Introduction: Key Factors in the Management of Chronic Lymphocytic Leukemia (CLL)

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the fifth of 11 programs we’re doing here at the ONS Congress, and tonight we’ll be talking about the fascinating area of chronic lymphocytic leukemia.

We have a great faculty tonight: Dr Jacqueline Broadway-Duren from the MD Anderson Cancer Center in Houston; Ms Corrine Hoffman from The Ohio State University Wexner Medical Center in Columbus; and Dr Bita Fakhri from the Stanford University School of Medicine in Stanford; and Dr Jeff Sharman from the Sarah Cannon Research Institute at the Willamette Valley Cancer Center.

As we’re doing in all these programs, we are discussing the use of nonapproved agents and regimens, so please consult the package insert for more specific information.

If you haven’t yet signed up for our Oncology Nursing Update podcast, just pick up your phone, go to podcasts, search Oncology Nursing Update, and follow us. We have a couple of programs on lymphoma and myeloma there now, and we’ll be posting all 11 of these programs in the next few weeks.

As I mentioned, these are the 11 programs we’re doing here at the congress. This is the seventeenth year we’ve actually been coming to ONS. We always have the same format. And why we’re really here today is to listen to our faculty. We have 44 outstanding participants joining us on stage this week. So far it’s been great, and it’s always a great opportunity to kind of pick their brains.

So we’re going to talk about CLL and particularly some of the new things that are happening. But just to kind of get started, I want to provide a little bit of an overview. This is a slide from Bita that I wanted to just maybe start out with before we started kind of get rocking and rolling here.

And Jeff, in some of the issues that come up, one of the interesting and important issues is actually whether a patient needs to be treated. Can you talk a little bit about how these patients usually present and are diagnosed and how you diagnose CLL, and particularly how you decide whether or not they need treatment or they can be observed?

DR SHARMAN: Right. So thank you, Neil. Because of the routine use of complete blood counts in primary care and so forth, most of the time this shows up in our clinic as just an incidental discovery of lymphocytosis, elevated lymphocyte count. That then, if it comes to us in clinic, we’ll run a flow cytometry, and typically flow cytometry is capable of securing the diagnosis just off peripheral blood. We don’t always have to do bone marrow biopsies. In fact, we rarely do bone marrow biopsies for diagnostic purposes unless there’s a question.

And we’ll get into a little bit later in my talk about when, indications for therapy, but most patients, not all, but most patients can be observed, and you don’t necessarily need to jump into therapy right away.

DR LOVE: So Bita, one of the themes here that we’re talking about, and a theme in oncology in general, are biomarkers particularly related to the tumor that we look at. What are some of the key issues that we look at in patients with CLL, particularly in terms of determining their risk status?

DR FAKHRI: That’s a very important and very critical, basically, part of the diagnostic workup. It gives us a lot of knowledge about how the disease is going to behave in the future.

So basically we definitely recommend ordering FISH panel. We check for 4 or 5 chromosome abnormalities, particularly 17p deletion, which portends an unfavorable prognosis. Then we have 11q deletion, which is another adverse prognostic feature, but in the era of targeted therapy not as bad as 17p deletion. And then we have trisomy 12, 3 copies of chromosome number 12, which is an intermediate risk factor. And then we have deletion 13q, which portends a favorable prognosis.

And I almost always recommend checking translocations between chromosomes 11 and 14, which results in overexpression of cyclin D1, which is pathognomic for mantle cell lymphoma. So even if someone is presenting with a CD5 monoclonal B-cell lymphocytosis coexpressing CD23, CD200, the immunophenotype, which we expect to see on flow cytometry in a patient with CLL, but if the translocation between chromosomes 11 and 14 comes back positive the diagnosis is mantle cell lymphoma.

And then the other prognostic feature is immunoglobulin heavy chain rearrangement, and this is how I explain it to my patients. So counterintuitively, mutated is associated with a better prognosis, and this means that the proliferation of the CLL lymphocyte was halted at a later stage, so the lymphocyte has had time to mutate its DNA, so we are dealing with a more mature, with a more differentiated lymphocyte. And like adults, they are expected to behave better as compared to unmutated IGHV, which means the proliferation of lymphocytes was halted at a very early stage, so the cell did not have time to mutate its DNA. So we are dealing with very undifferentiated cells, baby cells, and like babies, they’re expected to behave erratically.

And I don’t want to complicate things, but you’ll probably also hear about other mutations that we are grasping a more in depth understanding in terms of prognostication.

DR LOVE: And Corinne, we know that even in these high-risk situations if the patient does have symptoms usually they’re not going to be treated. A not too common situation in oncology to be diagnosed with a cancer and yet have the patient be observed. I’m curious how patients, Corinne, respond to you about this idea of holding off on therapy and just observing even though they have this cancer.

MS HOFFMAN: Yeah. So it can be kind of hard to hear at first. They are waiting for that new patient appointment after they hear they have this diagnosis of CLL, a cancer diagnosis, and then they come and see us for a visit, and we’re choosing to observe. And sometimes that can give them quite a bit of anxiety. You’re telling me I have cancer, but we’re not doing anything about it. So that can take a lot of education up front to kind of reassure them, let them know we’re keeping an eye on things, re-educate on those indications for therapy and letting them know that earlier treatment is not necessarily better for them in the long term that we’re aware of at this time.

DR LOVE: So Jackie, of course we’re going to talk a lot about new agents, particularly Bruton’s tyrosine kinase inhibitors, BCL2 inhibition, specifically with venetoclax, but it wasn’t that long ago that the usual first treatment for CLL was chemotherapy, often with an anti-CD20 antibody. BR — bendamustine/rituximab — was a common therapy. Also FCR, a very challenging, difficult chemoimmunotherapy. I know you treated patients in that era, which wasn’t that long ago, because these new agents have only come out in the last 10 years, at least that have been available.

What’s it been like to observe this shift from even very intensive chemotherapy in some cases to even oral therapy in many cases?

DR BROADWAY-DUREN: Yes. This has been actually a very positive shift for patients. As Corinne said, one of the difficult things is asking them to wait if they don’t need therapy immediately. But now with them coming in we have all these novel agents, most of them oral, with the monoclonal antibodies.

The patients are excited. They are happy they don’t have to take chemotherapy and worry about nausea. Fortunately, some of the older chemotherapy agents, the BR and FCR, didn’t necessarily cause hair loss, but they caused — maybe some of the late effects from those were damage to the bone marrow, and patients may have ended up with a subsequent MDS or something. So the patients are really happy now that we are no longer using those agents, and most are very happy to be compliant with the new oral agents.

DR LOVE: And Bita, one other issue I’m curious about is how often do you see people actually die from CLL. It’s often a very long-term history. This morning we did a program on CML. But also, when they do die, other than noncancer mortality, what do they die of? Some of these people undergo what’s called transformation, which is more like a shift towards something similar to diffuse large B-cell lymphoma. How often is that the cause of death? What’s the long-term outcome? Can these people be cured?

DR FAKHRI: Yeah. So I mean, Richter’s transformation is the orphan disease because unfortunately a lot of trials for diffuse large B-cell lymphoma exclude patients with Richter’s transformation, so how we’ve gathered information how to treat these patients is basically extrapolated from the clinical trials. So patients with CLL have a 2 to 5% risk of developing Richter’s transformation throughout their lifetime. It’s 90% of the time diffuse large B-cell lymphoma, 5% of the time Hodgkin lymphoma, and much less other kinds of lymphoma, like plasmablastic lymphoma.

I’ve been told that since we’ve been using targeted agents in the past 11 years, since the first approval of ibrutinib in the relapsed/refractory setting in February 2014, at least anecdotally CLL experts are seeing fewer cases of Richter’s, but they’re still there. Do I have any literature, robust literature to support this statement? I do not, so we have to gather information. But Richter’s syndrome is still hard to treat. The majority of these patients are not responsive to anthracycline-based chemotherapy, what we use for DLBCL, like R-CHOP therapy, and there are a lot of basically clinical trials, thankfully going on, to answer this unmet need.

And then we also know that infections are a very real risk in patients with CLL. We are in the recovery phase of COVID, if I may say that, and we lost a lot of patients to COVID with CLL, especially in the first 2 years of the pandemic. There was a lot of confusion. The vaccines, the medications, the antibodies had not made their way to the field yet. So I would say infections and also Richter’s, although rare, but it’s still a very hard to treat complication of CLL.

And I have to also say that aggressive TP53-aberrant CLL, meaning patients with CLL who have 17p deletion and/or TP53 mutation, when they get to that double-refractory stage, meaning after they stop responding to a covalent BTK inhibitor and a BCL2 inhibitor, their disease becomes very hard to treat.

