Roundtable Discussion: Exploring Frontline CLL Treatment With BTK Inhibitors

John N. Allan, MD (Moderator)

Assistant Professor

Division of Hematology and Medical Oncology

Weill Cornell Medicine

New York, NY

ALLAN: Based on the NCCN [National Comprehensive Cancer Network] guidelines, it is no surprise that targeted agents are preferred regimens in the United States. We have emerged away from chemoimmunotherapy for almost all patients. You can argue they are used in the low-risk subsets. But ultimately it’s category 1 for acalabrutinib [Calquence], ibrutinib [Imbruvica], and venetoclax [Venclexta].¹ Recently, zanubrutinib [Brukinsa] got a category 2 recommendation for preferred regimen, and I think they must publish the data to get their category 1, as well. So they have the phase 3 data there, in relapsed as well as frontline settings.

These drugs are all available now, and you can start to differentiate how you want to use them. Clearly there’s no standard, and these are eligible for any patient in a frontline setting.

D’SILVA: I picked venetoclax plus obinutuzumab [Gazyva] because of the fixed duration with this combination, and it is a better-tolerated drug. I think this has become the new standard of care.

ALLAN: Very good. We didn’t hear anything about the creatinine, bulky splenomegaly, and relatively high white blood cell count. Does that ever affect your thoughts about [leading with] obinutuzumab and the tumor lysis syndrome [TLS] risks?

D’SILVA: I’ve not seen that, but the LDH was elevated. Other than that, I didn’t see anything else.

ALLAN: Yes, very good. I think it’s absolutely a great option for this patient. There’s no reason not to use it unless the creatinine was elevated. It would be interesting to hear others’ experience with obinutuzumab lead-in; those first 3 weeks or so can be a little rocky [for] some of these patients, with reactions and even potential TLS, etc. In patients with bulky disease, it can be difficult to get it initiated. You could always get them through it, but you get a lot of calls from your infusion center the first couple days and weeks while you’re inducing it. Sometimes it pushes me to a BTK [Bruton tyrosine kinase] inhibitor. For anyone else using venetoclax plus obinutuzumab, is there another specific reason in the case vignette that swayed you, or is it just more of your practice?

NEWSOME: I’m a community oncologist out in Northampton, [Massachusetts]. I picked venetoclax plus obinutuzumab. I tend to lean more toward that. I always have the conversation with the patient, “Look, we can have you take a pill and keep you on as long as you’re tolerating it and responding. Or we can do this infusion, which is less convenient. You must come in regularly, especially in the first month, and then it becomes less arduous. But then you finish at 1 year, basically.” I must say, with the ramp up, it is certainly much less of a concern for TLS, although obviously it’s there if they have bulky disease.

ALLAN: Great. [Let’s consider] some of the data that [have] shown that the TP53-disrupted patients do have an inferior PFS [progression-free survival]. Obviously, it’s a median of [approximately] 4 years, so it’s good, and for 3 years they are off the drug, and we don’t know what retreatment looks like. Does that ever come into play for you?

NEWSOME: Yes, it does. That’s definitely at least part of the conversation.

ALLAN: For sure. Great. So who chose the BTK inhibitor and why?

SHPARBER: I chose that, but another choice would have been just the BTK inhibitor by itself.

ALLAN: Yes, it was plus or minus.

SHPARBER: I think now [with all the drugs] on the market, I see significantly [fewer] adverse events [AEs] in them than with ibrutinib; even in the elderly [patients] who take one of the DOACs [direct oral anticoagulants], there is significantly less bleeding. It is a prolonged course, but you tell them, “This is just like taking your antihypertensive or your oral hypoglycemic.” I don’t get too much resistance.

ALLAN: It sounds like you’re using monotherapy and you’re not adding the anti-CD20 therapy.

SHPARBER: I start with monotherapy, I see what happens, and then I think about adding the anti-CD20. I’m leery with anti-CD20 drugs due to COVID-19, and you probably must be leery with the BTKs, but out of the 2, I’ll just use the BTK inhibitor.

ALLAN: Which BTK inhibitor are you using?

SHPARBER: I’ve recently switched to acalabrutinib. I have no experience with zanubrutinib.

ALLAN: For this patient, being on a PPI [proton pump inhibitor] or an acid-reducing agent, does that affect your choice there, or do you try and get them off?

SHPARBER: I get them all off their H₃ [histamine 3] blockers.

ALLAN: Great. For the other BTK inhibitor choices, was that the same line of thinking?

SHPARBER: Yes.

ALLAN: Do you manage the hypertension? It’s an AE that is caused by [a drug we prescribed]. Do you let the primary care physician [PCP handle] it? Do you get [the patient] to cardiology, and do you work with a cardio-oncologist?

