Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the current and future management of chronic lymphocytic leukemia with Dr Peter Hillmen from the Leeds Teaching Hospitals in Leeds, United Kingdom.

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

If you’re into audio programs, check out our Oncology Today podcast series, including a recent program with Dr Hillmen on recent advances in CLL. We do webinars all the time now. Actually, this coming Saturday, we’re doing a webinar and a live meeting. We’ll be out in Phoenix in the Society of Gynecologic Oncology meeting doing a program on ovarian cancer this Saturday afternoon. Check it out online. Next Wednesday, we’ll be working with Dr Goldberg from Yale on immunotherapy of lung cancer. Back talking about CLL on the 31^st with Dr Kerry Rogers. And then, we’ll start a series on myelodysplastic syndromes on April 5^th with Dr Komrokji. We’ll conclude our lymphoma series with Dr Evens on April 6^th. And then, we’re heading out at the end of April to do our annual Oncology Nursing Society Congress visit. Let your nurses know. We’re up to, I think, we’re doing 10 symposia at this point over 3 days. Everything will be online. So for your nurses and for you all, the theme is What I Tell My Patients, something we can all benefit by.

But today, we’re here to talk about CLL. And as always, we have a bunch of great cases that are going to be presented by some docs today for Dr Hillmen.

Here’s where we’re heading. We’re going to start out talking about the cases. Then, we’ll go through some of the papers Dr Hillmen has done, including some recent presentations at ASH. Then, we’ll show you some of the faculty survey. And the last module, we have a whole bunch of slides, as always, for reference for you to refer to.

Case: A man in his early 60s with chronic lymphocytic leukemia (CLL) and Richter’s transformation to Hodgkin lymphoma — Amanda Blackmon, DO, MS

DR LOVE: But I actually want to start out with our first case which, as you can see, is a patient with Richter’s transformation. But before we get to the case, just to introduce this paper, Peter, that you did reviewing the whole issue. We actually did a symposium earlier this week with Sonali Smith and we had a case there of transformed FL. So today, we’ve got a patient who has transformed CLL. Can you talk a little bit about some of the issues you got into with the paper, particularly sort of the biologic understanding about what’s going on with these patients?

PROF HILLMEN: Yeah. Hi, Neil. Great to be with you again. It’s a pleasure, as always. Yeah. I think as we have more effective therapies for CLL, the patients who are doing badly are those ones who have the disease that transforms. And Richter’s transformation becomes sort of an important thing to be able to identify. And so what we tried to do in the guideline paper was to give it a framework for how we diagnose and who we should be suspicious of. So, for example, patients clearly who have a sort of single area of disease that’s out of keeping with the rest of the disease or if they have a high LDH, high calcium, we certainly start being suspicious of Richter’s in those patients. I think, we use PET scans, obviously, in those individuals because it’s reasonably sensitive although we have to get a biopsy because not all Richter’s is the same. We have about 80% of patients, well 90% are probably large cell lymphoma Richter’s transformed disease and of those, 80% are clonally related to CLL and have a very different outcome to those that are EBV-driven which are not clonally related. So we talked about that in the guidelines.

DR LOVE: So in a minute, I’m going to show an algorithm in those guidelines that I think is very helpful. But first, let’s bring in this case. As always, in the real-world, it’s never as simple as you would think it is. This is a 60-year-old patient of Dr Amanda Blackmon.

DR BLACKMON: This is a 60-year-old male who had CLL that never required treatment, and then developed diffuse nodal disease. He had a biopsy showing Richter’s transformation into Hodgkin’s lymphoma. He’s receiving ABVD. He just received his third cycle of treatment and his EF decreased from low 50’s down to 41%. He had a stress test and it showed some ischemic changes. Currently he’s going to undergo a catheterization and they stopped his anthracycline.

So what is the standard approach for these patients who have a Richter’s transformation into Hodgkin’s lymphoma? Should this patient be transplanted in CR1? Given his drop in his EF and new cardiac disease, it may be difficult. How is transformation confirmed? Should their transformed lymphoma be sequenced to confirm transformation?

DR LOVE: So any thoughts? We’ll get into your algorithm, but how about this particular case, particularly the complications of the drop in ejection fraction?

PROF HILLMEN: First of all, Hodgkin’s transformation and Hodgkin’s Richter’s is relatively uncommon. Richter’s is relatively uncommon generally in CLL, probably about 5% of patients will have Richter’s at some point in their disease course. And of those Richter’s, probably 10% are Hodgkin’s disease. With a patient such as this patient, Dr Blackmon’s patient, the question is, is it really related to the disease? Because this patient is previously untreated, relatively unusual for Richter’s although it can happen. Is it actually a completely different malignancy that just happens to occur in a CLL patient? So it probably doesn’t matter in terms of the Hodgkin’s transformation because we would, like she did, give these patients ABVD. The outcomes from Hodgkin’s in Richter’s are difficult because it’s so few patients, but they seem to be similar, in my experience, are similar to Hodgkin’s disease generally. So we see good outcomes in patients, but obviously, many of them are more than Stage I or Stage II, so they have issues.

I would agree with what she did with the patient, so dropping the anthracycline and starting with a particularly severe or affected LV function. I would not transplant them in first remission. I think there’s a risk, particularly with a cardiac history. And there’s a reasonable chance that the patient will be cured of their Hodgkin’s transformation and so that probably may not cause a problem. And so I’d reserve that for relapse and after platinum containing regimen.

And then the final question about biopsy, I think we should always biopsy Richter’s to confirm the transformation. And in fact, this case shows you exactly why we have to because using a PET scan, you may think there was a large cell lymphoma and be treating the patient with CHOP-R or in a Richter’s trial, but it shows that you can’t differentiate without a biopsy, the Hodgkin’s transformations from the Richter’s transformations, the large cell lymphoma transformations.

DR LOVE: She actually also asked about sequencing these patients. And we also have a question in the chat room. What do you do if the patient has double or triple hit lymphoma?