DR LOVE: So yeah. When you mentioned COVID, it almost sometimes seems like a dream to me, but I remember when COVID got started one of the key issues — we were doing a lot of programs on CLL because there were some real questions related, particularly related to all of the issues of COVID that were going on, and the increased risk that we see. We’ll get into that a little bit more.

Role of Covalent Bruton Tyrosine Kinase (BTK) Inhibitors for Newly Diagnosed CLL

DR LOVE: So we’re going to start out talking about the 2 novel types of therapies that are used, BTK inhibitors and BCL2 inhibitors, specifically venetoclax, and now — and particularly since a great presentation just in the last few months at the December American Society of Hematology Meeting, maybe we’re now moving toward a situation where we’re going to give both in a time-limited fashion. But we’re going to get to that in a second.

First though, we’ll ask Jeff to talk about a patient — or a situation where a patient’s going to be started on single-agent BTK inhibitor. Jeff was actually really in the middle of the development of all these drugs and was really instrumental in their evolution and really changed dramatically the experience of CLL for patients. So Jeff, let’s talk a little bit about how we think through BTK nowadays.

DR SHARMAN: Alright. Thank you, Neil. So this is one of these figures that can tie your brain up in knots. But if we just think that CLL is a cancer of lymphocytes, it’s a cancer of B cells, and the job of a B cell is to make antibodies. And this is a schematic of a B cell with an antibody receptor there, but inside of the cell is a signaling cascade that comes down from the surface of the cell and then gives instructions to the cell and a lot of really important life/death decisions for that cell. And what we’ve learned is if we inhibit that signaling pathway we can have a therapeutic benefit for those patients with the disease.

In the bottom box are 3 what we call covalent BTK inhibitors. These form an irreversible bond to BTK. The first-generation molecule was ibrutinib. Then there were 2 second-generation molecules, acalabrutinib and zanubrutinib. And then towards the latter part of our presentations tonight we’ll talk about pirtobrutinib, which was recently approved as a noncovalent inhibitor.

So here’s a 78-year-old male. He’s got known coronary artery disease. He’s got 2 stents and is on chronic aspirin. History of hypertension, well controlled on amlodipine, losartan, hydrochlorothiazide. No known history of AFib but reports that heart occasionally skips a beat when asked about palpitations. His creatinine is 1.5. GFR is 50. Importantly, he lives about 50 miles away from the cancer center, and his daughter takes off of work to bring him to appointments.

He initially presented 18 months ago, we observed, but now he’s got a white blood cell count rising to 180,000. Hemoglobin has dropped from 14 down to 10, and platelets from 400,000 down to 110,000. He’s developed moderate adenopathy.

He has IGHV unmutated trisomy 12 and TP53 wild-type. What the heck does that mean?

So I’m going to start with watch and wait, AKA watch and freak out, which is that over the last 40 years we’ve done many studies on early treatment of asymptomatic patients. We did it with chlorambucil. We did it with fludarabine. We did it with FCR. We did it with ibrutinib. All the studies showed the exact same thing: There is no benefit to treating early asymptomatic patients. And that has been shown time and time again. So the paradigm is watch and wait, and I think there’s a lot of psychological task there to get patients onboard with that. From Eugene maybe not so much, these patients are perfectly happy not to be on therapy.

But what we do have is the iwCLL criteria for when to initiate treatment: A rapid rise in the white blood cell count, emergence of bone marrow dysfunction, such as anemia or thrombocytopenia, symptomatic adenopathy. And there are other reasons, fatigue, infections and so forth.

And we talked briefly a moment ago about the key biomarkers, the IGHV mutated versus unmutated. And shown on the left panel here is the difference in survival. Now this is an older paper from around the year 2000 that showed those patients with unmutated disease died more quickly of their disease. They have faster-growing cancers. And on the right is what we call a Kaplan-Meier curve of the different FISH findings.

And I think if you can just at least remember 17p is bad that will get you most of what you need to know. 13q is good. That’s the most common. Fortunately, 17p’s not that common, but in between there there are several others. 17p is where the TP53 gene lives, and you can either have a mutated TP53 or a deleted 17p. Both are equally bad.

If you look at the current NCCN guidance for therapies you’ll see that the preferred regimens are BCL2-containing regimens, Dr Fakhri’s going to talk about those, and then amongst the covalent BTK inhibitors there’s acalabrutinib and zanubrutinib. You’ll notice that ibrutinib is listed in the “other” category, and that has to do with some of the differential cardiac side effects we’ll get to.

So with regards to BTK, the key thing here is that these are very simple, easy to use molecules. Typically we’ll start them on the drug, we might see them 4 weeks later, and if they’re doing well we can then see them every 2-3 months. So for a patient who’s traveling a longer distance that’s really desirable. No infusions. The downside to BTK inhibitors is that once you start them you take them until they stop working. So patients can be on these drugs for a long time, and I think there’s something about giving patients biohazard bags to take their medications, psychologically about doing this over the long haul, I think compliance and adherence is a real issue for our patients.

BTK-specific side effects. We do talk about atrial fibrillation, hypertension, ventricular arrhythmias. We’re going to get into those later. Bruising and bleeding are real common. Arthralgias can be common as well.

And there have been several studies that compare second-generation BTK inhibitors verus first-generation BTK inhibitors, and what we notice is that the rates of atrial fibrillation are lower, hypertension is lower, and that’s really why we see this preference for the second-generation BTK inhibitors.

So returning to the case above. This is an older, typical CLL patient. He does have cardiac risk factors, and we have to think about that. Ibrutinib, actually in clinical studies you’re not supposed to put a patient on ibrutinib if they’re on 3-drug hypertension. So this patient had 3 drugs. He does have some chronic kidney disease. Dr Fakhri’s going to talk about tumor lysis syndrome in hers. The distance away definitely plays a role. This patient does have an indication for therapy, but even with mixed molecular findings we can expect most of these patients are going to get 5 to 10 years of benefit out of this monotherapy. So very effective drugs have totally transformed how we treat the disease.

And I think that’s it. Thank you.

DR LOVE: So how did you treat this patient or how would you treat a patient like this?

DR SHARMAN: Yeah. So I think this is a patient that would be — the distance is a real issue, and I think once we talk about some of the monitoring required, the IV infusions and the monitoring with obinutuzumab and venetoclax, that makes a huge difference. With this patient we’re going to watch, of course, for atrial fibrillation, and we’re going to be attentive to hypertension, but given this patient’s comorbidities and so forth a BTK inhibitor’s a very simple, easy to use therapy for this patient.

DR LOVE: So Corinne, until recently or maybe it’s still the case, really, we had this interesting thing where we see the scale of 2 therapies that seem to be very similar in terms of efficacy, but a very different experience for patients. That algorithm was just maturing when COVID came in, and that’s why I — because at that point everybody was trying to figure out what to do, and then on top of that you have the issues of COVID, people not wanting to come to clinic, wanting to avoid anti-CD20 antibodies, which make you more vulnerable.

Even now, later, post COVID, we still have that same choice. I’m curious how you see patients processing it, how you involve patients in the treatment decisions. And one of the big differences between those 2 is that one is indefinite and the other is short term, a year, 14 months, et cetera. How did you see people processing? How do you see processing and making a decision?

MS HOFFMAN: Yeah. So there are multiple factors at play, and each patient sometimes ranks one factor as being kind of the deal breaker for them, whether it’s distance or maybe the potential increased infection risk you see with an anti-CD20 and venetoclax regimen, as well as the arduousness of the venetoclax ramp-up, which we’ll discuss. So a lot of times, too, it’s a discussion with family and considering other comorbidities, like Dr Sharman was just discussing.

But now I think later that were through — understand COVID a little bit more, have some better vaccines and other treatments available, we’re seeing more of the patients kind of warm up to coming back for the obinutuzumab-containing regimens and seeing kind of less of that fear that we saw early on during the pandemic.

DR LOVE: So Jackie, we asked you to talk about some of the considerations in the patients who are starting on BTK inhibitors, specifically covalent. And as Jeff was mentioning, ibrutinib is not often used right now up front or even at all, I think, in CLL. But you have 2 covalent inhibitors, zanubrutinib and acalabrutinib, that again haven’t really been directly compared. They seem to have similar efficacy. They have similar tolerability, maybe slight differences. But maybe you can talk a little bit about some of the things you think about in patients getting BTK inhibitors.

DR BROADWAY-DUREN: Yes. So you’re correct. We don’t initiate ibrutinib very often anymore except in a few of the trials we have at MD Anderson. However, we do have patients who are still on ibrutinib after 10 years, and if you try and take it from them that’s a problem.

