modulating the microenvironment, removing the stimuli that help keep the cells growing and dividing. And then the cells, obviously, do need to die off as part of that process, and there is a substantial early cell kill. But the mechanism may be different and may be p53 independent. DR LOVE: So are you saying that, perhaps, there’s a different mechanism of antitumor action of BTK inhibitors in 17p versus non-17p? DR BROWN: No, I think it’s the same across all CLLs, but the reason that it works in 17p is that it’s not as p53 dependent as a chemotherapy-based therapy. IGHV mutation status as a prognostic and predictive biomarker DR LOVE: So the other biomarker I know you’re going to bring up is IGVH. DR BROWN: Yes. DR LOVE: Can you kind of — so now that you brought out the 17p, p53 bucket that goes one way, which is, obviously, a minority of the patients, you have everybody else. Let’s talk about the other biomarkers that you consider, beginning with IGVH. And particularly what it is and why is it that it seems particularly in the — when it’s mutated, not only to have a good prognosis but to have some cures with chemoimmunotherapy, particularly FCR. DR BROWN: Right. So that’s a great question. The IGVH refers to the degree of somatic hypermutation present in the immunoglobulin gene within the CLL. And it was observed, almost 20 years ago now, that there is an approximate cutoff around 2% to 3% mutation. We use 2% clinically, but it’s actually a continuum that is associated with very different survival. And this is largely independent of therapy. That even in that era before very effective therapies patients with the more highly mutated immunoglobulin genes had survivals that were in the multiple decades, the median wasn’t reached at 25 years. Whereas those with less mutated immunoglobulin genes have steadily progressive disease, much more treatment resistance and survivals on the order of 7 or 8 years. Now, as you know, the reason it’s a very important biomarker is that we now understand that the mutated IGVH patients with more than 2% mutation actually have very excellent responses to chemoimmunotherapy, in particular FCR, where 55% are in remission 12 years later and many are MRD-negative and probably cured. Why they’re cured by chemoimmunotherapy compared to the unmutated is not entirely clear, although I think it’s becoming increasingly evident that in CLL, genomic instability is a major predictor of poor outcome — for example, complex karyotype. This has been measured also by SNP arrays. And we know that that’s associated with poor outcomes with chemotherapy, as well as with ibrutinib, in fact. And that type of genomic instability’s much more common in the unmutated patients. So they acquire more genetic abnormalities. The other issue too is that from the standpoint of the immune system, the unmutated CLLs have much more active signaling through the B-cell receptor, which is probably due to necrotic debris, apoptotic cellular debris throughout the body, that’s constantly stimulating the cells, and this may drive their ongoing survival, proliferation and acquisition of genetic abnormalities. The mutated ones, in contrast, are anergic. And so they are much more passive. They’re not dividing and proliferating in the same way. Benefits and risks of FCR as first-line therapy for patients with CLL with IGHV mutations DR LOVE: So getting back to practical clinical algorithms, we just asked investigators what they do. And when they all say the same thing, we call it a consensus. When they give 5 different answers, it’s not a consensus. But one thing we’ve heard for a long time is that “in the younger patient who can tolerate it.” For the patient without 17p, p53, who’s IGVH mutated, most investigators will go with FCR. And as I was telling John, we get a lot of pushback from that from general oncologists in the community. They find it very, very toxic, very problematic. And, of course, they find drugs like ibrutinib certainly a lot easier. Can you go through in your own mind how you go through with a patient the issues here? And I know you actually have this 60-year-old man who presented — actually, he was with unmutated disease, correct? DR BROWN: That’s right. I picked him deliberately because he is unmutated but with trisomy 12. And there’s some suggestion that trisomy 12 can particularly benefit from FCR, even in the unmutated setting. And as noted in the case, he remains MRD-negative in complete remission 7 years after FCR, which is quite a substantial benefit and duration of time not on therapy. DR LOVE: So what about this issue of FCR, particularly in the community setting? Do you think that people — I mean, you see lots of CLL patients. The average doc sees maybe one tenth the number that you see. Do you think it’s more toxic in people who aren’t using it a lot? And, do you think it’s really a standard of care to be using FCR, or at least presenting it in these patients? DR BROWN: I do think it’s a standard of care to be presenting it, certainly to the mutated patients. I believe it’s curative for a significant fraction of them, and that’s why. And there’s no evidence that BR is curative. There is a bit of a learning curve with giving it. And what I always like to emphasize is the importance of aggressive supportive care. So all the patients get prophylactic pegfilgrastim every cycle. All the patients get pneumocystis prophylaxis. All the patients get varicella zoster prophylaxis. In the first cycle, you need aggressive tumor lysis prophylaxis — fluids, allopurinol. I check labs through day 4, as well as then on day 8. DR LOVE: That’s interesting — tumor lysis with FCR. DR BROWN: Yes, just like any chemoimmunotherapy or like R-CHOP with diffuse large B-cell lymphoma. Especially the mutated patients, their white count will practically normalize within a couple of days. It’s very potent. Usually we don’t see tumor lysis, or at least I don’t when I do all this preventative therapy. But I do think that’s a big issue. And the other point I always like to make is that you have to watch the counts carefully with each cycle. And if patients are not recovering their counts and you have to hold for a couple of weeks, I tend to stop. And that’s potentially because you don’t want to push it to the point where you are doing their bone marrow damage. And there are patients whose bone marrow is quite sensitive to FCR for reasons that we don’t understand or can’t measure ahead of time, except for clinically what happens. And so I always am very careful about that as well. DR LOVE: When you’ve had to stop, usually after how many cycles? DR BROWN: It’s pretty common that patients may not make it through beyond cycle 5. The average in the trials is 5 cycles. But we sometimes have people who stop after 3 or 4. And I’ll do that regardless of their MRD status if they’ve had to hold for 3 or 4 weeks or have tried a dose reduction after 1- or 2-week holds and we’re still getting multiple week holds. Correlation between MRD status and outcomes for patients with CLL DR LOVE: So you mentioned MRD status. First of all, do you think MRD status is something that should be utilized or considered in a nonprotocol situation? DR BROWN: It’s really just prognostic for advising the patients about what we hope to get from their remission duration. And so in that sense, no. I don’t really use it to guide therapy. I don’t think it’s appropriate, really, to use it to guide therapy. In the context I was just discussing, if I’m discussing with the patients the risks versus benefits of continuing the therapy versus stopping, since I have that information, I’ll include that in the conversation. But mostly it’s a clinical decision to stop if you are getting cytopenias. DR LOVE: And if someone were to — you’d want to use an MRD assay, what type of assay do you recommend? DR BROWN: Right. So the standard, which is defined by the European Research Initiative on CLL, is a 4-color flow cytometry assay. There’s a specific validation procedure for it, and it is offered by at least 1 commercial