PROF HILLMEN: Yeah. So sequencing in terms of seeing if it’s clonally related to the cell, we don’t do that as a routine. EBV markers will often predict the nonclonally related patients because it tends to be an EBV-driven phenomenon. And so we don’t in routine sequence them. And I think Richter’s is bad lymphoma, so even if it was double or triple hit, a Richter’s transformation, the outcome is poor. And so I would not treat a clonally related Richter’s transformation in the same way as large cell lymphoma. I would take the patient, if they were transplantable, to transplant in first remission. Now many patients aren’t transplantable. We have trials of BTK inhibitors plus chemotherapy ongoing at the moment in de novo Richter’s — well Richter’s in CLL. And so we would certainly consider that because the outcome for clonally related Richter’s transformation, the outcome is really poor, 10% long-term survival. So I think moving to transplant is currently what we would aim to do.

DR LOVE: This is the algorithm in the paper. And first, it breaks it out whether or not it’s a newly diagnosed or in the relapsed setting, different algorithm. Without going through all the specifics, can you kind of globally talk about how you approach it and how it differs in those 2 scenarios?

PROF HILLMEN: I think this is a fair sort of representation of what we do. So we don’t have any evidence outside of clinical trials that shows anything is better than CHOP-R in Richter’s. CHOP-R is not adequate, but more intense therapies have not been shown to be effective. And often, as I said, the patients are elderly, may have had previous chemotherapy if they’ve had CLL for a while although nowadays, we’re using less chemotherapy, of course. And so I think I would definitely favor getting to CHOP-R or if people are failing a platinum containing regimen, moving to a more definitive treatment. So CAR Ts, I think, are sensible, but the issue is whether you can get the T-cells from patients. Allotransplant, certainly that’s what we’ve done in the past, but I think CAR Ts are probably, in the US where it’s more available, would be a much more sensible approach.

DR LOVE: So question from the chat room from Uzoma, would you treat a patient with CLL and severe persistent neutropenia, ANC 0 without recurrent infections, no other disease related symptoms, is AIHA an indication for treatment?

PROF HILLMEN: So 2 questions. Neutropenia and hemolytic anemia. So neutropenia really is relatively rare in CLL and usually is G-CSF responsive to be fair. So if the patient has not had infections and is asymptomatic, the answer is no, I wouldn’t treat the patient for their CLL. We see this is non-CLL patients and in our TLGL patients, that the patients can have low neutrophils and not have infection. So I would not treat them. There’s no evidence we should.

And autoimmune hemolysis can be an indication for treatment if it’s refractory to, well I would use steroids and probably cyclosporine before I got to treating the CLL. If the patient was not responding to those 2 or was either dependent on steroids or not responsive to cyclosporine, I would be thinking about treating their CLL. And then to answer, I was going to say the targeted therapies appear to be safe in that context. And both BTK inhibition and ven plus obinutuzumab can be effective while trying to control the hemolysis first.

DR LOVE: Interesting. Another question from the chat room back to transformation. Do you ever use CNS prophylaxis?

PROF HILLMEN: We have used it in the past. There’s little evidence that it is of any use. Obviously, these patients have bone marrow disease, so they are at high-risk potentially for CNS disease. I’ve seen a number of patients with CNS CLL over the years, either transformed or not transformed, and they can respond to CNS-directed therapy. But generally, we haven’t used CNS prophylaxis. I think if a patient had large cell lymphoma in the marrow, it might be different. So I’d probably follow the same criteria we’d use for primary diffuse large B-cell lymphoma, but ignore the CLL in the marrow for staging.

DR LOVE: Anybody who is very clear in their mind how to approach CNS prophylaxis in diffuse large B-cell, please give me a call. We were talking about that on Tuesday. Of course, that’s another area of controversy.

Case: A man in his mid 70s with relapsed CLL after 3 years of second-line ibrutinib — Jeanne Palmer, MD

DR LOVE: Okay. Let’s get back to our cases. This is a patient from Dr Palmer, a 76-year-old man who started out with fludarabine-based regimen, then got ibrutinib and now is on for a third line therapy. Here’s Dr Palmer.

DR PALMER: This is a 76-year-old gentleman. When I met him, he actually had a fairly prolonged history of CLL. He was initially diagnosed in 2009. He was treated with fludarabine and rituximab. His treatment was complicated by PCP pneumonia. So he got quite ill from it. He achieved a nice response though after treatment and didn’t require therapy again until 2015. In 2015, he had progression of his white blood cells up to 67,000 as well as an anemia of 9.7. He was initiated on ibrutinib monotherapy and tolerated it extremely well. Then, he started to experience progression of disease. His white blood cell count was increasing, he had rapidly growing lymph nodes. He had a PET CT that showed lymph nodes with an SUV of 18 in one of the lymph nodes. We biopsied that lymph node to rule out Richter’s transformation. Bone marrow biopsy was 100% cellular, 80% lymphocytes. The patient was initiated on venetoclax and obinutuzumab.

What is the response rate of venetoclax in patients who are pretreated with ibrutinib? Now we have these great therapies. Are we selecting out patients who are going to have a more aggressive course?

DR LOVE: And I’ll add onto that, how do you approach, because it’s so interesting to ask people how they approach, second line therapy with venetoclax in terms of choice of anti-CD20, obin versus rituximab, duration of therapy, you know, MURANO versus CLL14?

PROF HILLMEN: Yeah. So obviously, this is a key patient really. This is a 76-year-old man so that limits to some extent some of the therapies that he may be able to tolerate going forward, transplant, for example. In a patient like him, we would, and this is more of academic interest, would look for BTK mutations to see if we have a defined BTK mutation. It doesn’t actually alter the outcome because he’s clearly progressed through ibrutinib. We would certainly treat with, well we would use venetoclax/rituximab based on, because of the trial data. I think personally, obinutuzumab is clearly a better antibody in CLL. We just don’t have any relapsed data, or much relapsed data with ven/O. But if I was allowed to use obinutuzumab, I’d use obinutuzumab in this patient. I’d use 2 years of venetoclax if I was using obinutuzumab because that’s the data we have in relapsed disease. Most patients will respond. We don’t have any comparative data compared to the patients who are really upfront, but they’re relatively comparative. But the median progression free survival for these patients treated with venetoclax, it’s certainly beyond 2 years. So we would expect a reasonable remission for these patients.