So generally we’re now using more so acalabrutinib and zanubrutinib. We still seem to have a little bit less side effect panel. We don’t see as much atrial fibrillation incidence as we did with the ibrutinib. But each of them have their own set of specific things that we look for in them.

The patients are generally very compliant on these drugs. We talk to them about adherence from the very beginning. So as far as side effects, I would still say hypertension is one of the things that we continue to work with and make sure all of those patients have a primary provider that is managing their blood pressures.

So when we look at — this is a patient that I chose to look at as far as starting a BTK inhibitor. The patient presented with a total white blood count of 52,000 with an ALC of — that’s absolute lymphocyte count, of 8.3. The hemoglobin was already decreased somewhat at 11 grams, and the platelets were also decreased at 110.

The patient was found to be mutated on prognostic indicators with 13q, and the next-generation sequencing panel was negative. So the patient had good prognostic factors. They had symptoms including drenching night sweats and significant fatigue. So when the patient’s telling me I need to go back to bed by 11 o’clock in the morning that is significant.

So some of the side effects, as we talked about that they all have in common, is the possibility of atrial fibrillation, although that was seen more so in first-generation with ibrutinib. Ventricular arrhythmias are still a strong consideration, and because of that if we have a patient coming in that has any history of cardiac problems they are sent to a cardiologist for baseline evaluation. We also do — initially do EKGs on all these patients. And I tell them all to go out and buy an Apple Watch because they can read AFib.

Hypertension. We try, again, to manage that as indicated and work closely with their primary care or cardiologist. Arrhythmias definitely has been a problem among all 3. Patients complain of joint aches and pains, and if they’re bad enough the patient just will not take the medication. So you have to educate them up front that this may be a possible problem. Muscle spasms and cramps.

Specifically with acalabrutinib are headaches. Some patients never have them, but the majority of them who do. They are transient, and they usually occur within the first couple of weeks of therapy, and then all of a sudden I never hear them complain about it anymore. So some of the patients, just the power of suggestion, they have every side effect that you mention, but we have to tell them. But we usually tell them just manage that with some caffeine, a cup of coffee or so forth, and that tends to work for most patients.

Bruising and bleeding is a problem with — more so with the zanubrutinib. All of them can cause that. So I tell the patients up front when you see bruises and petechiae don’t get upset about it because that’s just an active platelet — effects to the platelets from the BTK inhibitor, so you can expect that.

And then infections. Of course they can lower the white blood cell count, and some of these patients actually may have some degree of neutropenia, a low white count, and may present with infections and have to be treated with antibiotic therapy.

So this is a 72-year-old female who was previously untreated and who now presents to clinic with recommendations due to progressing lymphadenopathy. Hypertension. Those are her past medical problems. Most older patients are going to have some type of comorbidity.

After discussion of BTKi the patient was encouraged to start acalabrutinib, and we discussed the possibility of headaches, as I stated. She did develop headaches, but they were minimal and only lasted for a short period of time. We discussed the possibility of AFib and told the patient you won’t know if it’s safe for you unless you have an Apple Watch, so just tell us if you’re having any heart palpitations or irregularity.

Another one is diarrhea. And so we talked to the patients up front to just — if you have more than a couple of diarrheal stools in a day go ahead and start loperamide. And if they last and persist for several days you need to notify your primary provider, whether it’s us or your primary care doctor.

So the patient was able to stay on the acalabrutinib. So one of the things I wanted to reiterate to the community is, if you’re not familiar with patients on BTK, initially they will have an increase in the white blood count. That is what they’re supposed to do. That’s the mechanism of how these drugs work. So I have literally had a patient who went to their primary provider in the community, and they called us and told the patient they needed to get back immediately because the white count was going higher. But that treatment was effective.

We monitor the blood pressure, have the patient keep a log of that. If they have muscle/joint aches or pains we try do nonpharmacologic management like warm compresses, stretching exercises, those type of things. But again, if they have any cardiac palpitations, flutters or anything, report it immediately.

As far as GI toxicity, we talked about diarrhea. It may be self-limiting and may not ever need to take anything. Most of the patients with a history of constipation are pretty well happy with these drugs because it kind of evens things out for them. Loperamide seems to work in most cases. Sometimes we have to prescribe something other than that. I tell patients to avoid high-fat diets and just simple things that you know will potentiate the diarrhea. We’re constantly telling these patients to drink water and stay hydrated, whether they have diarrhea or not. And again, contact the provider.

So persistent joint pains. Again, stretching exercises, different nonpharmacologic things. I will tell them figure out maybe it’s not the drug. Maybe you have a low potassium or magnesium or something. So we need to — we follow those when they come to the clinic, but everybody doesn’t.

I won’t even mention the apple cider vinegar, but this is not a medical recommendation. This is what my patients come in and tell me works for them. I generally don’t promote that with the patients though.

Again, get a baseline cardiac evaluation. Patients with AFib generally are put on beta blockers like metoprolol or something, but they all go — we have a cardio-oncologist on site at our facility, so we’re happy to refer those patients over. Monitor them and keep a record of everything.

And now in the case of ibrutinib, we have patients who some of them we just could not prevent — or manage the AFib and subsequently had to stop the drug after many things. I have a patient now who has been in sustained AFib. We took him off the acala — I mean off the ibrutinib, and he’s done fine.

Neurologically, again, the acalabrutinib is pretty notorious for the headaches, and so generally patients tell me that they do well if they drink a Coke or — but there are times we do give them caffeine tablets for a few days, tell them to rest, stay hydrated, that’s very important, and make sure they’re not having a fever with those headaches because it could be a virus or something. Cold compresses, and then always make sure you’re not just having allergy problems, and that may be the cause of it. Make sure the patient hasn’t had any falls or head trauma as well.

So change in BTKis. We’ve taken many patients off ibrutinib because of the AFib and switched them to acalabrutinib and even a few to zanubrutinib, and they’ve not had any persistent problems with it. At times they just have to come off BTKis.

Patients who have progressed on some of the first-generation BTKis have been successfully been treated on second generation with acala and zanubrutinib. We saw more persistent bleeding, I think, in the earlier years with the ibrutinib, but we are seeing some cases with zanubrutinib, as well, but most patients do not have persistent bleeding. And if the patient’s having any type of surgical procedure we educate them up front to notify us so we can tell them to hold the drug. And it depends on which procedure they’re having how long that drug should be held.

DR LOVE: So thanks, Jackie. So many great practical point there. A lot of times I think does everybody else know this, and I don’t know it? I’ve never heard about the BRAT diet that you put there.

DR BROADWAY-DUREN: Oh, yeah.

DR LOVE: I don’t know if you made that up or I missed that day in med school, but banana, rice, applesauce and toast. BRAT, is that your invention?

DR BROADWAY-DUREN: No.

DR LOVE: Everybody knows it except me.

DR SHARMAN: Show of hands.

DR LOVE: Sorry. What can I say?

So Jeff, certainly, cardiac arrhythmias are potentially a serious consideration.

DR SHARMAN: Yeah.

DR LOVE: I’m curious. There are patients who already have atrial fibrillation, they’re already on anticoagulation, and then they present with CLL and require treatment. What do you do in that situation? In general what do you do with a patient who’s on anticoagulation, where you want to give them a BTK inhibitor?

DR SHARMAN: So one of the biggest issues really is the anticoagulation because in the original studies we didn’t actually understand that this was going to have an antiplatelet effect, and we saw really patients coming in early with a lot of bruising and bleeding we set up the studies so that essentially nobody got the concurrent administration of warfarin and BTK inhibitors. And fortunately we have the direct oral anticoagulants now, and you can coadminister a DOAC with a BTK inhibitor. But it’s kind of like each drug that you add that bruising and bleeding becomes more common, and I think we’ve all see the 78-year-old guys who come with arms that just look like they got in a bar fight, and that’s actually not terribly uncommon.

So for patients who have atrial fibrillation it’s not a contraindication to go on a BTK inhibitor. It’s really clear that there’s an associated exacerbation with ibrutinib. It’s hard to really say with certainly whether acalabrutinib or zanubrutinib contribute to AFib. If somebody’s well controlled, they’re not getting super bad tachyarrhythmias, their beta blockers are working, they’re on a DOAC, stable, you can treat them with a BTK inhibitor right through. But as you know, some patients are symptomatic from AFib, and in those patients sometimes you can try BTK inhibitors. But I have had some patients over the years where we just decided that wasn’t a good drug for them because they continued to have problems with AFib.