company that I know of that one can send samples to. DR LOVE: So in terms of using FCR, in general, what’s kind of the age at which you pull back regardless of the patient being in great condition? DR BROWN: Around 65, 60 to 65 is also a little bit borderline, but patients who are in great condition it’s still quite easy to give FCR, relatively speaking. You start to get into the later sixties, probably there’s more bone marrow susceptibility to cytopenias, it comes much harder to deliver the therapy. DR LOVE: Now this concept, particularly in the mutated patients, of going for cure, in your mind, does that apply to other forms of chemoimmunotherapy? I mean, BR, chlorambucil, obinutuzumab, et cetera, et cetera? DR BROWN: No, I don’t believe that there’s any evidence for a plateau on the long-term survival curve even with BR or with chlorambucil/obinutuzumab. However, I do believe that IGVH mutation status is a very strong indicator of a patient’s overall expected disease course. And so even though there might not be cure, I still think that particularly mutated older patients who might want to start with a time-limited therapy and not commit to years of continuous therapy, those patients can get quite prolonged benefit from BR or obinutuzumab/chlorambucil. And it’s not unreasonable to continue to decide to offer that option. I do find that many of my patients like the idea of time-limited therapy. Choice of obinutuzumab-based therapy in the first-line setting for CLL DR LOVE: So you mentioned obinutuzumab, and I’d like you to get into the issue of even whether to use chemoimmunotherapy at all. But if you are going to use it, where are you today with obinutuzumab, and what situations are you using it? DR BROWN: Right. So mostly in older patients with chlorambucil. There is a lot of activity of obinutuzumab with bendamustine. Data are continuing to emerge on that, mostly from Europe. And so that is a very potent regimen. I have not used it that much outside the context of a clinical trial, because it does result in more neutropenia, for sure, than bendamustine/rituximab. And, similarly, I would not tend to use obinutuzumab with fludarabine or cyclophosphamide, because we actually did that Phase I study, and there were quite a few more cytopenias. And as you know, we heard from a press release that the iLLUMINATE study, which compared ibrutinib with obinutuzumab to chlorambucil with obinutuzumab, met its primary endpoint. So hopefully we’ll see that data at ASH. But that will likely shift the standard from obinutuzumab/chlorambucil even more so than RESONATE-2 has. DR LOVE: So this is first-line therapy. DR BROWN: Right. The older patients. Use of ibrutinib for patients with previously untreated CLL DR LOVE: So what about the fundamental question of the patients who aren’t younger or the patients who aren’t mutated and chemotherapy versus novel therapy, particularly BTK inhibitors, specifically ibrutinib? There’s a lot of discussion about that right now. It kind of seems like things are shifting away from chemoimmunotherapy, but you tell me. DR BROWN: I think that’s certainly true in the older patient population where we have the RESONATE-2 data comparing ibrutinib to chlorambucil. We’ll hopefully see more data in that patient population at ASH, as I just mentioned, in combination with obinutuzumab. So it’s definitely shifting that way. I tend to have a long conversation with the patients about the risks and benefits of both time-limited/short-duration therapy with chemoimmunotherapy versus continuous ibrutinib. Those risks and benefits depend both on the risk profile of their disease, as I was saying the mutated patients with favorable cytogenetics can get quite prolonged benefit from chemoimmunotherapy as opposed to non-17p but still high-risk patients, for example, those with 11q deletion, those who are unmutated or have complex karyotype, in particular, who are not likely to get prolonged benefit from chemoimmunotherapy. And so ibrutinib would be a better choice. Adherence to treatment with ibrutinib and reasons for discontinuation DR BROWN: As you know, we do continue to see that in general practice there is significant discontinuation of ibrutinib. And this, I think, is related to some of the issues that include fatigue, atrial fibrillation, infections, neutropenia, really a panoply of issues. And so that remains an issue for patients. And as we start to get next-generation inhibitors, that tolerability profile might improve and make it simpler to push more of the patients toward the continuous inhibitor therapy. DR LOVE: I’m kind of curious to what extent, if any, you think the issue of adherence is important in CLL, particularly with novel agents. Your breast cancer group’s done a lot of work with tamoxifen and adjuvant endocrine therapy at Dana-Farber. And we think about the way things are moving in ALL with long-term treatment with drugs like ibrutinib. What do we know about the issue of adherence? And also, you were referring to data from the general or community setting. Are people not staying on ibrutinib as long as they do in tertiary centers? DR BROWN: Right. So we don’t know that much about adherence in CLL. I think in the early clinical trials, with the drug diaries and whatnot, it was clear that those patients are very, very adherent, but many of them had been quite sick when they went on the trial, and they knew the very great importance of staying on the drug. And as we moved the drug up earlier and earlier, and as people get some side effects and don’t necessarily feel that their disease is that threatening — and, in fact, their disease may not be that threatening — adherence will be a bigger issue, and that may lead to more resistance. The data I was referring to are from studies led by Anthony Mato, which actually are patients not on clinical trials but treated still in academic centers. And those patients not on clinical trials actually had a 42% discontinuation rate for ibrutinib at a median of 17 months. DR LOVE: Wow. DR BROWN: Yes, in both the front-line and relapsed setting — 25% of that was due to adverse events. And it includes all the things we know about: atrial fibrillation, infection, neutropenia. Arthralgias are actually quite prominent on the list and can be quite severe. DR LOVE: You said 25% of the discontinuation was related to side effects? DR BROWN: Yes. DR LOVE: What was the rest, progression? DR BROWN: No — it was a relatively high-risk population, 11q, 17p deletion in about 40% of the patients. So there was a significant rate of progression as well. DR LOVE: Hmm. Interesting. Efficacy and side-effect profile of acalabrutinib DR LOVE: So maybe you can talk a little bit — we got into this issue of people staying on ibrutinib. We now have another BTK inhibitor, acalabrutinib, approved in mantle cell, but there’re also data with acalabrutinib in CLL. But can you kind of provide us an overview of what we have right now in terms of data with acalabrutinib in CLL, both in terms of efficacy and tolerability? DR BROWN: Right. So in terms of efficacy, the Phase I relapsed/refractory study, which we participated in, was updated at ASH with about a 2-year follow-up. And we’re seeing efficacy that looks quite similar to ibrutinib at that point in time. Insofar as one can tell, about 90% progression-free survival. The median had only been reached in the complex karyotype population — 17p had not reached a median but appeared to be dropping a bit below the curve, similar to the Phase I with ibrutinib. There’s also a treatment-naïve cohort where the progression-free survival is extremely high in the initial early report. And those data will be updated at ASH. In terms of tolerability, my clinical impression has been that it is more tolerated, particularly in terms of some of the issues like fatigue or arthralgias, bleeding. We do see some arthralgias still with acalabrutinib and some minor bleeding, but I haven’t seen as severe arthralgias or as severe bleeding. And I haven’t seen as many cardiac side