The anxiety, of course, is the patient is now running out of options and we wouldn’t think to go back to chemo, obviously. I would say that actually, if he’s in remission now, we have coming down the track the reversible BTK inhibitors. So pirtobrutinib being the one that’s leading. And if he has a BTK mutation, or even if he doesn’t have a BTK mutation, I’m referencing to ibrutinib, there’s a reasonable chance he will respond to both pirtobrutinib or LOXO-305. And we’ve seen some remarkable responses. So I think keeping him alive and in remission with a ven approach allows the reintroduction of a BTK inhibitor later on. Now the only other thing I’d say is what if that were to happened now and we thought pirtobrutinib was available? Well I would possibly try zanubrutinib. I think there’s no data in that setting yet. But for biological reasons, I would think of that as being, if I had availability, I would try that. But we don’t have any good evidence, well any evidence really for switching from ibrutinib to zanu for progressive disease.

DR LOVE: Yeah. I want to ask you about that later if we get to it, some of the zanu stuff you presented at ASH. But let’s get back to venetoclax. I want to show you a comment or question really or comment that was brought up by a doc in practice. Dr Lorber was presenting to me a younger patient. He brought up an interesting question about the issue of ven/obinutuzumab. I’m not sure exactly how the approval is in the UK. But technically, it’s for older patients or frail patients. I think most of the time, people are able to access it anyhow. But it kind of, his question really gets into the issue of even why these trials are done this way. Anyhow. Here’s his question.

DR LORBER: An issue I run into quite a bit is patients who are well-educated or read up on CLL who are very interested or requesting venetoclax/obinutuzumab regimen even if they don’t really qualify for the label. They’re not elderly, they’re not frail, but they’re interested in the short-term therapy rather than chemotherapy or indefinite BTK therapy. The data is still pretty good even though you don’t need to be frail to have good data. And how I approach that is kind of an issue that keeps coming up. I have a lot of highly functional 60-year-olds who also don’t want to be burdened. They’re working, they may be executives or are very active and they don’t want indefinite therapy. And they view, and I sort of agree with them, that shorter term therapy might be better.

DR LOVE: So your perspective on this, Peter, and also, your experience with patients in terms of this issue about preferring shorter term therapy and whether you see that more in younger people.

PROF HILLMEN: Yeah. First of all, we have access to venetoclax/obinutuzumab for all of our CLL patients, including the younger patients. The data from the CLL14 German trial was obviously in elder patients unfit for FCR, but we have data now from the CLL13 trial showing good MRD responses with ven/O in younger patients. So there’s no biological reason why a younger patient would behave differently to older patients in terms of response to ven/O.

The issues we have, first of all, how do we select therapy? So we have a choice of a BTK inhibitor or ven/O in the frontline which is what Dr Lorber was really alluding to. I think patient choice is important. And so does the patient want a relatively simple therapy, twice a day, tablets probably, that’s taken continuously, but doesn’t mean then coming to the hospital or are they prepared to go through the infusions and the tumor lysis monitoring of ven/O? COVID has an impact on that because we’ve obviously had an issue with COVID and I guess we’ll talk about that possibly later on.

The biology of the disease has an impact. So if a patient says to me, well, Pete, what would you recommend for me? An IGHV mutated patient regardless of age will have a good outcome from ven — is likely to have a good outcome from venetoclax/obinutuzumab, better than FCR for a younger patient and certainly better than chemo. So in those patients, we can expect a 12-month duration of therapy and 80% to be progression free at 5 years. So I think if they’re mutated, that’s a sensible approach for those patients. For the 17p patients, they don’t do as well with a 12-month period of therapy. They start relapsing during therapy and many of them relapse within a year or 2 of treatment. And I would favor a BTKi in those patients. And for the IGHV unmutated who aren’t 17p, I think the jury it out. If I’m pushed, I would say a BTK inhibitor. But I think it’s also reasonable to give 12 months of ven/O because we know at 5 years, about half of them have progressed. So many patients will have an average of 4 years off therapy and then we probably can retreat them with venetoclax again. And so I think there’s, in those patients, a discussion.

Specifically about the age, I agree. We’re exposing patients to long-term BTK inhibition if we’re treating them at a younger age, obviously, for longer. I think the less of a concern to me would be next generation BTK inhibitors where we don’t have the same safety signals although we have to be honest and say we don’t know what the impact of BTK inhibition at 10, 15, 20 years’ time is. And so I would favor ven/O in patients who have a strong preference for that.

Case: A man in his early 50s with newly diagnosed IGHV-unmutated CLL — Del(17p), TP53 mutation — Alexey V Danilov, MD, PhD

DR LOVE: So you mentioned high-risk del(17p) and Dr Danilov has a patient, a 52-year-old man, unmutated disease. Here’s the case.

DR DANILOV: We have a younger 52-year-old gentleman who has no medical history, so completely healthy. He has noticed fatigue, progressive lymphadenopathy over the past 6 months, no weight loss, mild anemia and mild thrombocytopenia and mild elevation in white cell count. The white cell count also notes lymphocytosis, but the physician palpates neck nodes. And so a CT is done which demonstrates diffuse lymphadenopathy and an abdominal mass of 11 cm. So a lymph node biopsy is pursued and essentially, diagnoses CLL/small lymphocytic lymphoma. FISH reveals presence of del(17p) and unmutated IGVH. Next generation sequencing panel also reveals a TP53 mutation.

So the first question is, would anybody in the group use chemoimmunotherapy such as fludarabine, cyclophosphamide, rituximab for this younger patient with CLL? I would be curious to know what faculty would use in this particular setting.

DR LOVE: So you mentioned your sort of general preference for BTK in this situation. What do you think about this particular case?