DR LOVE: So Bita, again, ventricular arrhythmias, where now we’re getting into another scenario that’s potentially very concerning. Theoretically what we love with our patients, again, we were talking about it this morning with CML, they live a normal lifespan and die of another problem. But then you hear about — I remember there was a case presented where a patient passed away in their sleep, and I was like whoa, I wonder if there was a ventricular arrhythmia there. What do we know about the incidence of this? Do we see sudden death that we think might be related to that? And is there a difference between ibrutinib, as we see with AFib, and the second-generation agents in terms of risk of ventricular arrhythmias?

DR FAKHRI: Yeah. That’s very important. In reality that’s one of the main reasons that ibrutinib is falling out of favor, because ventricular arrhythmias with ibrutinib have been reported. And it’s really sad, because someone has a potentially treatable malignancy, and then they face mortality because of this side effect. And despite the fact that ibrutinib has truly transformed the field, because of this very real complication we are not using it as one of our basically first-line options when offering a covalent BTK inhibitor to a patient.

And because of this very real side effect, and because it happens mostly in the first 6 months of starting a covalent BTK inhibitor, the combination of ibrutinib plus venetoclax, which was investigated in the CAPTIVATE trial, in the European GLOW trial, in the UK FLARE study, is not going to get FDA approval in the United States because of the risk of mortality associated with ibrutinib. It’s a low risk, but it’s a very real risk. And, as you just mentioned, the newer generation BTK inhibitors, zanubrutinib and acalabrutinib, are thought to be associated with a risk of atrial fibrillation but not ventricular arrhythmias.

DR LOVE: And Corrine, another question I have. We’ve done programs for an hour just on side effects of BTK inhibitors. There’s a lot to talk about here. What about quality-of-life issues like arthralgias? What do you see there?

MS HOFFMAN: Yeah. So that can be a big one for patients. And as you were discussing about a patient, sometimes we find that patients will, especially earlier on with ibrutinib, find they didn’t even call us, just stopped taking them because they were quite miserable having these migratory arthralgias and kind of some impacts to their quality of life. I think about one patient I had that he had just retired, found out he had CLL, started ibrutinib, and because of the arthralgias he wasn’t able to play piano anymore or work on cars with his son the same way that he used to.

So it can be an impact to their quality of life. We typically manage those — again, now that we have more than 1 BTK inhibitor to choose from we can try different ones to see if they tolerate that better, and oftentimes we are able to get them through that. We advise acetaminophen, typically avoiding NSAIDs due to that heightened bleeding risk. But the arthralgias in a better place now, kind of earlier on with ibrutinib were quite limiting.

DR LOVE: Jackie, any thoughts? And also in patients who are having really difficult problems with, for example arthralgias, do you ever switch, let’s say from acalabrutinib to zanubrutinib, and maybe see that the patient tolerates it better?

DR BROADWAY-DUREN: Yes. We have switched, and some patients have been able to better tolerate the zanubrutinib. Just one caveat, we found several women who persistently complained of arthralgias, and we sent them to rheumatology, and they had underlying autoimmune disease. So that is a consideration now that we are looking. Don’t just assume that it’s the drug. Look at other factors that can be contributing as well.

DR LOVE: Yeah. That’s a great point, and again a theme that goes throughout oncology, and we’ll talk about it all week, which is we talk about toxicities, but you also have to think about other causes of the problem that the patient is experiencing.

Role of Time-Limited Up-Front Treatment, Including Therapy Combining BTK Inhibitors and Venetoclax, for Newly Diagnosed CLL

DR LOVE: Alright. Let’s bring in the other — what up to recently has been the other potential choice, which is BCL2 therapy. Now we’re moving into a situation, maybe, where we’re going to use both together. But Bita, we asked you to talk about a situation where a patient’s actually going to get a combination, but also for you to go through what happens when you give a patient venetoclax and what are the considerations there.

DR FAKHRI: Yeah. Thank you, everyone. And I’m sorry, I’m recovering from a laryngitis, so please tolerate my voice.

So we did talk about key factors in managing patients with CLL. Dr Sharman pointed to all of these factors, timing of therapy, the iwCLL criteria, making patients embrace their diagnosis and understand what it means to live with CLL, and it takes time to process the diagnosis. There are a lot of emotions with living with cancer for a potentially lifetime. And then we did talk about the importance of FISH and IGHV mutation status. And also you heard a lot about covalent BTK inhibitors, and my focus is mostly going to be time-limited therapy with BCL2 inhibitors.

Just to walk you through the history of CLL in the past 11 years, you heard about how ibrutinib was first introduced to the front-line setting through the RESONATE 2 trial, just deriving from RESONATE 2 going to the right. So they compared ibrutinib to chlorambucil. Ibrutinib was the winner molecule. And when you look at curves like this, so it means the 2 arms — the 2 arms of this study, and the higher line means that was the winner arm.

So here in RESONATE 2 they compared ibrutinib versus chlorambucil, and as you see, the yellow line, ibrutinib, was the winner. And as we gained confidence about ibrutinib, we were like let’s compare it to some real deal, which was chemoimmunotherapy at that time. So Alliance and ECOG group compared ibrutinib to chemoimmunotherapy, and as you see, ibrutinib was the winner molecule. And based on these 2 trials the field of CLL left chemoimmunotherapy behind toward targeted agents.

I will spend a lot of time talking about the CLL14 trial, and you did hear about acalabrutinib and zanubrutinib as the newer agents in the covalent BTK inhibitor family.

So CLL14 is a the German CLL Study Group, and the 6-year follow-up of this study was recently presented. So CLL14 is a landmark trial because for the very first time in the field of CLL it introduced the idea of time-limited therapy.

And what does that mean? It was a combination of a BCL2 inhibitor. BCL2 is a protein that is overexpressed in CLL and some other hematologic malignancies, and it’s a pro-survival protein. It’ll tell the CLL cell to go survive. So a BCL2 inhibitor is a prodeath molecule. It’s an anti-survival, so it potentially kills the CLL cell. And then it was combined with obinutuzumab, which is a newer generation CD20 monoclonal antibody. We are all familiar with rituximab.

And how this combination is administered. Obinutuzumab for cycle 1 was given weekly, and then on day 22, when we were confident that we had debulked the disease to a level to reduce the risk of tumor lysis syndrome, venetoclax was introduced in a 5-week ramp-up fashion, 20, 50, 100, 200 and 400 mg, for a total of 1 year.

And the study randomized patients to receive obinutuzumab/venetoclax for 1 year versus chlorambucil/obinutuzumab, and CLL14 did not cherry-pick patients. These are patients truly representative of the CLL patient population. Creatinine clearance was — the median creatinine clearance was 62, so really not patients with the best kidneys. And patients had a lot of comorbidities. There is a score that we give in clinical trials called CIRS — cumulative illness rating score — and the median CIRS in this patient population was very high, meaning these are patients with CLL that we see in community, patients with a median age — disease with a median age of 72 years of age.

So here you see that the 6-year follow-up shows the 6-year progression-free survival was 53%, and I really want to translate these findings. It means patients took the combination for 1 year, they were — they enjoyed a 5-year treatment-free remission, and 6 years later 5.3 out of 10 patients are still enjoying their remission. This is a success in the field of CLL.

And there are some concerns that it’s time-limited therapy, the answer to everyone with CLL, including patients with high-risk features. And if you look at the cohort with TP53-aberrant disease, I have to emphasize it was only 10% of the patients, so you see that the median PFS was 52 months, meaning patients took the combination for 1 year, they enjoyed a 3-year treatment-free remission, then their disease came back.

So the question is are you happy with this number. Is the patient happy with this number? If so, there is nothing wrong with giving a patient with TP53-aberrant disease this time-limited therapy. And in IGHV-unmutated status, that number was 65 months, potentially 4 years of treatment-free remission.

And the way this study was administered, I hear a lot of tumor lysis syndrome, the fear of tumor lysis syndrome in the community, and I totally get it. It takes a village to administer — to cure cancer, and at academic centers we have the luxury of working with the best APP and nurses who support us, but please note that on the trial out of 216 patients who received venetoclax and obinutuzumab only 3 met the lab criteria for tumor lysis syndrome, and none of those patients met the clinical criteria. So it means that the way the treatment was administered, starting with obinu, and then introducing venetoclax, significantly reduced the rates of tumor lysis syndrome.

And the cytopenias, meaning lowering of the blood counts, is real with venetoclax, and there is a lot of management. Venetoclax is also associated with GI upset, change in bowel habits, and we sometimes ask the patients to take their medicine at nighttime because they’ll get a bowel rest, and sometimes those symptoms get resolved. So just don’t consider dose reduction or treatment holidays prematurely because it’s a 1-year treatment period, and we want the patient to get the maximum dose for the course of 1 year.