effects. Incidence of acalabrutinib-associated atrial fibrillation and headaches DR BROWN: There was a presentation at ASH which looked at the experience of toxicity with acalabrutinib in about 650 of the patients on the trials. And they did see some atrial fibrillation. The rate was about 3%, in contrast to what we see with ibrutinib, which gets up to 10% to 15% over time. But in a comparable length of time was probably 6% with ibrutinib. Many of the cases with acalabrutinib were in the setting of pneumonias and infections and hospital admissions. And so how exactly that’s going to play out in larger use, we’ll see. There is, also, an experience that was reported at ASH that looks at use of acalabrutinib in patients who’ve discontinued ibrutinib for adverse events. And in that experience, many of the — essentially all of the patients were able to stay on acalabrutinib. Some of them had recurrence of their prior side effect but not as severe. And then there were only a couple of atrial fibrillation cases there, one of which did recur. And so that was not fully contributory. DR LOVE: If acalabrutinib were available or approved — or maybe it’s even accessible now — for CLL, are there situations with the data that we have right now that you would use it, particularly in a patient with atrial fibrillation on anticoagulation? DR BROWN: So for a routine patient with well-controlled atrial fibrillation or requiring anticoagulation, I would not necessarily use it yet. What I usually do is switch the anticoagulant to a novel oral anticoagulant and have had pretty good luck with apixaban with ibrutinib. And if it’s in older patients, the low dose. The patients who worry me most for initiation of ibrutinib are older patients, older than about 75 or so, who have significant cardiac comorbidity preexisting. Which doesn’t necessarily mean just well-controlled atrial fibrillation. It means congestive heart failure, it means yes, low ejection fraction, et cetera. And so those patients — particularly if they had high-risk disease — I would try to get acalabrutinib rather than ibrutinib. DR LOVE: One thing I’ve heard from several investigators — I’m curious if you have observed or believe — is the issue of headache with acalabrutinib. Have you seen that? DR BROWN: Yes, that’s definitely true. It happens in the first few weeks to a month or two, but it really goes away. It goes completely away. So you just have to counsel the patient, and it’s usually responsive to fairly minor interventions like acetaminophen or — we don’t encourage patients to take much ibuprofen because of the bleeding issue, but they can take some ibuprofen or caffeine. So it’s usually pretty responsive to those interventions, and it resolves. DR LOVE: And how is it described? When I’ve heard it described, it almost sounds like a stress headache or something. DR BROWN: It does, just like a regular stress or tension-type headache. DR LOVE: But you think it’s an off-target effect, or it’s an effect of BTK inhibition? DR BROWN: I’m not sure. I have thought that it might be related to peak levels of the drug in the CNS, although I’m not aware of any data addressing that, and I’m not sure what the mechanism would be. Treatment options for patients who experience disease progression on ibrutinib DR LOVE: So let’s talk about management of relapsed disease. And particularly interested in the issue of the patient who gets started on ibrutinib and then has disease progression. First of all, what’s the spectrum of when you see progression on ibrutinib first line? How many years later? DR BROWN: So we don’t actually really know the answer to that yet if we’re talking about front-line therapy. In the relapsed setting, we tend to see Richter’s transformation in the first year to year and a half. And then CLL progression starts coming up at about a year and a half and appears to continue to rise steadily out to about 4 years, when it’s about 25% in the Ohio State series, which has the longest follow-up. And that’s also actually about the rate in RESONATE with longer follow-up as well. In the front-line setting, there are really not enough data. There’s the NHLBI study of 17p-deleted front-line patients where they actually have a 5-year progression-free survival of about 75%. But they did have some early Richter’s transformation, and then they’ve had steady relapses up to that level since then. And in the RESONATE-2 study, we haven’t actually seen data on the timing of relapse. But it was about 10% or so. DR LOVE: So what has been your approach to patients who — let’s say nondel(17p), because, obviously, with del(17p)/p53 you’re going to go venetoclax. But what about the rest of the patients? How have you been approaching it in the past, and what about right now? DR BROWN: Those who progress on ibrutinib, you mean? DR LOVE: Yes. DR BROWN: Right. So I think because I have access to clinical trials, if they don’t have a particularly aggressive relapse, I tend to use the trial options and save venetoclax for later, because we know venetoclax has quite a lot of activity in very heavily pretreated relapsed/refractory disease. But in the absence of a clinical trial, venetoclax is really the only drug with well-established activity in a patient who actually progresses while taking ibrutinib. And those patients definitely need to be distinguished from patients who stopped for an adverse event and progressed some time later, who may not actually have the same biology as those who progress while taking ibrutinib. Clinical implications of the MURANO trial investigating venetoclax/rituximab for relapsed/refractory CLL DR LOVE: Can you talk a little bit about the MURANO trial and how that has affected your practice and the practice of your other colleagues? DR BROWN: Right. So the MURANO trial is a randomized trial comparing venetoclax for 2 years with 6 months of rituximab to 6 months of bendamustine/rituximab. And the patient population was in their early sixties and had a median of 1 prior therapy, which was a chemoimmunotherapy. So almost all of them were ibrutinib naïve. And at this first report, which was also published in The New England Journal of Medicine shortly after ASH, the progression-free survival in the venetoclax/rituximab arm was about 83% compared to about 30% or so in the bendamustine/rituximab arm. And overall survival, as a point estimate, was also significant, although it didn’t meet the trial criteria for prespecification of significance. And so that was quite an impressive difference. One thing to note is that most of the patients had not yet discontinued the venetoclax. Only a few were out past the 2-year point of discontinuation. And I think we’re going to see at this coming ASH an update where patients have reached a better year/year and a half point after discontinuing. Now, that being said, I’m quite enthusiastic about this regimen. I like the idea of time-limited therapy rather than continuous therapy, because it limits side effects, it limits cost and it also probably limits the severity of resistance that can develop. The main issue with using venetoclax/rituximab prior to ibrutinib in a relapsed setting is that we don’t have a lot of data on how well ibrutinib works after venetoclax, whereas we have pretty good data, including a prospective trial, on venetoclax after ibrutinib. That being said, I still think that this will be quite a popular option for patients in first relapse who are novel agent naïve, because it’s time limited. The other thing is, venetoclax is very well tolerated by patients. You have to get them through that first 4- to 5-week risk of tumor lysis, but then after that the side-effect profile is very favorable compared to ibrutinib. And so that is also very advantageous. DR LOVE: So how are the data from the MURANO trial — how do you think they’ve affected clinical practice? DR BROWN: In my practice, I am sometimes now using venetoclax/rituximab in preference to ibrutinib. I mostly try to put patients on trials of one type or another, obviously. But I think because it’s