PROF HILLMEN: Yeah. Hi, Alexey. Nice to see you. So first of all, I wouldn’t use chemoimmunotherapy in 17p. We haven’t used chemoimmunotherapy in 17p deleted disease for at least the last probably 10 years. I wouldn’t use it actually in anybody with CLL now. And we can argue — we can discuss that. But I’ve yet to meet a patient who wants chemotherapy over a targeted treatment. My preference for this patient, he’s got very classic poor-risk disease, 17p deleted, he’s a young, fit patient. But some of these patients will do very well with prolonged BTK inhibitor use. So outside of clinical trials, I would be using acalabrutinib probably as my first therapy. We have salvage options. Obviously, ven/R which at that point, if it became necessary, we would then be thinking CAR T, transplant. In the first setting, it’s likely he’ll have a prolonged remission and response to a BTK inhibitor. I should say that we’ll present some data at EHA from the FLAIR study and there’s been other data from CAPTIVATE of the combination of BTKi and BCL2 inhibitors. We saw that with zanu as well where we’re seeing deep remissions even in 17p deleted patients. And so I suspect going forward, we’ll be looking at combinations to eradicate disease.

DR LOVE: Yeah. And we definitely are going to talk about that with some of the other videos, so I’m just going to hold off on asking you more about that.

PROF HILLMEN: Yeah.

DR LOVE: Here’s the follow-up on what happened with the patient.

DR DANILOV: The patient actually chose to proceed with Bruton tyrosine kinase inhibitor treatment. He was very busy, didn’t want to come for infusions, didn’t want to travel, so he chose to just take acalabrutinib. And he achieved complete response when we restaged him which was actually about a year after starting treatment and remains in complete response today.

DR LOVE: No tolerability issues? No headache?

DR DANILOV: He has headache occasionally as a concern, but practicing on the West Coast, everybody sees me and has a cup of coffee in their hand. And as you know, I think that coffee is a great mitigator of headache. Also in patients where it does happen, it tends to get better over time. So it’s mostly a concern in the first couple of months and then it goes away just like many other side effects.

DR LOVE: So I’m curious what you think about the case. And also, before we started, you were talking about some pharmacologic differences between the 3 BTK inhibitors, at least that we’re talking about nowadays, which I found really interesting. So can you comment on the case and also, how you see the mechanism of action of these 3 agents?

PROF HILLMEN: Yeah. First of all, the case. I think that’s what I would have predicted would happen. The patient, I don’t know how long ago he’s been on treatment for now. It could be relatively recently because it was a year when he was analyzed and acala has only been available for a relatively short period of time, so 2 or 3 years maybe. The outcome for patients even with 17p is still 80% of patients, 70, 80% are still progression free after 3 or 4 years and so hopefully, his response will continue. Whether I would actually do the bone marrow, it would be fairly unusual to see a clear bone marrow at a year of acala in my experience although it can happen. So I think that’s predictable.

In terms of the BTK inhibitors, the ones that are available now, obviously, are the irreversible BTK inhibitors. And so they function mostly by irreversibly binding to the cysteine in BTK. And actually, if you look at ibrutinib, most of the time during the day, obviously, it’s given once a day, the free drug is below the IC50 for BTK. So it’s not inhibitory, but because it irreversibly binds to the tumor BTK, it obviously works for longer than the half-life of the drug. If you look at acalabrutinib which we have available in the UK as well, it’s similar. It was twice daily but, again, the PK is above the IC50 of BTK for a few hours after each dose and some of the time, it’s below the level. Now the data that I alluded to before with pirtobrutinib, reversible inhibitor, it works in a very different way. So it doesn’t bind to the BTK, but it relies on there being levels above the IC50 all the time so that the BTK pocket is continually occupied by the BTK inhibitor.

So as soon as pirtobrutinib falls out, another one goes in and so it’s constantly blocked like a reversible inhibitor. What’s interesting about zanu is that zanubrutinib, the PK is different to acala and actually, the level of zanu through is above the IC50 of BTK. So I wonder, and this is very hypothetical, whether there’s a reversible component to zanu. Now the head-to-head trial we have, the ALPINE study, which we presented, and I presented, data at our peer meeting last summer showed an early follow-up that the pyruvate was better with zanu than ibrutinib in a refractory group of patients. But what I must emphasize is that’s 15 months of follow-up, so it’s really not long enough yet to be confident that this is robust. We’re going to see that data published. It’s being submitted. We’re going to see a longer follow-up. And it’ll be really interesting to see how the ALPINE data matures over time and whether the difference between zanubrutinib and ibrutinib is maintained.

DR LOVE: Any suggestion in any other trials of a greater benefit with zanu over other BTK inhibitors?

PROF HILLMEN: There’s certainly a Waldenström study which is a head-to-head smaller study.

DR LOVE: Right.

PROF HILLMEN: But the only head-to-head trial we have in CLL for zanubrutinib is the ALPINE study. We have the ELEVATE-RR trial for acalabrutinib which shows similar efficacy, but less toxicity for acalabrutinib.

Case: A woman in her early 50s who presents with persistent lymphocytosis — Rajalaxmi McKenna, MD

DR LOVE: So I want to present another case to you. This is from Dr Raji McKenna. Dr McKenna has been online with us since we started doing these things 2 years ago. She’s always putting questions in the chat room that I don’t even understand. She functions at a level above my head. She was in academic medicine, now she’s in clinical practice. Anyhow. She’s got a 53-year-old woman with a very interesting question. I kind of showed you all the data in the case. I didn’t want to go through all of it. But here’s Dr McKenna.

DR MCKENNA: It’s a 53-year-old Caucasian lady who was referred for persistent lymphocytosis. Her father has CLL. She had fatigue and a miniscule cervical node, persistent lymphocytosis with absolute lymphocyte counts between 4500 to 7900 over the past 3 months, with a mild macrocytosis and monocytosis. It’s been my experience that in patients with CLL, it’s not uncommon to see a monocytosis. I’ve never figured out why.

The million dollar question I have here, does she have a monoclonal B-cell lymphocytosis, or does she have CLL?

DR LOVE: And so I’ll also say, apparently, she’s in the chat room again tonight and is putting some new information she has on the patient from the blood somatic NGS. I don’t even know if you want to hear about that. But maybe you can first start out and just kind of your reaction to the case and her question.