So this is an example, a 56-year-old gentleman with CLL diagnosed 2 years ago, with trisomy 12, unmutated IGHV. He presents with weight loss, drenching night sweats and a CBC showing a decline in hemoglobin with negative hemolysis labs and a platelet count of 73,000. He has excessive fatigue. No other comorbidities.

I am putting this patient here because 56 is a very young patient for CLL, and putting this patient on a covalent BTK inhibitor is potentially 3-plus decades of indefinite therapy, and I don’t see that right, to be honest with you, in a young patient with CLL. So I always tell patients yes, it is more inconvenient, it is most intense, but don’t be myopic. It’s 2 hard months, and then the patients will find a rhythm, and at the end of 1 year they’ll be done. And they’ll potentially enjoy a prolonged treatment-free remission as compared to covalent BTK inhibitor, very effective treatments, the new generation, very well tolerated, but potentially lifelong.

And then just moving to the rationale behind combining with — BCL2 inhibitor and a BTK inhibitor. So just to simplify this diagram, what BTK inhibitor does, it brings the lymphocytes from the lymph nodes out to the peripheral blood from the tissues, including the bone marrow, out to the peripheral blood. That’s why patients are excited. Three days later their lymph nodes are shrinking. And then, if you give a covalent BTK inhibitor alone, those cells, it takes 6-12 months to die on their own. And that’s the rationale behind introducing venetoclax, because venetoclax is a pro-death molecule, so will go and kill these cells in the peripheral blood, so potentially patients can enjoy time-limited therapy.

And this was a study presented by Dr Sharman at ASH 2024. The AMPLIFY trial randomized patients with treatment-naïve CLL to 3 arms. One of the arms was acalabrutinib plus venetoclax, I’ll refer to this arm as AV or doublet, another arm, AVO — acalabrutinib/venetoclax/obinutuzumab — and then the other arm chemoimmunotherapy, FCR or BR. And because 1 arm contained chemoimmunotherapy patients with 17p deletion were not allowed to be enrolled on this trial, because by this point we knew it’s unethical. Those are patients who are going to have very short duration of response, and their disease is going to come back more aggressively, because chemo gets rid of the good CLL cells and enriches the bad CLL cells.

And if you look at the 3-year progression-free survival, on the left, at 3 years 83% of patients on the triplet are still in remission as compared to 76% with the doublet, as compared to 66% with chemoimmunotherapy. But if you look at the overall survival the doublet and triplet curves flip, meaning the 3-year overall survival is actually better for the doublet. And why is that? The trial heavily enrolled at the time of COVID, so obinutuzumab is associated with immunosuppression.

If you look at neutropenia between AV and AVO the high-grade neutropenia is 32% versus 46%, and if you look at the rate of infections, with AV it’s 12% versus 24%, so a very real risk of infection in patients with CLL. They have inherently dysfunctional lymphocytes, and now you’re giving them treatments that make them more immunocompromised, so they're basically going to suffer from mortality.

I put this here to just simplify things. The 3-year PFS was 76% versus 83%. If you look at the overall response rate, very similar between the 2 arms. And if you look at the COVID-19 deaths, 2 and a half times more in the triplet arm as compared to the doublet arm.

So my questions. Most likely AV will be FDA approved in the front-line setting based on the AMPLIFY trial. The question is will FDA approve AVO based on mortality data, and the mortality was really real, and I can see the conversations going both ways. This is a post-COVID era. Obinutuzumab results in a deeper remission. Patients died, and that’s a very real risk.

And then the major question is as AV, an all-oral regimen, is making its way to the front-line setting in CLL, is AV better than OV. And this question is going to be elegantly answered in your MAJIC trial, which is basically 2 arms, AV versus OV for 1 year. At the end of 1 year everyone gets tested for MRD, which is an indicator for the depth of response. If they have achieved deep response they’ll stop after 1 year. If not, they’ll continue the oral agents for another year.

And I think the MAJIC trial will elegantly answer the question of long-term outcomes of AV versus OV. Yes, in terms of convenience, AV is the winner. It’s all oral. You heard about distance and other issues. They’re both time limited. Obinutuzumab is associated with infusion-related reactions, but at the end of the day which time-limited therapy is going to result in more durable remissions?

And I will end with this note that the landscape is changing. Another trial just finished accrual. That was CELESTIAL-TN — treatment naïve — which compared obinutuzumab/venetoclax to another covalent BTK inhibitor, zanubrutinib, combined with a new BCL2 inhibitor, sonrotoclax. This trial is going to read out in the next 3-5 years. And then the MAJIC trial is also going to elegantly answer the question of OV versus AV.

And with that, I know I’ve been above my time, but thank you for your attention.

DR LOVE: Good job with that voice. It’s hanging in there. Alright.

So yeah, looking at those — the data there it was amazing to think about doing that trial during COVID. When COVID was going on we were like can we even keep doing research, and the trial was in the height — before vaccines also they were putting patients on the trial. And so hopefully — I think people don’t expect you’re going to see this now, but really interesting.

So Jeff, there are certain moments that flash in my mind when I think about CLL. I remember the first time — usually you see this at the American Society of Hematology meeting. That’s were all the big hematologic cancer programs — trials are presented. I remember when we first saw FCR, a really high-intensive chemo versus ibrutinib, and ibrutinib was much better, which is — people were — I was shocked by it. I think that was the beginning of getting away from chemoimmunotherapy.

And then this past December with this AMPLIFY study, really the first study, so-called Phase III trial big enough to really influence clinical practice. I talk to both oncologists in practice, as well as investigators. It seems like people are ready to move toward this. It’s well, this is only for patients who would prefer to be on all-oral therapy temporarily. Well, who wouldn’t want to do that? How do you see this playing out? Do you see the FDA approving it? And what do you think docs — what would you like to do? And who would you give, for example, the triplet with obinutuzumab to versus just the all-oral AV?

DR SHARMAN: Yeah. It’s already endorsed by the NCCN guidance, so you can oftentimes get away with this now, even though it’s not approved. AV is very appealing. It’s all oral. And our CLL patients, sitting in an infusion room, when you’re sitting across from somebody with metastatic colon cancer or metastatic — there’s an experience where you’re seeing somebody who’s really sick, and patients, they don’t always distinguish one cancer from the other. And I think it’s a real existential experience to be in an infusion room, even if you’re getting immunotherapy, if you’re sitting across the room from somebody getting doxorubicin or so forth. So patients really like the all-oral regimen.

You asked where would I use the triplet. Look, I think that the triplet is probably more effective. It’s also a little more toxic. So where would I do it? I would do it in the younger, healthier patient who’s motivated for optimal duration of benefit.

DR LOVE: So my team’s sending me messages here on my computer they can’t believe I didn’t know what the BRAT diet was. Sorry. I guess I’m not a good dad or something. I listen to everything else.

Alright. Well, let’s talk about another issue here, the issue of time-limited treatment, but particularly the issue of venetoclax, because again, not everybody’s been getting that. A lot of people have been getting BTK alone. And now it could be that a lot of people are going to be getting venetoclax, and some of the considerations there, particularly the risk of tumor lysis syndrome, Corinne, comes up. So we asked you to kind of review that because this is going to be — the future is here.

MS HOFFMAN: Yeah. So when we’re starting the discussion with a patient about starting time-limited venetoclax/obinutuzumab. It’s quite involved education and can be confusing for patients because you’re talking about a very confusing and time-intensive schedule. So I kind of find that using a calendar or visual when I’m explaining how the cycles and everything works is very helpful.

But kind of starting at the basics, we talk about how venetoclax is the oral portion of the regimen, a BCL2 inhibitor. It’s an oral tablet that needs to be ramped up over the course of 5 weeks. And obinutuzumab being the infusion that they’ll receive. Again, the treatment is the duration of a year, with the obinutuzumab starting first, and it’s given every 4 weeks with the exception of that first cycle, where they come for day 1, day 2, day 8, day 15. You can see where the calendar starts to get helpful. And then generally at cycle 1, day 22 we start slowly ramping up the venetoclax dosing. And this next table kind of shows week 1 is 20 mg, week two 50, 100, 200, and then we finish at 400 mg daily, and that’s what they continue through the end of cycle 12 of their treatment.

So preparing to start, we do assess the tumor lysis risk. Again, because this drug works well and quickly we tell patients they’re at risk for electrolyte and lab abnormalities that can happen quickly and sometimes that need intervened on, which is why we have to monitor labs and bring them in for the slow dose ramp-up.