time limited and well tolerated that it’s reasonable to use it as a first novel agent and save ibrutinib for later. I have not seen a lot of adoption of venetoclax in the community, which I think may have to do with that first 4- to 5-week monitoring period. DR LOVE: What do you think is going on right now in terms of patients who get first-line ibrutinib and then have progression? What do you think’s happening in the community? DR BROWN: So I think that’s a good question. I think that we are seeing a lot of those patients come for possible trials and that probably those are the patients who are getting venetoclax in the community. Patients who stop ibrutinib for adverse events and progress later, it’s not unreasonable to consider trying chemoimmunotherapy for them or a different kinase inhibitor like a PI3 kinase inhibitor such as idelalisib. Because they may not have the same resistance profile. Monitoring and prophylaxis for venetoclax-associated TLS DR LOVE: You mentioned the issue of tumor lysis syndrome. Obviously, that’s been a really important and interesting issue since the drug first became available. Where are you today in terms of how you actually attempt to prevent it and monitor? And are you following kind of still the package insert box algorithm? DR BROWN: I definitely still follow the package insert box algorithm. In fact, I sometimes am even more careful than the box algorithm. So a patient with reduced renal function, especially an older patient, even if they’re on the lower end of moderate risk, I might admit them for the first time or two until we figure out how well they can clear the byproducts of the cell lysis. And so I really do follow it quite aggressively. I also often get 2 sets of labs at, say, 4 and 8 hours rather than just the 6-hour labs and then the 24-hour as well. DR LOVE: And with that approach and the dose escalation, have you actually seen cases of tumor lysis syndrome? DR BROWN: You can see laboratory tumor lysis syndrome. I certainly see elevation in phosphorus, elevation in LDH — those are pretty common. Uric acid, usually beat down with allopurinol, which I usually start at least a week ahead of time, as well as I usually give IV fluids more than the package insert necessarily says as well, and then that usually takes care of that. But I haven’t seen any dangerous tumor lysis following that. The main issue is, you do need to get the labs back in a timely fashion, and I think that that sometimes is challenging in a community setting. Activity and tolerability of PI3 kinase inhibitors in CLL DR LOVE: You mentioned PI3 kinase inhibitors. And we have idelalisib out there that is approved in CLL, but also copanlisib that’s approved in FL. Can you talk about what we know about PI3 kinase inhibitors in CLL? DR BROWN: Right. So we know that idelalisib and duvelisib both have quite a lot of activity in the relapsed/refractory setting. With idelalisib, there’s actually no difference based on 17p deletion or IGVH mutation status in the registration trials, and the median PFS was about 19, 20 months. The activity of the drug is actually such that if patients can stay on it, they can potentially have much longer benefit than that. The main problem has been discontinuation due to adverse events. And the adverse events come in a few flavors. So one is, you can get neutropenia, which can result in even sepsis and infection. And so if I’m using one of these drugs, I usually give patients growth factors if they become neutropenic to avoid that issue. Second issue is, you can get opportunistic infections, so you need to give people pneumocystis and varicella prophylaxis, which I do in everyone. But the main issue, I think, is what we now understand to be a profile of autoimmune toxicity. The most prominent issue with which is a delayed diarrhea and colitis, which, in the trials, happens at a median of 7 months or so. So there’s an early mild diarrhea that sometimes happens, readily manageable with loperamide, for example. But if you start getting late diarrhea, you have to have a very low threshold for suspecting that it’s the drug. And I will often start patients on oral budesonide, even with very mild late diarrhea. And if you do that, a lot of times you can head it off at the pass and even be able to continue the drug. But if it gets worse despite that, you have to hold the drug. Maybe you have to give some prednisone and lower the dose. In doing that, you can often keep people on, but not always, and sometimes it’s more severe. But many times there’s this lower-grade prodrome before it gets severe, which, if you’re watching out for it, you can often avoid. With duvelisib, we don’t know yet if the extent of the colitis is similar. It seems that patients have been able to stay on the drug more consistently than on the idelalisib trials in terms of the registration trial. But overall, the profile’s similar with the colitis. And then the other issues are, you can also get liver function abnormalities, so that requires monitoring every week or two in the first couple of months. And then the other issue is pneumonitis, which can be drug related. And so if patients do come in with a pulmonary syndrome, usually I hold drug immediately, evaluate for infection for 24 to 48 hours. If you don’t find any infection and it looks radiographically like a drug-related pneumonitis, I’ll often start steroids. DR LOVE: But that pneumonitis is also autoimmune? DR BROWN: We think so. There is less data from a biopsy perspective to prove that, but… DR LOVE: Are there any data with copanlisib in CLL or other PI3 kinase inhibitors? DR BROWN: So there were a few CLL patients in the initial copanlisib trial, but the data aren’t really broken out, and it’s fairly limited. We’re actually planning on doing a trial ourselves, because this is one interest of mine. But the interesting thing about copanlisib is, it’s actually a pan inhibitor. It’s built as alpha/delta, but it’s really pan. But as you know, the side-effect profile’s a little bit different. It has infusion-related toxicities of hypertension and hyperglycemia, which are probably related to alpha inhibition. And there seems to be less diarrhea, less transaminitis, which may be because of the IV administration and/or the punctuated dosing, where patients have a gap rather than continuous dosing. DR LOVE: Wow. That’s interesting. I hadn’t heard about that. Yes, I heard — FL, I was getting this message that there are less autoimmune issues, but I hadn’t heard — that other thing makes sense in terms of the IV, et cetera. Right now, in what situations are you using idelalisib, and do you use it alone or with rituximab? DR BROWN: Right. So I use it in, often, older patients who may have cardiac comorbidities, may have renal comorbidities that are issues with both ibrutinib and venetoclax. And we have actually studied the autoimmune toxicity in some detail in relation to a trial we did. And we found that the risk of it is much greater in younger patients. It’s higher in patients with mutated IGVH. And so the older patient population who’ve had a few rounds of chemoimmunotherapy are well suited to it, and that’s where I tend to use it, sometimes even ahead of the others, as I was saying with the comorbidities. But more commonly in patients who’ve had ibrutinib or had venetoclax. Perspective on the efficacy of ibrutinib with venetoclax DR LOVE: So things are swirling around so much in CLL, so many exciting things. But one thing that you hear a lot of people talking about, maybe as the wave of the future, you referred to the challenges of indefinite treatment with novel agents, is the combination strategy. And there are lots of them. The one I want to ask you about first is ibrutinib and venetoclax. DR BROWN: Obviously very exciting. And as I mentioned, I do like the idea of time-limited therapy. So we only have very early data combining ibrutinib and venetoclax, but venetoclax, in contrast to ibrutinib, does very potently clear blood and bone marrow, and so you get deep remissions, complete