PROF HILLMEN: I think this is really an important patient case actually. I can tell you a little anecdote. We, myself and Andy Rawstron, decided to look for MBL in normal individuals in 1999. I can remember exactly the point. It was BCL and we looked for this for CLL in normal individuals. And we found that 6% of 60-year-olds have a clear clone of CLL even with a normal gluc count. And so we had to —

DR LOVE: Wow.

PROF HILLMEN: Yeah. And as you get older, it gets higher. So in the 80’s, it’s up to 20% of individuals we can find CLL.

DR LOVE: Wow.

PROF HILLMEN: And so the question then is, well we can’t — these individuals, I’m not going to say patients, they’re not patients, these individuals will not go on to develop CLL. The vast majority will just have a sort of preleukemic state. And so we had to define an entity and that’s where monoclonal B lymphocytosis came from. I remember the discussion around the Blood editorial of what we would call it. And so we arbitrarily cut off 5 times 103 of, so 5000, clonal CLL cells. And your patient probably has less than that looking at the level because the majority of cells may not be CLL. So they’d be right on the borderline of 5 times 103 clonal B-cells. What we find is that patients with lower clonal cells are less likely to go on to aggressive disease. These patients are largely good-risk CLL, so they have IGHV mutated disease which I think Neil told me you put in the chat was the case. And their outcomes are as good as the general population. That’s even before we had targeted therapy. So I would be trying to reassure the patient. I should also say that we’ve surveyed large numbers of individuals, of patients, in the UK and the key question that comes up more than anything else is watch and wait. 90% of our patients are diagnosed with Stage A CLL, this sort of low level of lymphocytosis and it creates immense stress for patients. It has an impact on their quality of life, we know that, and the fatigue. And then for this lady particularly, because her father’s got CLL, that’s obviously another concern that we see this in families. About 3% of patients with CLL have a first degree relative, bother, sister or parent, with CLL. I have a family at the moment, I’m looking after a gentleman who has got 4 siblings with CLL. And we’ve done a lot of work on this familial CLL issue. So what might be of interest to you is that I mentioned that we see MBL in 6% of 60-year-olds, generally. In first degree relatives of someone with CLL, it’s 15%.

DR LOVE: Wow.

PROF HILLMEN: So we see higher levels of MBL, so clinical MBL, in first degree relatives of patients with CLL. And what Richard Houlston and Danny Catovsky some years ago now showed was that these individuals, the families, have a predisposition to develop CLL. Most individuals will not develop CLL. There are 6 loci which we identified which help predispositions to CLL. And just out of interest, that family I told you had 4 patients, 4 siblings, all with different types of CLL. So my patient had 17p deleted, another one has got MBL, the other one had FCL and is in remission. So they’re not inheriting the same disease. They’re inheriting a predisposition to it. So I would, for your patient, be reassuring them that she’s got at worst Rai 0 or Stage A CLL, at best MBL. Probably doesn’t matter too much which we call it. The likelihood that she’s got IGHV mutated disease, she’s not likely to progress to treatment maybe forever. And if she does, we have very effective therapy, so we should be able to control her disease.

DR LOVE: You were mentioning the anxiety that patients have to not be treated. Any clinical pearls or things that you’ve found that help with that? And also, any comments on the monocytosis that Dr McKenna is referring to?

PROF HILLMEN: Yeah.

DR LOVE: Are these actual monocytes, incidentally?

PROF HILLMEN: Okay. So for the monocytosis, I suspect, we do see that some and I think it’s probably if you use a conventional 5-diff analyzer, it’s leakage of lymphocytes often into the monocyte gate. So I’m not sure it’s a real phenomenon in my experience. Obviously, we haven’t seen it when we’ve done flow cytometry studies. It’s obviously very different to how we saw the chemo where you see monocytopenia in those patients. Absolute, on occasions. So I’m not convinced there’s a real monocytosis in CLL. I’ve not seen evidence of that.

In terms of reassuring patients and about early treatment, I think the first thing to say is that patients coming to see me have usually gone to Dr Google first and have googled CLL and they read the average survival is 5 to 10 years. That’s not true anymore. We know that from the targeted therapy. And I think reassuring patients that first of all, the outcomes are clearly better in CLL now. In Stage A disease, many patients may never need treatment. There’s no evidence that early treatment is beneficial. And we have a wide range of nonchemotherapy approaches that are going to control these patients’ diseases. Some patients will still be anxious about it and I think they just need more reassurance really. There’s no, in terms of the initiation of therapy, it’s an interesting observation that when we only had FCR or chemotherapy, we would delay treating patients and patients didn’t want to be treated if they didn’t want FCR. And then we treated patients and they said I’ve not felt this good for 4 years.

Well the reason is that they’ve had symptoms of their CLL for 4 years, but we don’t want to treat them because of the toxicity. So I think what we’re going to see is those patients will be treated earlier as we get safer and better combinations of targeted treatments. But I wouldn’t change the indication for treatment because as soon as we do that, we start treating patients who may never need treatment. And obviously, the risk/benefit changes in that group. So I think the IGHV mutation is useful in those Stage A patients. If they are mutated, we can reassure them and follow them less frequently. If they’re unmutated, we can watch them more closely and be prepared to treat them as soon as they get symptoms.

Case: A man in his late 50s with CLL who receives FCR and remains in complete remission 5 years later — Dr Blackmon

DR LOVE: So speaking of FCR, I’d like your thoughts about this next case, the classic situation where you hear people bringing up the possibility of chemotherapy, the young patient with mutated disease. Here’s Dr Blackmon again.

DR BLACKMON: This is a 58-year-old who has CLL that’s mutated IgHV. She has a 13q deletion which is favorable. He developed painful nodes, weight loss, and fatigue. He received 6 cycles of FCR and is in a molecular CR. His marrow has a negative flow cytometry and now, 5 years out, remains in CR off treatment.

Is there a role for chemoimmunotherapy in mutated CLL in the younger patient population?

DR LOVE: Did he have any adverse sequela from the FCR?

DR BLACKMON: No. He actually has no side effects and he’s doing well. I’ve seen him in remission but not during his treatment since it was 5 years ago.

How would you treat this patient who presented today, given this was in 2015?

DR LOVE: Any thoughts?