So I’ll talk to the next slide more about how we kind of risk stratify them, but we also — it’s good to kind of start the conversation about hydration. We want them to kind of have a goal intake of 1.5 to 2.0 liters, and a lot of patients aren’t there, including myself. So you’re going to have to assess if the patient is a good water drinker, are they drinking all coffee for their hydration, and kind of start that conversation early and prepping them that they are going to have to ramp that up, and that’s for their safety.

We also want them to start allopurinol to keep their uric acid level in check. So when they do start venetoclax, with the cells turning over quickly, that uric acid level can increase and cause other issues, so they usually start that at the time of venetoclax initiation, or a lot of times a little bit earlier.

We also want to do a good med rec to see — reconciliation to make sure there’s no interactions with venetoclax. We involve our pharmacists a lot, and sometimes you’d be surprised to find that they have certain medications that require us to dose reduce the venetoclax due to an interaction.

So when we assess the TLS risk we kind of group them into categories, and we look at how much tumor burden, or what are the sizes of their lymph nodes. Are there lymph nodes that are exceeding 10 cm? In the 5- to 10-cm range? Less than 5 cm? And then we’re also looking at their absolute lymphocyte count.

In the low-medium risk we can initiate the venetoclax outpatient, and then in the higher risk the usual recommendation is to do the first 2 dose escalations inpatient for closer monitoring and longer IV hydration. Again, with the — with this regimen, with the obinutuzumab working so well to kind of debulk patients up front a little bit, it’s very rare that we have to start the venetoclax inpatient with this regimen because already their lymphocyte count has decreased tremendously, oftentimes, and also seeing regression in their lymph nodes.

Other factors we might consider when we prepare — consider starting inpatient or outpatient is their tolerability of hydration, oral hydration. Are they at risk for fluid overload, things like that, their baseline renal function, and just any kind of baseline chemistry labs we’re concerned about.

And again, circling back to the obinutuzumab, which starts first? As you guys know, along with rituximab there’s that risk for that infusion reaction, especially on that first day of therapy. So we talk about what to look for there, and that they’ll be getting premedication, which often include a steroid, an antihistamine, maybe acetaminophen prior to the therapy to try to help prevent that. But also we have to tell them to kind of prepare for a long day because if they do have an infusion reaction, which a lot of times the nurses are great at looking for those signs and informing the providers, they might have to stop the therapy for some supportive medications, and that can kind of extend their day.

We also want to explain to them what the days look like for this 5-week ramp-up of the venetoclax. So at cycle 1, day 22, assuming their starting outpatient, they come pretty early in the morning. They bring their venetoclax with them from home, not having started that yet. They get pre-dose labs. If those look good we give them the go-ahead to dose. Six to 8 hours later we repeat labs. They’re usually hydrating during the day. If the labs look good, we don’t see any concerns for laboratory — lab TLS, we can discharge them home, and then they’re coming back 24 hours later for repeat labs.

So for the patient who lives far away, has transportation issues, the fact that they’re doing this every week for 5 weeks can be a bit intensive, so sometimes too we’re involving our social workers to look for maybe assistance with hotels or transportation to help get them through this time period. Also, again, stressing the importance of hydration, especially when they go home, the work’s not done after just the first day while they’re with us, and also to confirm that they’re staying on that allopurinol throughout that dose escalation period.

Some of the side effects we talk about and manage with patients are diarrhea, again usually self-limited, but we have them take loperamide as needed at home, often asking about how many stools per day they might be having. Nausea, equipping them at home with an antiemetic to take as needed. Sometimes they can get past this, again, with maybe dosing it at night or kind of experimenting with the types of food and the amount of food they’re taking the venetoclax with. We also monitor their counts closely. They are at risk with this regimen for neutropenia. We see thrombocytopenia, especially on the obinutuzumab combined with the venetoclax. So we’re looking at their labs. Are they low enough that it would warrant that we need to hold one or both of the agents? Potentially if it’s a persist issue we might consider dose reduction, as well, or also supporting them with growth factors.

And again, circling back now to the time-limited regimen that’s all oral, so BTK inhibitor with venetoclax. Of course, we talk about each agent and the associated side effects and that there is a potential for increased toxicities than with either agent alone. But overall we see things well tolerated, not so much diarrhea building on each other because they're on 2 agents that can both cause GI effects. We do get concerned about that increased potential risk for infection and neutropenia, so we might have some more frequent lab monitoring and considerations with that, but overall find it well tolerated.

Role of Pirtobrutinib for Relapsed/Refractory (R/R) CLL

DR LOVE: So really amazing to come here every year and think about what’s happened over the past year. I’m thinking about what we’re going to be talking about next year, and that’s what we’re going to talk about for the rest of the time here, because in spite of all the excitement of the research and developments we just talked about, there are other new developments coming in. And one of the most exciting, we started out talking about BTK inhibitors, is a new — a different type, a noncovalent BTK inhibitor, pirtobrutinib, where you actually see responses in people who’ve had previous progression on these other second-generation covalent inhibitors.

And that’s the scenario we’re talking about here, a patient who’s already had disease progression. And we asked Bita to talk a little bit about what pirtobrutinib is, where it is right now, and where it may be heading in the future.

DR FAKHRI: So I’ll start by presenting this case. This is a 66-year-old gentleman diagnosed with CLL 6 years ago, after being admitted with significant abdominal pain due to intra-abdominal lymphadenopathy. His FISH showed deletion 17p and mutated IGHV. He got started right away on obinutuzumab/venetoclax, this is the year that obinutuzumab/venetoclax was approved, and he enjoyed a median remission of 3 and a half years and then started developing rapidly progressive lymphadenopathy again.

At this point he was started on acalabrutinib. He had good disease control for 3 years, and now he’s re-presenting with cervical lymphadenopathy, 6 years later. He’s 72 years of age, and he’s interested in oral therapy. So what are the options for this patient?

So this is a patient that we label as double-exposed/double-refractory CLL patient, meaning a patient with CLL who has seen and failed both a covalent BTK inhibitor, in his case acalabrutinib, and a BCL2 inhibitor, and it is going to be an area of unmet need in the next 5-10 years in the field of CLL.

If there is 1 thing I can do right today is to make you understand the difference between covalent and noncovalent BTK inhibitors. So covalent, or irreversible, ibrutinib/acalabrutinib/zanubrutinib. All these 3 drugs, they form a covalent bond with the BTK receptor, so if anything happens, a resistance mutation happens, that changes the shape of this receptor, none of these drugs is doing to be able to sit on the receptor and form that tight covalent bond. As a result, they won’t be able to exert their function anymore.

That’s where the noncovalent BTK inhibitors come into play, or reversible BTK inhibitors. They’re more liberal on their action. They don’t require that strict shape of the receptor to be able to sit and inhibit the BTK enzyme. They bind, unbind, rebind, and that’s why when patients develop resistance to covalent BTK inhibitors, then the idea of putting them on a noncovalent BTK inhibitor, like pirtobrutinib, makes sense. So please do not see this just as another me-too drug. This is very different. The same target, Bruton’s tyrosine kinase, but different indication and different mechanism of action.

So we did talk about pirtobrutinib. Pirtobrutinib was first investigated in a Phase I/II study called BRUIN trial. Phase I and II studies are for finding the right dose, the right dose that shows basically effectiveness and also tolerability for the majority of patients. So the BRUIN trial had multiple cohorts, including one for mantle cell lymphoma, the middle one that I’m going to focus on, CLL, and then other B-cell lymphoproliferative disorders.

Out of 320 patients with CLL, 282 had previous exposure to a covalent BTK inhibitor, and out of those 282, here you see that 128 met the definition for double-exposed/double refractory. And this is a very heavily pretreated patient population, with median 3 prior lines of therapy, ranging from 1 to 11, just imagine 11 prior lines of therapy, and very enriched in high-risk features in unmutated IGHV/17p deletion.

So here you see in this heavily pretreated, high-risk patients the overall response rate for all-comers in CLL was 82%, and the majority of those responses were PR. And it’s understandable because CR requires complete response in CLL, requires all the lymph nodes to go to less than 15 mm. And it’s almost impossible. These are patients who start with bulky lymphadenopathy. There is going to be a lot of scar tissue, and numerically they might — the majority of them do not necessarily get to that level, but if you do a PET/CT you’ll realize those lymph nodes are not actually lighting up.

If you see the PFS, or progression-free survival, a fancy term for remission, in this heavily pretreated patient population patients enjoyed a median remission of 19.4 months, or 1 and a half years, and for the double-exposed cohort it was 15.9 months, 16 months. So this means that patients with double-exposed CLL, they potentially can enjoy 1 and a half years of remission. And based on the results of BRUIN trial, in December 2023, pirtobrutinib was approved for the double-refractory/double-exposed patient population.