remissions and MRD-negative remissions. And the early data that we have do suggest that there are high rates of complete remissions and MRD negativity with that combination. Not all the studies do stop the therapy. Some are planned to, but none of them are out far enough that we know what happens if you stop the therapy. But it’s certainly a very exciting combination. And I think particularly for the patients with the very high-risk genomically unstable disease, it’s likely to reduce the development of resistance. Because we have 2 different mechanisms being employed together, it’s harder for the cells to become resistant to that, hopefully. DR LOVE: What kind of trial do you think it’s going to take to bring a combination like that into practice? Maybe there are trials out there right now that really would be definitive. Are there? DR BROWN: The German CLL Study Group has a study in young, fit patients, randomizing them to chemoimmunotherapy, to venetoclax with rituximab, to venetoclax with obinutuzumab or to the 3-drug ibrutinib/venetoclax/obinutuzumab combination. So there’s an opportunity there to demonstrate that that dual drug combination is more potent than a venetoclax-based regimen. Study does not include ibrutinib-based arms on its own. I believe the next generation of cooperative group trials are planning to try to compare the 2-drug versus an ibrutinib-based regimen. There is a registration trial for the combination of ibrutinib/venetoclax comparing it to chlorambucil/obinutuzumab. DR LOVE: Chlorambucil/obinutuzumab — so, I mean, do you think it’s going to take a Phase III trial comparing the combination to ibrutinib or even to venetoclax alone to really change practice? DR BROWN: That’s an interesting question. I don’t think that would be required to change practice if the Phase II data, particularly with MRD negativity and the ability to stop therapy look very promising, as they do now. The question is, can we get it paid for? Because obviously the 2 drugs together are very expensive. Now, it may turn out to be cheaper in the long run if you do the 2 of them together for 6 months or a year and are able to stop for 8 years compared to 9 years of ibrutinib, right, but it’s hard to prove that until you have data. Role of obinutuzumab with venetoclax for previously untreated CLL DR LOVE: You mentioned the — I think the German trial had the arm of, I think you said, obinutuzumab/venetoclax, right? DR BROWN: Right. DR LOVE: Which is interesting. That’s like the venetoclax/rituximab regimen that you just talked about, but substituting obinutuzumab. What do we know about that combination theoretically or even practically? Is it an advantage using obinutuzumab compared to rituximab when combined with venetoclax? DR BROWN: Right. So the venetoclax/obinutuzumab combination, I think, is very exciting, and we do have some data in the front-line setting on about 30 patients from a Phase I that were presented at ASH. It actually has the highest CR and MRD negativity rate of most any regimen, not counting the fit ibrutinib/FCR combinations that we and the MD Anderson are doing. A 70% CR rate and virtually everyone’s MRD-negative, and this is for a 1-year regimen of venetoclax with obinutuzumab. And so the German CLL Study Group actually has another registration trial for that regimen, which is expected to read out pretty soon, probably within the next year, or venetoclax/obinutuzumab for 1 year versus chlorambucil/obinutuzumab. And I think when that gets approved, it will be very appealing for this older patient population in terms of a very deep remission with just 1 year of therapy. We don’t know for sure the question of obinutuzumab versus rituximab. The randomized data that we have are with chlorambucil, and we do know, as recently reported at the European Hematology Association, that obinutuzumab/chlorambucil actually improves not just progression-free but also overall survival compared to rituximab/chlorambucil. And venetoclax appears to be a drug that does have synergistic benefit from adding anti-CD20 antibody. So I would expect that we’ll unlikely — we will actually get that comparison directly from the German study, but that’s many years off. But in general, for patients who are able to tolerate it, I like the venetoclax/obinutuzumab. Benefits and risks of ibrutinib with FCR DR LOVE: So you mentioned the regimen that you’ve been looking at with MD Anderson. I’ve heard it called iFCR/ibrutinib plus FCR. What do we know about that combination? DR BROWN: So we’ve been doing iFCR. MD Anderson has been doing iFCG, which is obinutuzumab. And so that combination is extremely potent in the young, fit patient population. And we’ve done it in all comers — both mutated and unmutated IGVH. And the bone marrow MRD negativity rate is about 75% in all comers. But if you focus just on the low-risk mutated patients, it’s 100%. So it’s improving that much on FCR. And the MD Anderson has similar results. Their study focuses only on mutated patients. But essentially at the end of therapy, it looks like they’re all in MRD-negative complete remission. DR LOVE: You were talking before about the issues involved with giving FCR. And I would like you to talk a little bit, particularly in terms of infectious issues that you see with, let’s say, ibrutinib or FCR or ibrutinib FCO. The issue of infections with ibrutinib itself. So maybe we can start there about what we know about that and how you approach infection prevention in patients on ibrutinib. DR BROWN: Right. So we know that in the relapsed/refractory trials with single-agent ibrutinib, we saw similar high rates of pneumonia Grade 3-type bacterial infections in that patient population for at least the first 6 months to a year, as we have with every other therapy. Those were on the order of 40% Grade 3 and included some deaths. It does appear that over time on ibrutinib the rate of those types of bacterial and routine infections does go down, which is good, and may relate to the improved disease control. Some people speculate that it may relate to the effect of ibrutinib on T cells. One thing that we know right now that has emerged over the last year or so is that there does appear to be a specific susceptibility to fungal infection associated with the BTK inhibitors. And, in fact, in a BTK knockout model, the mice die much more quickly when exposed to a fungal infection if BTK is knocked out compared to if it’s intact, and similarly with the drug. And so the detailed mechanism of this is unclear, but it does appear to be an on-target effect. I actually prophylax all my ibrutinib patients treated in the relapsed setting with PJP and varicella prophylaxis. That’s basically my practice for all relapsed CLL patients to prophylax them, and I continued that with ibrutinib. In the up-front setting, I often do it as well, but this is not that common. Most people don’t. We don’t really know how important it may be. There is a report of 5 cases of PJP out of about 96 patients in the NHLBI study, but they were mild cases, and patients got better with therapy and then didn’t necessarily recur as their disease was controlled better. So the necessity of this is not clear, and I don’t push it as hard in the up-front setting as in the relapsed setting, but I do usually put patients on prophylaxis. This has mostly to do with CLL getting any therapy. DR LOVE: What about the patient getting ibrutinib plus FCR? What does that end up with in terms of infection risk? DR BROWN: So it was actually lower in our study than reported with FCR, but that’s probably because the median age of the patients was in their midfifties, and they were extremely healthy. And we do all the same supportive care that I would do for FCR: mandatory pegfilgrastim prophylactically, zoster prophylaxis, pneumocystis prophylaxis. Anyone has a fever, they come in for an aggressive work-up, usually hold ibrutinib initially while we’re evaluating that before restarting it. So it’s been pretty similar with ibrutinib/FCR. In the MD Anderson study with obinutuzumab, they