PROF HILLMEN: I think that’s a really important case again, a really important question. So we have a lot of data that shows that it isn’t the treatment you have, it’s the depth of remission you achieve with chemoimmunotherapy and obviously, with targeted treatment as well. So I’ll give you an example. In CLL8 which was an FCR versus FC trial, the outcomes for MRD negative patients were the same if you had FCR or FC. But twice as many patients achieved MRD negativity with FCR than FC. So, therefore, the outcome for the whole group was better. And so it’s sensitivity to treatment and depth of remission that’s important. The reason I make that comment is that we see higher MRD negative remissions, higher rates of MRD negative remissions with ven/O than we do with FCR with much better tolerated disease — treatment, sorry. So we just presented some data from FLAIR and we’ve had previous FCR trials where we treated a lot of patients. 80% of the patients will tolerate 6 cycles of FCR. The MRD negative rate is around 50% across both the trials. And the outcomes of the MRD negative patients are really good.

The MRD positive patients, the ones who relapse early, and you can’t predict them, obviously, before you start the treatment reliably, will have more difficult disease to treat and will have — the delivery of treatment will be more difficult because of the FCR in some of those patients. And 20% of the patients don’t tolerate the FCR and you probably harm them by exposing them to it. The ven/O data we have suggests at least a similar or maybe better progression free survival for the mutated patients than we see with FCR. So I think putting it all together, I, in this patient, would consider venetoclax/obinutuzumab as the most appropriate therapy for a good-risk mutated CLL patient who requires treatment. I think FCR is toxic. And if you’re going to counsel the patient on FCR, you’ve got to counsel that they have a 3% chance of secondary AML MDS which is almost invariably fatal. So we’re going to kill 1 in 33 patients with the therapy. So your patient’s done well, most patients will do well. But if you’re treating the patients, you’ll take the best-risk patients, so these mutated patients generally don’t die of CLL because we’ve got effective therapies and we’re going to kill them with our most intensive treatment. So I’ve yet to meet a patient when given the option of targeted therapy versus FCR who said I want FCR.

DR LOVE: So question in the chat room from Baskara, a patient with uncontrolled hypertension on ibrutinib. Would you consider switching to acala or zanu? Maybe you can comment also on some of the information you presented at ASH on ventricular arrythmias and ibrutinib and hypertension.

PROF HILLMEN: Yeah. And that’s a very important question, I think, as well. So to this data, the FLAIR data, we showed data in frontline with ibrutinib, 370-odd patients randomized to ibrutinib arm for that trial. And we saw a risk of sudden death, a low risk of sudden death. And that’s seen across multiple trials at a very low level, sudden cardiac death. And what we saw in FLAIR was these patients were really those patients who were hypertensive going onto treatment on therapy for hypertension. So they effectively, when we looked at the postmodern studies from those patients, they had a hypertensive cardiomyopathy. So first of all, ibrutinib is safe, in my opinion, if you don’t have a previous history of cardiac disease or hypertension being treated. If you do have that and you only have ibrutinib, you need to do cardiac assessment of the patient.

For patients who are on ibrutinib and stable and not having side effects, I would not switch them to acalabrutinib. I would leave them on ibrutinib and watch them closely. Obviously, you have to monitor their blood pressure and hypertension which can emerge. For your patient who has got cardiac complications or got mucinous side effects on ibrutinib, most of those patients are actually in a good remission because they’ve been on treatment for some time. So my approach to those patients is we need to stop the ibrutinib and watch the patient. And then at some point, and it could be, we know from the ECOG 1912 trial, it could be 2 years before the disease becomes active again. And then, switch them to acalabrutinib at that point rather than just switch them from one therapy to another.

The other advantage that’s had, and this is very unidentical, is we see reduced COVID vaccine responses to patients on BTK inhibitors. Only maybe 30% will respond. I’ve had 1 or 2 patients who have done this break because of side effects to ibrutinib and they’ve had a vaccine response in their holiday off BTK inhibitors. So we just don’t have enough evidence as to how we would use that in the real-world. So I would do exactly like that with this patient. If they’re in a good remission, stop the ibrutinib, watch them until they progress, start acala. If they’ve got slowly active disease, as some patients will start with lymphocytosis, I would switch them over to acala if they’ve got significant cardiac side effects.

Case: A man in his early 70s with relapsed CLL who is concerned about contracting COVID-19 — Dr Danilov

DR LOVE: So we’ve had a number of people in the chat room, and you also, referred to combinations with BTK and venetoclax. Here’s Dr Danilov with some questions about that and your GLOW study.

DR DANILOV: Another question I’d like to ask is whether faculty has used combination of ibrutinib and venetoclax. As you know, CAPTIVATE was one study which demonstrated high efficacy of I+V combination. GLOW study demonstrated superior efficacy of I+V versus chlorambucil-based therapy. So I wonder how many of you actually use it in everyday practice or in some of your patients and what kind of patients you would feel are appropriate for this kind of regimen today? Or are you waiting for approval? And if you have any concerns with ibrutinib because of the side effect profile, have you used venetoclax in combination with acalabrutinib?

PROF HILLMEN: Okay. So —

DR LOVE: So actually before you answer that question, I want to ask the audience a question. So, audience, you have a 60-year-old patient with unmutated disease, no del(17p), no TP53, regulatory issues aside, so assume you could access any of these or others, in general, how would you think through the management of this patient? And, Peter, before you comment on the global question and also some of the specific questions that Dr Danilov said, asked, here is our poll of the faculty here of the same question we just asked the audience. And interestingly, 3 of you, you, Dr O’Brien and Dr Wierda who actually did this program recently, say GLOW. Any thoughts?

PROF HILLMEN: Yeah. So we don’t have access to this outside of trials although we have a number of trials with different BTK inhibitors in combination with venetoclax. So the CAPTIVATE study was relatively young patients. The GLOW study was for elderly patients unfit for FCR. So it was compared to combinations of obinutuzumab. We will present in about 3 months’ time the initial data from the second part of FLAIR which had the 800 patients of which one-third got ibrutinib plus venetoclax. So that was FCR, ibrutinib monotherapy or I + V. What we’re seeing is that the IGHV unmutated patients have a higher MRD negative rate than even the mutated patients with the combination of BTK inhibitor and venetoclax. And that makes sense because the unmutated patients have much stronger signaling through the B-cell receptor. So biologically, you’d expect them to respond better to a BTK.