This is the BRUIN CLL-321 study Dr Sharman presented at ASH. Patients with previously treated — with covalent BTK inhibitor got randomized to either receive pirtobrutinib at 200 mg daily or chemoimmunotherapy, bendamustine/rituximab, or PI3 kinase inhibitor, idelalisib and rituximab at physician’s discretion. And they allowed patients with 17p deletion, and they also stratified patients based on prior venetoclax exposure.

And here you see in the key eligibility criteria patients with prior history of atrial fibrillation were allowed. And here you see that the median progression-free survival in the pirtobrutinib arm was 14, kind of similar to the BRUIN trial, as compared to 8 months in the other arm.

And here, if you see — look at the time to next therapy, it’s very subjective, but it’s a very good endpoint in a disease like chronic leukemia. So patients did not require a new line of therapy for 2 years, the median time was 2 years, in the pirtobrutinib arm, as compared to the other arm, which was about 11 months.

And if you look at the adverse events, pirtobrutinib is a very well-tolerated basically molecule. If you look at the high-grade atrial fibrillation it’s 1.7%, which is pretty amazing. And if you look at hypertension, high-grade hypertension, it’s 2.6%. And these are really — very real side effects. As we just heard, someone is potentially going to be on indefinite therapy, and then they develop complications, and they have to be on 2, 3 medicines to manage those complications, so the polypharmacy associated with these agents should be taken very seriously.

And pirtobrutinib is currently being investigated in other clinical trials. We did talk about the BRUIN trial. We did talk about the BRUIN 321 trial, which is in patients with previously treated BTK. They got pirtobrutinib versus idelalisib or BR. BRUIN CLL-322 is another one, which is including patients with previously treated CLL, and they get fixed duration of pirtobrutinib , venetoclax and rituximab versus venetoclax/rituximab based on the MURANO regimen. And in BTK inhibitor-naïve patients the BRUIN CLL-313, it’s pirtobrutinib versus BR. And BRUIN CLL-314 is pirtobrutinib versus ibrutinib. So we are going to hear a lot about this molecule in the next few years as these studies read out.

Thank you.

DR LOVE: So thanks, and in a second I’m going to ask Corinne to talk about some of the nursing considerations in patients receiving pirtobrutinib. But Jackie, I’m curious. Pirtobrutinib, there’s not that much experience in the community with this agent yet, in the academic centers I think a lot more. You can see these trials with the data. But I’m curious what you see in patients clinically on pirtobrutinib. Do you think you can detect less toxicity?

DR BROADWAY-DUREN: The patients are doing quite well on pirtobrutinib, probably more so than some of the covalent BTKs. They still have — can have some of the same possible side effects or adverse effects, but we’re just not seeing a lot of those. Generally the pirtobrutinib is being used in combination with another agent. But as far as side effect panel, I can tell you, I don’t see a lot of problems. The patients are tolerating it very well.

DR LOVE: Yeah. It’ll be really interesting to see whether pirtobrutinib ends up in the first-line setting, maybe an AMPLIFY-type combination, sometime in the future, but we’ll see.

So for now, Corinne, let’s talk about some of the things you think about in a patient who’s about to receive pirtobrutinib.

MS HOFFMAN: Yeah. So pirtobrutinib has been a very comforting piece of news for many of our patients, especially a lot of times when they’re on these BTK inhibitors, or on a venetoclax-containing regimen, a lot of times the question is what’s next for me, and now we have another tool in our toolbox for them to use that we’re finding is very well tolerated.

So not to kind of repeat too much information, but again, we kind of explain to patients why this works. It binds to BTK differently than the previous covalent BTK inhibitor they were previously taking, allowing it to have activity despite those known resistance mutations. Overall pretty similar side-effect profile as the covalent BTK inhibitors, so we kind of hammer home a lot of the same points.

I think one important consideration is for some of these patients they have not been on a — might not have been on a BTK inhibitor now for a few years, so it does take some re-education about some of the common adverse effects. And we also want to make sure we have a good update on their health history since they were on that BTK inhibitor originally. Do they have any new cardiac events we should be aware of? New medications? Frequent infection issues? Are they on anticoagulation now? So kind of good to kind of reassess a good baseline risk as they proceed on with another BTK inhibitor. A lot of times, too, they are happy to know that it’s once daily dosing.

Again, we’re seeing a lot of these adverse effects occur at much lower rates, which is encouraging. We still want to talk about the common ones. We inform them of the risk for bleeding. They might notice easy bruising. We want them to call us and inform their team about any upcoming procedures they might have. A lot of times we find patients might forget to do this, especially as they’re doing well, maybe seeing us every 3 months. But we want to know even about things as simple as a colonoscopy or dental work because that alone might warrant a hold of the pirtobrutinib.

Again that risk for arrhythmia and atrial fibrillation, while it’s low, it’s still there, so we want to make sure the patient monitors for and updates us if they’re having anything like dizziness, syncopal events, palpitations, just so we’re aware. We might do an EKG in the office. Also, as you know, that doesn’t always capture everything, so maybe a cardiac monitor if they’re having frequent palpitations.

And then if we do find a new onset of an arrhythmia or atrial fibrillation we’re referring to cardiology for a more thorough evaluation to see their candidacy for anticoagulation, optimize their symptoms, maybe get started on a beta blocker. But as we were saying earlier, this doesn’t necessarily preclude them from continuing on with the pirtobrutinib, especially if we can achieve good rate control and symptom control.

Again, there’s still that always risk for infection that’s there. For CLL patients on or off therapy we’re always talking about infection and also having them update us promptly if they’re having fever or other signs or symptoms of infection, especially if they’re persisting for a while. We might consider prophylaxis, like valacyclovir or other things in high-risk patients. You also from time to time kind of revisit the discussion and make sure they’re staying up to date with vaccinations for flu, COVID, pneumonia vaccination to also kind of help us in the infection category.

They’re also at risk for cytopenias, so we’re monitoring their labs for neutropenia, things like that. We may alter how we’re monitoring them based on what we are seeing at each visit. It might be every few months, but some patients might warrant more frequent lab checks.

Again, there’s the diarrhea and GI effects, usually self-limited and manageable. They can do loperamide as needed. The musculoskeletal pain, again, much more tolerated, I think, better in this area than some of the covalent BTK inhibitors. That patient I was talking about earlier that really struggled with arthralgias and doing the things he loves, like playing piano and working on cars, he was very apprehensive about going back on a BTK inhibitor, but now is doing well and not having — he’s now on pirtobrutinib and not having any of those effects, so that’s been encouraging.

DR LOVE: That’s really interesting.

CAR (Chimeric Antigen Receptor) T-Cell Therapy for R/R CLL

DR LOVE: So we’re going to talk about kind of moving farther down the line in a situation where most patients don’t actually get to this point. We’re going to ask Jeff to talk a little bit about patients with transformation, and then again, in patients beyond pirtobrutinib, the possibility of CAR T therapy. So Jeff?

DR SHARMAN: Yeah. You know, Neil, we get so spoiled with so many options that I think we get lulled into a sense that most patients with CLL are going to do great, and most of them are, but the younger patients, or those patients with higher-risk disease, we’re — if you’re thinking about a 20-to-30-year runway, a lot of these patients are going to get through these therapies. And I think this is something that’s really exciting, and if you haven’t seen CAR T, boy, it’s really something special.

So this is a 67-year-old diagnosed at age 60 with high-risk disease. So again, this is kind of a — you see these high-risk features, IGHV unmutated, deletion 17p, bulky nodes. And actually this was a patient who showed up with an indication for therapy. Platelets were like 60,000.

He was initially treated with ibrutinib for 3 and a half years, had disease progression, treated at that time with rituximab/venetoclax, responded to treatment but then once again progression and enrolled on a pirtobrutinib study, did well for a while but progressed. Now what, right? We’re kind of running out of options unless we’re thinking about going to chemotherapy and so forth.

So I wanted to take a little sidetrack and talk about Richter’s syndrome, what is it? Richter’s syndrome is where chronic lymphocytic leukemia evolves into a more aggressive disease, diffuse large B-cell lymphoma. There is a typo on this slide. I grabbed it off the web. I promise I didn’t put that in there, but we’re just going to go past that.

But these are patients who have MYC activation, TP53 disruption, NOTCH and so forth. And to a pathologist, what they see under a microscope they would call diffuse large B-cell lymphoma most of the time, absent the history of CLL may not know that the patient had a history of CLL.