have quite a bit more neutropenia, and they have had more infections. They also, initially, didn’t mandate prophylaxis, as they’re only doing 3 cycles of the chemoimmunotherapy, but they had to modify the study to include prophylaxis. Case: A 75-year-old woman with relapsed CLL/small lymphocytic lymphoma with del(13q) and unmutated IGHV achieves an excellent response to venetoclax on a clinical trial DR LOVE: So let’s talk about some of the cases. You mentioned the one man who’s doing so well after getting FCR. How about your 75-year-old lady? Can you talk a little bit about her? DR BROWN: This is an older patient who has actually more of an SLL-type presentation. And she was 65 when she presented. She had received a couple of cycles of BR — this is before I met her — and she didn’t have a very good response. So then she was given a couple of cycles of FCR, which did induce response, but the response was quite transient. She progressed after about a year. And that’s when I met her. And at the time, we were doing the Phase I study of venetoclax. This was before any of the novel agents were FDA approved. And so we enrolled her on the Phase I study of venetoclax. And she had an excellent response, which continued for about 5 years or so until about a year ago. DR LOVE: How was her quality of life during that time? DR BROWN: Oh, excellent. As I was mentioning, venetoclax — typically what you may see other than the tumor lysis at the beginning, which goes away, you may get some mild neutropenia. But what I’ve observed is, a lot of times the patient’s neutrophils drift down, and they live around 1,000/1,200, but they don’t get sick, and they don’t dip down more. If they do dip down more once or twice, we’ll usually give them pegfilgrastim, and then it doesn’t happen again. And then occasionally you’ll get a little bit of GI side effects, but most of my patients don’t have that. You do usually have the patients switch dosing of either venetoclax or ibrutinib, if they have GI side effects, to nighttime, because that seems to help. DR LOVE: Hmm. Interesting. Sequencing of treatment for patients with relapsed/refractory CLL DR LOVE: So what happened after 5 years? DR BROWN: Right. So she mostly had nodal progression and some development of anemia, whereas her counts had normalized previously. And so then at that point, we had a trial of ibrutinib with obinutuzumab in relapse, and so she enrolled on that. And she’s done very well on that. She had a rapid response with ibrutinib. We don’t know very much, as I was saying, about response to ibrutinib postvenetoclax, which is why she and other patients from that Phase I study are interesting to us — so now transitioning to ibrutinib. We do have some data from the Australians suggesting that you can get good and prolonged responses with ibrutinib after progression on venetoclax. DR LOVE: What was her biomarker status? DR BROWN: She had unmutated disease with 13q deletion. DR LOVE: And I’m just kind of curious. Do you think that this sequence that she ended up getting of first venetoclax followed by ibrutinib, in your own mind, do you think that there’s a difference between that and going the other way? DR BROWN: I think we have no data, really none. Unfortunately, most of our data on sequencing is really based on historical availability. The main thing that I like about venetoclax followed by ibrutinib is that most of the venetoclax regimens — unlike what she did — most of them are now planned to be short, 1 or 2 years, and so patients stop. And then if they remain in remission for some time and progress later, they probably don’t have as marked evolution of their disease as if they had progressed on the drug, which is what’s happening, say, with patients on ibrutinib continuously. They progress on drug. We know that the biology of that progression tends to be more aggressive. And even with venetoclax and ibrutinib progressors, the response rate’s only 65%, which is not as high as we’ve seen in patients not progressing on ibrutinib. And most of them don’t get complete remissions, which again, is distinct from patients who’ve not progressed on ibrutinib. DR LOVE: Now, this lady, has she had any tolerability issues with the ibrutinib or ibrutinib/rituximab? DR BROWN: This lady has actually done quite well. She’s had a couple of infections. That’s an on-and-off issue for her historically. And so she does get IVIG. But basically nothing specifically related to ibrutinib. DR LOVE: We’ve been focusing a lot on the issue of problems that occur with BTK inhibitors. But in your own mind, when you start, for example, ibrutinib, what, in your own mind, is the likelihood that they’re just going to cruise through it, no problem, for years? DR BROWN: I don’t actually view that as all that likely. A lot of my patients have problems. I feel like it’s maybe only 20%, 25% that have no problems at all. And we’re not talking about problems that are insurmountable, but just issues that need to be addressed, especially in the early period. If they do get through that first 6 months or so without any major issues, I think after that the likelihood is much better, although we do see ongoing development of atrial fibrillation for sure, at later times. Case: An 85-year-old woman with relapsed CLL with del(13q) experiences recurrent congestive heart failure after receiving ibrutinib DR LOVE: So I want to just, in terms of this issue of ibrutinib, and you were talking before about the cardiac problems, can you talk about what happened with your 85-year-old lady? DR BROWN: Right. So this, again, older patient, no prior cardiac history. She had relatively low-risk CLL, which had had a prolonged remission to fludarabine/rituximab and progressed — this was a couple of years ago now after probably 7 or 8 years on the fludarabine/rituximab. And so she didn’t want to come in much, wanted something easy, oral, so we didn’t enroll her on a trial. We just started her on ibrutinib. But then a couple of weeks later, she was admitted with a heart failure and, at least acutely, a reduced ejection fraction needed to be diuresed. And so we held the ibrutinib then for a while. But then I tried again a month later in case it wasn’t related to the ibrutinib. But the same thing happened, and she was readmitted. And then she said she was done with it. Fortunately, she actually did have some disease response from this very short duration, and we didn’t need to do anything again. DR LOVE: So you’ve just been observing her? DR BROWN: Yes. DR LOVE: Still a pretty scary story. How many times have you seen something like that? DR BROWN: The congestive heart failure recurrently not that many times, maybe 3 or 4. The other issue that’s come up with the very old patients is complete heart block. I’ve had, perhaps, 4 or 5 patients need pacemakers in that setting, and we did have 1 patient here who had a cardiac arrest from complete heart block, fortunately was in the hospital at the time so was able to be resuscitated. DR LOVE: Wow, interesting. Case: A 65-year-old man with CLL with unmutated IGHV and a TP53 mutation receives acalabrutinib as second-line therapy DR LOVE: So we were talking about acalabrutinib, and I see you have a 65-year-old man who received it. Can you talk about what happened to him? DR BROWN: Right. So he had high-risk disease, unmutated IGVH and he actually did have an isolated TP53 mutation. And again, when he started therapy, it was prior to the novel agent era, and we enrolled him on a front-line trial we had combining lenalidomide, which was thought to have activity in p53- and 17p-deleted disease, along with bendamustine/rituximab. He actually had a hard time with that. He had several infections but did appear to achieve a decent partial remission. But again, relapsed relatively soon thereafter, in about 16 months. And then at that point we had the acalabrutinib trial, which seemed like a good opportunity for him, especially given the TP53 mutation and a short relapse-free interval. And so he’s done very well on that. He has