The GLOW study initiated that there were an elderly group of patients that actually the MRD rate was lower because of tolerability issues. So one of the questions when we’re using relatively intense therapy such as the combination of ven and a BTK inhibitor is can the patients tolerate this combination? And I think we’re going to be, a 60-year-old and a younger patient with unmutated disease is probably the type or even 17p. We have a trial open at the moment which is zanubrutinib plus venetoclax and all patients get it and we’ve putting unmutated patients in that trial and have seen nice responses. So my sort of decision process, if I had, and I am extrapolating the data to some extent from the trials, the Phase II and Phase III trials we have mostly which is in the public domain, is the VH mutated, I would give ven/O, the VH unmutated, I think, and probably 17p, will in the long-term be a BTK plus BCL2. But we need more data to be comfortable that that’s the right approach compared to a BTK only therapy.

And then the other comment that I think 1 or 2 of the faculty said was using acala plus obinutuzumab and that’s a reasonable approach and we see MRD negativity in that group of patients. But I’m not sure we know how to use that combination most efficiently yet.

DR LOVE: Interestingly, the audience is, as typical the case is, is pretty much split between ven/O and BTK. Only 7% of the audience says ven/ibrutinib. Interestingly, one-quarter of the audience says ibrutinib which kind of surprises me. What situations right now do you use ibrutinib alone? One thing to talk about GLOW, but what about ibrutinib alone? Is there a role for that?

PROF HILLMEN: Yeah. We don’t have funding for ibrutinib in frontline, but we do have funding for acalabrutinib in front line.

DR LOVE: Wow.

PROF HILLMEN: So we are sort of forced to use acala in frontline apart from 17p. And so I think the answer to your question is the only patients where we struggle with acalabrutinib are the patients who are on the PPIs, pantoprazole, omeprazole, where there’s a history of interaction. And in those patients, we switch the patients to azatadine, an H2 antagonist. Now the problem there is that these patients may have relatively acute symptoms of their CLL. And we stop the PPI, they get terrible symptoms of heartburn. So you can actually make patients more symptomatic by stopping the PPIs. I think on the horizon, there is a formulation of acalabrutinib which is going to be useable with PPIs. So I think within hopefully months, we’ll have the tablet form of acala available which doesn’t, I believe, have the same interaction.

DR LOVE: So I want to, we mentioned COVID before, and we get a lot of questions about particularly anti-CD20 therapy nowadays, antibodies. So I’m going to go through a couple questions we asked the faculty. First, whether or not COVID has affected their choice of first line therapy. And a lot of people say they’ve used more BTK for obvious reasons in terms of sort of logistics, et cetera. But we also asked what patients, and I know you put down here that Evusheld is not or tixa/cilga which is a short name I give it, is not available in the UK. But we also asked faculty when they use it. And faculty here in the US are using it relatively liberally. I want to ask the audience a question. And then I’m going to ask you how you manage patients who develop COVID while on treatment.

So, audience, in general, if you have a patient who is asymptomatic, but found to have a COVID infection on a BTK inhibitor, would you keep the BTK inhibitor going? Would you hold it? Or maybe you’re not sure about what to do. I’ll let you say. This is what the faculty says which other than, interesting, Dr Sharman who did the work on the benefits of BTK in CLL would hold it, but everybody else would continue. Any comments on BTK? We had a case where a patient was symptomatic on a BTK inhibitor and they stopped the BTK, got more symptomatic, put back on the BTK, less symptomatic. I don’t know if you’ve ever seen that. What do you do?

PROF HILLMEN: Well first of all, there was a rumor early on in the pandemic that there might be benefit from keeping patients on BTK inhibitors in terms of the COVID response, but I don’t think there’s any evidence for that. Our approach has been to keep the patients on BTK inhibitors until they’re admitted to the hospital because when they’re admitted to the hospital, we then subsequently introduce other drugs, interventions, lines, et cetera where the BTK causes a problem.

I think what’s critical is to get anti-COVID therapies into these patients rapidly. We have a rapid access program for our CLL patients, in the UK generally, where they get sotrovimab or Molnupiravir or Paxlovid is now available. Now one point I’ll make is that I’ve certainly seen patients who are symptomatic with COVID have responded to those therapies. And we know that in CLL, many patients can take a long time to clear the virus, weeks and weeks to clear the virus and may not develop antibodies, even after an infection. So get the asymptomatic patients on anti-COVID treatment.

The final thing I’ll say is that Paxlovid interacts with CYP3A4 drugs. So Paxlovid will interact with ibrutinib or acalabrutinib or ven. And so if we’re going to use Paxlovid, which may be the most effective of these antivirals, certainly the oral ones, I would hold the ibrutinib during the Paxlovid treatment because you’ll have higher levels of the BTK inhibitor while it’s given concomitantly with Paxlovid. But I don’t think there’s any evidence of holding the ibrutinib or acalabrutinib that’s of use.

DR LOVE: So I’m curious about patients who are on obin/ven. We see in the faculty here a consensus, just kidding, among 5 people we have 3 different answers. And also, it kind of gets into another question I have which is what do we know about the impact of obinutuzumab versus rituximab in terms of COVID? But any thoughts about why you hold the obin and keep the ven going?

PROF HILLMEN: Yeah. Well first of all, the patient has to go to the hospital for the obinutuzumab and we try to avoid doing that. What we know is that patients who receive a CD20 antibody are some of the lowest responders to COVID vaccines. We rarely see a COVID response, vaccine response, in a patient who has had a CD20 antibody within 6 to 12 months of finishing that antibody. I know of no data to say there’s a difference between obinutuzumab and rituximab. I think it’s probably similar as far as we’re aware. We have in the pandemic, so at the beginning of the pandemic, the first year or 18 months, not used as much obinutuzumab because we’ve been avoiding face-to-face meetings with patients as much as possible. But now in the last year, we’ve gone back to using ven/O and managing through the issue. I’m more comfortable now that we have antivirals. I think they really are going to impact. And then, the Evusheld. I can’t say the proper name of it. I think that promises for our patients to be an important prophylactic. And if I had it available, I would use it as a preventative treatment for our CLL patients, certainly the ones who don’t have a significant conversion after the vaccine which is many of the patients.