And this is a very aggressive disease. This is an older paper looking at the survival of patients with Richter’s syndrome, and you can see it’s just like a vertical drop, right? This is in the pre-targeted therapy era, but patients were surviving just a few months. We used to treat them with R-CHOP or dose-adjusted R-EPOCH. If we got lucky and got them to respond we might take them to a transplant. But this is an area where increasingly we’re using CAR T, and CAR T can be a therapy for CLL, but we do use it in Richter’s as well.

Now what is CAR T? CAR T stands for chimeric antigen receptor T-cell. Essentially, a chimera comes out of, I think, Greek mythology, I don’t remember exactly where, but it’s like half goat and half tiger or liger, I don’t remember. And what they’ve done is they’ve taken a portion of the B-cell receptor and a portion of the T-cell receptor, glued them together, and then plugged it into a virus. And then they give that virus to the T cells, which then creates this protein on the surface of the cells and essentially reprograms these T cells to go after the CLL. And that sounds crazy, and it is, but it works.

How do we do it? Patients go through a process called phoresis. We collect their T cells — collect their cells, isolate their T cells. We do a viral transduction. We then expand those cells in a lab and then infuse those cells back to the patient.

And you can see from this press release here this was actually approved just a little over a year ago for patients with CLL. Specifically, read the fine print there, it’s for patients who have received at least 2 prior lines of therapy, including a Bruton’s tyrosine kinase and a BCL2 inhibitor. So that’s where it’s used in CLL currently.

Now this is the TRANSCEND study, and I think the thing that’s really exciting is in some diseases, like diffuse large B-cell lymphoma, acute lymphoblastic leukemia, we’re seeing patients get cured with CAR-T when they were going to die very soon. And what we don’t know is are we actually curing some patients with CLL, and I think the jury’s still out on that. My own personal conviction is that some patients are.

This particular dataset, I will argue, is like the worst dataset you’ll ever see for the molecule because the way the study was done, these patients were like really in trouble when they showed up for the clinical trial. And now with pirtobrutinib we can get patients under control and get them — but you can see in blue, across the top, those patients who do get a complete response, that looks like those patients are doing really well. We’re not seeing progression events in those patients, and I think as we follow the data longer I do think we’re going to start feeling more comfortable saying that some of these patients can be cured.

Now it does come with some unique side effects. One of them is called cytokine release syndrome, and this escalates in Grades 1 through 4. One can just be a mild fever. Two can be fever where maybe you need to give fluids or oxygen. Grade 3, sometimes these patients have hypotension. You might need to give pressors. Hypoxia, where you might need to give higher-flow oxygen. Grade 4 can be really quite dangerous, fortunately pretty rare, but these are patients with multipressors. These are patients in the ICU really quite sick from the process. Again, rare, but not zero.

Another side effect is what’s called ICANS, which stands for immune effector cell-associated neurologic syndrome. And at low grade it’s just patients awaken spontaneously, but maybe they’re a little fatigued. We can do this thing called an ICE test, which gives us a score. At Grade 2 maybe they awaken to — they might get a little bit delirious or somnolent. Grade 3, this is really getting into a quite sick patient, somebody who awakens to tactile stimulus, might have some MRI changes in their brain. Grade 4 is really quite frightening. These are patients who are comatose, cerebral edema, life-threatening infections — excuse me, life-threatening seizures, motor weakness and so forth. Again, rare but obviously high drama when it occurs.

This is actually a patient of mine who did have Richter’s syndrome. This is really just an amazing case for me. On the left, you see he had a lot of disease in the neck. He’d actually occluded his jugular. His eyes were swelling out of his head. It was really an amazing case. And you see the before on the left and the after on the right; all the neck stuff has cleared up.

And you probably can’t see it because it’s in small print, but if you notice the dates on those scans were March 2021 and September 2021. I just saw this patient in clinic a couple weeks ago. He hasn’t had any therapy since that time, and he’s back to teaching at a university in Washington. So a really cool case to be a part of.

When to refer. In my mind, if somebody’s been exposed to BTK and a BCL2 I want to get that patient to a CAR T center for an evaluation because it does take some time to manufacture these cells, and patients need to be able to relocate to a CAR T center for a while. It’s certainly not going to be for all patients. A lot of the older patients might struggle with the toxicity. But again, our younger patients with more aggressive disease, something we definitely want to think about.

So thank you, Neil.

DR LOVE: So when you mentioned cytokine release syndrome I was just flashing on the fact that we also have these bispecific antibodies that are being used that have similar cytokine release syndrome, occasionally ICANS as well. Tomorrow morning we’re doing a program on the use of CD3 bispecifics in small cell lung cancer. Imagine a patient, a lot of tumor, a heavy smoker, typical small cell patient, having cytokine release syndrome. So I’m really curious tomorrow morning. We’re going to have bunch of cases of patients who got that therapy.

Jackie, we asked you to finish out here talking about some of the nursing considerations in patients going through CAR-T therapy. MD Anderson is one of the leading places for CAR-T in the world, and you have a lot of experience there. Jackie?

DR BROADWAY-DUREN: Thank you. So the fact of the matter is we do have a pretty strong CAR T-cell therapy but it’s more so for acute leukemias, ALL more so. We are and have been doing it in CLL patients. So just to give you a brief overview. He just talked about how those cells are genetically modified with the T cells that are extracted from your body — from the patient’s body. It takes about 15 days to make the CARs, if there are no problems or anything, once those have been sent to the lab. And then again, the patient goes through depletion with phoresis, leukophoresis, before to prepare them for the process.

So the patients ahead of time, once this whole process has been done, and in preparation for the patient, we tell patients that, you know, be prepared, if there are complications they may be in the hospital as long as 3 to 4 weeks. We hope not. Generally they are there about 2 weeks, and then they have to remain in the area, in close proximity to the medical center, because they’re there pretty frequently for evaluation and laboratory tests.

As he stated, cytokine release syndrome is a possible adverse effect of CAR T-cell therapy. Myelosuppression, because you remember, prior to getting the CAR-Ts they actually do get some chemotherapy agents. These patients are monitored very closely for fevers. They also have an increased risk for bleeding and tumor lysis in the early stages. I’ve seen several patients who had significant mucositis after getting the CAR T-cell, and so you go through all the nursing interventions you normally would with these patients to try and manage mucositis. That in itself can be a very miserable situation for patients. They may develop skin rash and some hair loss and nausea. So we always make sure these patients have some type of antiemetic on hand for them.

Now, as far as the ICANS, I have literally seen — 2 patients that come to immediately that had ICANS neurotoxicity to the point where they were in the ICU, and one lady, she literally was delirious. I mean, she had periods of aphasia, involuntary muscle twitching. She was having hallucinations and eventually she did have some seizure activity. I have seen a patient that got to the point where it was so accelerated that they ended up having to give her an antibody and reverse it. But it can get to be pretty bad.

So with these patients, when they’re done with the process, and they’re outpatient, every single time they come to the clinic for laboratory tests we always do ICE scores on them. And I know one of the questions is count backwards by 10 from 100. I don’t know whether I can do that myself some days. But I’m like yeah, they’re in better shape than I am.

The CRS — cytokine release syndrome — can occur within 5 days of them getting the CARs, and they’re graded and managed accordingly. Those patients, we are not doing CLL CAR as an outpatient. They’re all admitted to the hospital. Patients get tocilizumab, about 80%, if they are above Grade 2 CRS. They get steroids. Depending on how accelerated the grade is they may get higher doses of steroids. And again, in extreme cases, which we hope to never see, we try to support them through it so they don’t end up having to get antibodies.

So this is a case of a 64-year-old female with refractory CLL who is status post multiple lines of therapy. She’s double refractory to BCL2 and BTKis. She has TP53 and unmutated, which I omitted off the slide. This lady has a history of sarcoidosis and hypertension. And so she was admitted to the hospital for CAR T-cell therapy.

She received lymphodepletion and was conditioned with fludarabine and cyclophosphamide. The CAR-Ts were infused on day 1, and within a 24-hour period she developed a low-grade fever and CRS within 5 days. She was treated for neutropenia with broad-coverage antibiotic therapy. She was admitted to ICU when she advanced to a Grade 3 and was treated with toci and high-dose steroids. The patient eventually did get pressor agents, and this was the case I was telling you about, where we had to go ahead and reverse the CAR T. But that’s not the usual for these patients.

In the patient’s case the CRS was reversed. The patient did well the following weeks, and she remained in the medical center for the next month for close follow-up. As a matter of fact, she did get a second CAR T. I talked to her on the phone yesterday. She’s doing quite well. She’s showing MRD-negative status, so she did tolerate the second time around.

DR LOVE: Oncology’s really fascinating nowadays, and CLL’s a great example. Thank you so much. An awesome job by the faculty. Come on back tomorrow morning, we’ll hear about tarlatamab in small cell lung cancer.