absolutely no side effects now, about 3 years in. Response, as with ibrutinib in these relatively high-risk patients, is relatively slow. His white count went up and has been slowly coming down. And he hasn’t completely resolved his lymphocytosis. He still has 5,000 to 10,000 circulating lymphocytes probably at this point. And the other interesting thing about him is, his platelet count when he started was maybe 90 or 100, and it’s remained lower, in the order of 75, fluctuating fairly widely down to 65 to 90, which is acalabrutinib related. When we’ve held acalabrutinib for procedures, we see that it goes back up over 100. And that you can also see with ibrutinib. A subset of patients, maybe as many as a third, will have a significant decrease in their platelet count. DR LOVE: That’s fascinating. Just out of curiosity, did this man have that headache you were talking about? DR BROWN: No, this man didn’t, actually. DR LOVE: Interesting. Case: A 49-year-old man with CLL with unmutated IGHV and del(13q) achieves an MRD-negative complete remission on venetoclax and obinutuzumab DR LOVE: We were also talking about the issue of venetoclax and rituximab, but I see you have a 49-year-old man who got venetoclax/obinutuzumab. You were talking about that combination. What happened with him? DR BROWN: Right. He’s doing great. He’s a very complicated and difficult case with unmutated disease with 13q deletion initially. Got about 4 years out of FCR, was enrolled on our Phase I trial with BR and ibrutinib and got about 4 and a half years out of that. Progressed with a cystine mutation in BTK. But his progression was not that aggressive. We tried enrolling him on a trial with idelalisib and an investigational HDAC inhibitor called ricolinostat, but he actually had some of that severe autoimmune hepatotoxicity early on, likely related to his very young age as well as his unmutated IGVH. And so he wasn’t able to stay on that. We then tried another trial with CC-122, which is a novel lenalidomide-like drug, and obinutuzumab. He didn’t have enough response to that, and he was already on obinutuzumab. And so then I introduced venetoclax and continued with the obinutuzumab. And his nodes, which had been in the 6-, 7-cm range, were completely resolved within 2 months of that combination. And his bone marrow, which was completely packed, 90-plus percent, was down to about 10%. And I think the interesting question with him now is what to do with him. He’s very young, 45. I didn’t mention, but he also showed evidence of acquisition of a TP53 mutation as well as this BTK cystine mutation. And now he’s going to achieve, likely, an MRD-negative complete remission on venetoclax/obinutuzumab. So do we just observe him on that regimen when we have nothing else known that we can give him after that? I think that probably he should strongly consider an allogeneic stem cell transplantation as potentially a curative therapy, given his high-risk disease. DR LOVE: Yes, I was asking John Gribben — because he wrote one of those “How I treat” papers on using allo in CLL — and I said, “Nowadays, how are you approaching it?” He said, “I start thinking about it when I know there’s no option beyond that.” Is that where this patient is right now? Is that your approach to allo? DR BROWN: I would say so. I do start thinking about it in people who progress on active ibrutinib therapy who are young enough to be candidates. CAR T or allo, I start thinking about it. The issue is, we do have venetoclax. As I mentioned, responses are not as good or as deep after ibrutinib progression. And then we don’t know what we have after that, because we don’t have data with the PI3 kinase inhibitors in this setting. And so I start the conversation then, so we can think about timing and think about risk/benefit and monitoring. Patients who do achieve, say, an MRD-negative complete remission on venetoclax, though, it may be safe to monitor them closely and then proceed at first early relapse. But patients will only achieve partial response on venetoclax. The data suggest they progress — that, unlike ibrutinib, unlike kinase inhibitors, partial responses are not so stable on venetoclax. And so one needs to be aware of that to potentially move to the next option. Approach to TLS prevention for patients receiving venetoclax DR LOVE: Just finishing out with this case, when you started the venetoclax, what was his situation in terms of white count and lymph node size, and how did you approach TLS prevention in him? DR BROWN: Right. So because he’d actually started the obinutuzumab as part of the prior clinical trial, it cleared all his circulating disease. So his white count was actually normal. It had been 200,000 prior to starting the IMiD with the obinutuzumab. And so that cleared that out. And his lymph nodes were — I mentioned the largest was maybe 6 centimeters, but he had a very excellent renal function and very young. He really didn’t want to be admitted to the hospital. So I did manage him — actually, I believe the first time I did admit him, but mostly I managed him as an outpatient with aggressive hydration. And I did bring him back a couple of extra times in the first week because his potassium tended to run on the higher side. DR LOVE: Do you ever use rasburicase preemptively when you’re starting venetoclax? DR BROWN: So only if someone’s uric acid is still on the upper limit of normal after allopurinol and they have high-risk disease. If their uric acid goes down to 3 or 4, I usually won’t. You can always give it if you see an elevation of the uric acid, and it works pretty instantaneously. So that’s the one thing I don’t do as aggressively, perhaps, as the package insert. But if you do have someone with an elevated creatinine, with high-risk disease, depending on how severe their disease is — and especially if they are borderline renal function, and you can’t get the uric acid below the upper limit of normal or so, down into the low/normal range — then I would consider it. Case: A 90-year-old man presents with loss of vision and is diagnosed with CLL with unmutated IGHV and del(11q) DR LOVE: So let’s finish out with your 90-year-old man. Wow, this is really an interesting case. DR BROWN: Yes, I thought you’d like this one. So this patient I met when he had presented outside with decreased visual acuity and was thought to have optic nerve infiltration. And he was noted to have an elevated white count with circulating CLL. And they had done an MRI, which did not show any abnormalities. And a flow on his peripheral blood, again, was consistent with CLL. The lumbar puncture showed elevated protein and on 2 separate occasions showed a significant enrichment for lymphocytes with a CLL phenotype with very minimal blood contamination. Now, I have to say, I’m usually quite a strong skeptic of LPs that show CLL, because there’s almost always blood contamination, and it’s almost always the case that you’ll get CLL cells from the peripheral blood contaminating the LP. But with this patient, the blood contamination was pretty minimal. The severity of his symptoms was quite high. And then we also worked him up otherwise, and we found that he had an aggressive phenotype CLL, unmutated IGVH, 11q and complex karyotype. In fact, on PET scan he even had some lymph nodes with SUVs in the 6 to 7 range, which is a little bit high for newly diagnosed CLL. So also, in addition to being very careful to rule out an infection causing the lumbar puncture findings, you also have to make sure they haven’t transformed. Certainly anyone with parenchymal disease on MRI needs a biopsy of that to rule out transformation. But in this case, he didn’t have parenchymal MRI disease and had the elevated SUV on his PET, so we biopsied the abdominal node. But it was consistent just with the CLL, again, consistent with the aggressive CLL phenotype. So we’ve been using ibrutinib for our handful of cases in which we’re convinced that CLL is involving the CNS, and we’ve had quite good luck with that. Ibrutinib does have excellent CSF