DR LOVE: Question about TLS and obinutuzumab. Do you ever hospitalize patients when you’re giving obinutuzumab to prevent TLS? For example, if they were high-risk, under the venetoclax algorithm, but they’re getting obin, do you follow that algorithm?

PROF HILLMEN: Well for obinutuzumab, we don’t really see a lot of tumor lysis. Occasionally, you see it when it’s venetoclax. Now we don’t, we very rarely admit patients for venetoclax escalation now. We would hydrate them. We have a good service that will hydrate patients well. If they have signs of tumor lysis, then we would admit them for more intensive hydration. But we very rarely do it prophylactically. And we may, you know, there’s always exceptions of a patient who has had significant renal dysfunction or we’re worried about their food, we would probably give them rasburicase and we may think of admitting them certainly if they went through this when they were in the hospital, for example. But I can’t remember the last time we admitted a patient and we treat a lot of people with that.

Journal Club with Peter Hillmen, MB ChB, PhD

DR LOVE: So I want to ask you about this paper, consensus paper, on MRD. We get so many questions about that. Of course, the big question is what do you do at the end of a year in somebody who had CLL14 if they’re MRD positive? We see a real controversy about that. Can you talk about how this group kind of went through the whole issue of MRD in clinical practice nowadays and where it’s heading?

PROF HILLMEN: Yeah. So obviously, it’s very complicated. We’re using MRD in lots of different ways. But I think that it’s fair to say that in general practice, MRD does not have a role for guiding therapy. There are some exceptions, most transplant, but there’s very few patients in that situation. We’re using it in our clinical trials to define the duration of therapy. And I think it’s also a much more sensitive way of predicting outcome for patients. So you’re right that after 12 months of ven/O if you’re MRD negative, you’re going to leave it several months after obinutuzumab before measuring the peripheral blood in my experience. So immediately after is too early. I’d probably leave it 3 to 6 months before the testing of the peripheral blood unless you’re going to do a marrow which we don’t do outside of trials. If the patient is MRD positive, they go into relapse. And if they’re MRD negative, there’s a chance they won’t relapse. And if they are going to relapse, it’s going to be a long time before they do. So for patients who want to know the likely outcome to treatment, we have no evidence yet that continuing therapy or changing therapy at the 12-month timepoint will change outcomes. And that’s probably a trial that needs to be done.

DR LOVE: So question from the chat room. In what situation do you add obinutuzumab to acala as opposed to just, in general, adding anti-CD20 to BTK? You hear people, at least before the pandemic, you hear people talking about younger patients who have a lot of disease. What about nowadays?

PROF HILLMEN: Yeah. So this year for the ELEVATE-TN trial where there’s a difference in terms of PFS in favor of obinutuzumab to acala which there’s no difference in overall survival yet. And we aren’t stopping the acala in that trial. So the acala, even if the patient achieves an MRD negative remission, continues on acala. So in that trial, we had 2 patients with acala who were MRD negative out of the whole trial and 22 with acala/obinutuzumab. So my bias, because we’ve done trials with ibrutinib and obinutuzumab in our group as well as the OATN, is that we’re using the antibody at the wrong time. All the evidence would suggest that the antibodies are more effective when you use them when there’s less disease around. So using it at the beginning of treatment isn’t logical. I think what we should be doing, and we need data, we need to do trials, is to introduce obinutuzumab after the patient is in a clinical remission where there’s less disease around. Our evidence with ibrutinib would suggest that we’ll get a much higher population of patients into an MRD negative remission. And then, we need the trials instead of stopping therapy. So I just think we need more clinical data. My bias is that adding obinutuzumab will be beneficial for patients, particularly progressed patients, but we’ve probably got the wrong regimen at the moment.

DR LOVE: So why don’t we close out with a case. This is from the chat room. This is from Daniel. 67-year-old with relapsed CLL status post BR times 6 cycles, then ibrutinib, now has progressive disease with predominant prolymphocytes. Bone marrow biopsy reveals complex karyotype including t(8;14). Lymphoid NGS reveals BTK and SF3B1 alterations. What would you be thinking about? Venetoclax? Transplant? Pirtobrutinib trial?

PROF HILLMEN: How old is the patient, sorry, Neil?

DR LOVE: 67.

PROF HILLMEN: Nicely borderline for transplant.

DR LOVE: Yeah. Perfect.

PROF HILLMEN: If I had pirtobrutinib available, I’d probably give him pirtobrutinib. It’s not available outside of clinical trials yet, but we’ve seen some nice responses in patient with BTK inhibition. Prolymphocytic is not a transformed disease, so it’s not equivalent to Richter’s. And it basically identifies a proliferative patient. And they tend to respond well to BTK inhibitors, but obviously, this patient has developed a mutation. And so I think if you had the option, I would use a reversible inhibitor and we’d put the patient in a trial if we had one open. I think ven/R is what we would use outside of clinical trials for this patient and there would be a reasonable chance they would respond. But most likely, because we know they’ve got genetically bad-risk disease, it’s not going to be a durable response. So I’d be then thinking is the patient transplantable? Certainly, if they didn’t achieve an MRD negative remission, possibly if they did, I’d be talking about transplant to the patient. At the moment, we don’t have mature enough data with CAR Ts to use it at this stage of the disease, but I suspect in the future, CAR Ts may be an option. But in non-transformed disease, it’s a little bit difficult to justify CAR T in this setting. So I would use a ven/R approach outside of clinical trials.

DR LOVE: So, Peter, thank you so much for working with us today. Audience, thank you for joining us. Come on back Saturday afternoon at 2:30 PM Eastern Time or if you’re in the Phoenix area, drop in the SGO meeting. We’ll be doing a symposium on ovarian cancer. Be safe, stay well and have a great night. Thanks, Peter.

PROF HILLMEN: Thanks, Neil.