penetration, although at the 420 dose it’s a little bit low, and so we usually use the 560-mg lymphoma dose, even for people with CLL. And then you get solid CSF levels. DR LOVE: Is ibrutinib being used right now in primary CNS lymphoma? DR BROWN: Yes, that’s actually part of how the fungal infection issue was identified. The study at NCI initiated single-agent ibrutinib and had multiagent chemotherapy and steroids, and they had a very high rate of fungal infections. And so it does have excellent activity in that setting. And they actually dose escalated significantly more in that study. DR LOVE: And what’s this man’s current situation? DR BROWN: Oh, he’s doing very well. He actually has tolerated his ibrutinib very well. He was in excellent physical condition for his age when he started, but he has not really had any significant side effects. He was feeling generally unwell, in addition to his optic nerve symptoms, and the general unwellness has gone away in his case. So he definitely feels better. And his visual symptoms have completely resolved. His visual acuity is back to normal. We did, I should say, when we were working him up, we had given him 5 days of high-dose steroids and low-dose radiation, and then we started the ibrutinib when we finished the workup. DR LOVE: I was going to ask you, at age 90, how he tolerated the methylprednisolone. And also, by the time you started the ibrutinib — and he’d already had this radiation that you were giving to his eyes. Did you see any change in him or any tolerability problems with the steroids? DR BROWN: He actually did fine. He had some minor elevation in his glucose, but it wasn’t a big problem. DR BROWN: We saw some minor antitumor effects. He had some mild improvement in his vision. But we started the ibrutinib pretty quickly after the 5 days of steroids and the radiation — probably a week to 10 days — so the radiation was probably still having some effect. But there’s clearly been ongoing resolution over the first couple of months, I think associated with the ibrutinib. We repeated his LP again recently, and that’s completely cleared. It’s normal now. DR LOVE: Hmm. Interesting. Emerging data with checkpoint inhibitors for Richter’s transformation DR LOVE: Anything new in terms of Richter’s transformation? DR BROWN: Richter’s transformation remains the biggest problem in CLL. There are some new things. So there’s a little bit of activity of both ibrutinib and venetoclax as single agents in Richter’s transformation. You can even get complete remissions, but they tend not to be very durable. I think the most exciting thing is that there appears to be activity of checkpoint blockade. Pembrolizumab, in a Mayo study, has been published to have a 40%, 50% response rate, particularly in Richter’s developing on ibrutinib. And then the MD Anderson is doing a study combining ibrutinib to treat the CLL with nivolumab to treat the Richter’s, and they’ve reported some excellent responses in that setting as well. How durable these responses will be we don’t know yet. And it is pretty clear that the CLL doesn’t seem to be controlled by the checkpoint blockade. And so, hence, the combination with ibrutinib in the case of the MD Anderson. DR LOVE: Have you or would you use a checkpoint inhibitor outside a trial setting for Richter’s? DR BROWN: I have, yes, and I would. Because we just don’t have a lot of options. I have to say, the main case where I’ve had significant benefit from doing it was a patient with an EBV-positive Richter’s, which I think is consistent with what we might expect for viral-type cancer potentially responding to checkpoint blockade. And so that’s where I’ve gotten the most mileage out of it. But we typically have so little for these patients that I have used it outside of a trial. DR LOVE: What about chemotherapy or chemoimmunotherapy with a checkpoint inhibitor for Richter’s transformation? Is that being looked at? DR BROWN: That’s interesting. I am not aware whether that’s being looked at currently. We’re actually doing a trial of venetoclax with R-EPOCH ourselves for Richter’s transformation. DR LOVE: Wow, that’s interesting. No, I’m just reflecting on all the checkpoint plus chemo trials and data — your lung cancer, everybody’s getting it, small cell, squamous, et cetera. So I don’t know if there’s really a synergy there and whether it would even apply in CLL. But I’ve had a hard time understanding the biology of what Richter’s transformation is. What’s your view? DR BROWN: That’s an interesting problem. I think it is a unique kind of diffuse large B-cell lymphoma. It’s not exactly GCB or ABC. It has some of its own genetic features. It certainly has marked genetic instability compared to CLL, typically with TP53 mutation, often with MYC, often with NOTCH1 and often with 9p deletion, CDKN2A deletion. It remains a very big problem, and that’s something we’re trying to study in the context of our trial. We’re getting biopsies pre and post the venetoclax and trying to better understand the biology. But it’s hard to get enough samples from enough patients to really understand it. Efficacy of chimeric antigen receptor (CAR) T-cell therapy for CLL DR LOVE: CAR T in CLL, you referred to that before. Have you had your patients go for CAR-T therapy, and where are we with that? DR BROWN: Right. So I think we’re about to see a big explosion in that, as many of the companies that have moved first in ALL and diffuse large B-cell lymphoma are now starting trials up more broadly in CLL. And so we’ll be doing a couple of those later this year or next year. We continue to see data from NIH, from Penn and from Hutch suggesting that you can get excellent responses in CLL. Complete response rates have tended to be lower than other diseases, although it appears that the combination with ibrutinib may be helpful. And one speculates that this is because ibrutinib restores the T-cell function and that allows the CAR T cells to potentially work better. DR LOVE: Ibrutinib plus CAR T? DR BROWN: Either ibrutinib beforehand, leading in, which normalizes the T cell, but also in combination. And I think we may get some updates on some of those ongoing studies. Both UPenn and Hutch both have studies combining ibrutinib with CAR T cells. We may get those updates at ASH. DR LOVE: Some of the first patients with CAR T were CLL patients. And then, kind of, like, I wasn’t hearing very much about it. And I kind of wondered whether the prognosis of CLL becoming so much better that that pulled attention away from CAR T, because people weren’t dying of CLL. Is that a crazy thought or a reality? DR BROWN: That was one of the reasons. The other reason was that after the initial successes and the big splash, the CR rate was lower in CLL. It was actually — the response rate at Penn in their larger expanded trial was only about 40%, and the CR rate was only about 20%, and no one really could figure out why. One imagines it’s due to the T-cell defects associated with the disease. But between that, then the risk of giving the CAR T cells and the fact that we have all these new oral agents that were coming to the fore, that’s what’s pushed it to the back burner. I think it’s now clear that the 17p-deleted patients, the complex karyotype patients, they still have high-risk disease even in the era of these novel agents. And those are the patients that the trials now coming along are focusing on, as well as those who progressed on ibrutinib. DR LOVE: You were telling me you see maybe 100 new patients with CLL a year. I’m kind of curious how many patients a year in your practice die of CLL as opposed to other causes. DR BROWN: Right. So no one really dies of their CLL anymore. I would say only a handful of people, maybe 5. DR LOVE: Now, are you including Richter’s transformation? DR BROWN: No, so I was going to say, what they die of is Richter’s transformation, they die of infection, primarily. But disease burden tends not to be the reason that they die anymore, which is somewhat in contrast to what we were seeing before the novel agents. |