ROSENBERG: Usually if it’s simple hypertension, I will monitor it. But if we get to a point where it’s not well-controlled, I would probably initially have them go to their PCP. If they develop new atrial fibrillations, they go to a cardiologist. I don’t have easy access to a cardio-oncologist; I’m in a community practice.

ALLAN: What is your experience convincing patients they might need blood pressure medicine? I’m just curious about your experience of trying to get them to get started on one.

ROSENBERG: I think patients are open to that. I haven’t had much difficulty with that.

ALLAN: Dr Georges, are you managing the hypertension? I don’t think any of us are managing the atrial fibrillation, necessarily, but for the hypertension, or the arthralgias, are you managing that or shipping that out to the PCP or cardiologist?

GEORGES: Yes, I’m a community oncologist in York, Maine. It is a small practice. For basic stuff like hypertension and arthralgias, we tend to manage those locally in our practice. I’m comfortable managing hypertension. For more complicated stuff, atrial fibrillation, and so on, I’ve worked with our local cardiologist on managing those cases with success. I haven’t had a need to send somebody to a tertiary care center yet, and I do not have access to cardio-oncology at my practice.

ALLAN: Are you using BTK inhibitors, or are you using venetoclax plus obinutuzumab?

GEORGES: Both. In the past couple months, I’ve started patients on acalabrutinib, and most recently I started [a patient] on venetoclax plus obinutuzumab 2 weeks ago. The reason I chose it was because he had atrial fibrillation, which is controlled, and is on a blood thinner. He is somebody who doesn’t want to be on long-term therapy. He’s been my patient for a few years, progressed with splenomegaly now, which was massive. He was losing weight. I did a scan just to make sure there’s no evidence for Richter transformation, because his spleen was enlarging quickly, but we ruled that out and I treated him with venetoclax plus obinutuzumab. I like the fact that I was able to give him the obinutuzumab initially, and the bulky spleen went back to normal size after 3 weeks. His white blood cell count normalized, and he just started the venetoclax ramp-up phase last week with no evidence of TLS so far. He’s done well on that.

ALLAN: Dr Zhou, how about in your practice? Are you managing this? Are you using mostly BTK inhibitors? Are you using venetoclax or a mix? Is it up to patient preference?

ZHOU: Mostly, we consult cardiology. We do have a cardio-oncologist on site, who is easily accessible. My question to them is always, in the setting of hypertension, whether calcium channel blockers are better than the diuretics or the ACE [angiotensin-converting enzyme] inhibitors. That’s something I am interested in learning from them. So we refer them, yes.

ALLAN: I think the [answer to that] question remains unknown. I don’t know if one has been identified as an ideal candidate. There was at the ASH [American Society of Hematology annual meeting] a signal for ACE inhibitors potentially being implicated in these sudden cardiac deaths. But, with bigger analyses, it doesn’t seem like it necessarily shakes out across all the studies that have seen this. It’s not that I avoid it or take patients off it now, but I am much more aggressive at managing, or at least initiating and talking to patients about managing, their hypertension and getting things under control, because we do know hypertension is a predictor and a risk factor for developing atrial fibrillation, etc. I think we can be more aggressive than we might be normally.

When I try to start patients on amlodipine [Norvasc], or a β-blocker, or [another antihypertensive], there is strong resistance. I have 80% of patients say, “At home, [my blood pressure is] completely normal. At my primary care office, it’s completely normal,” even though it’s clear [it was] normal in my office before this BTK inhibitor and it’s risen. So I have a lot of resistance from patients [because] they’re taking a lot of medications. Sometimes they’re on a blood pressure medicine, it’s just not at a high enough dose, and there’s room to move. But I’ve seen a lot of resistance. I don’t know if anyone else has had that experience, but it sounds like most are trying to [delegate] it to the PCP or cardiologist, etc. Anybody have that experience?

KOCH: [I have had a] few patients along the way who were a little bit resistant. They generally tell me exactly what you’ve said. In my office their blood pressures are high, but they’ll swear they’re fine. I always told them, “Well, get a blood pressure cuff if you don’t already have one. Mark your blood pressure down every day, at different times, for a few days or 1 or 2 weeks, and bring back the data to me or to your PCP so we can be clear if this is truly drug-induced hypertension.”

ALLAN: For sure. Yes, I’ve [had a few patients] with bad cuffs, and they’re doing it with these little cheap ones that go around their wrist, and then they get a good one and, boom, it was real. That was finally what convinced them, sometimes. But even then, [they’ll say], “Oh, it’s [only] 145 systolic.” That’s still hypertensive, and they still don’t want to start something, even though it was 120 systolic before they started, and they think that’s OK. It’s fine, it’s not the worst, but I still get a lot of resistance even when they’re bringing in their counts.

I guess this group is kind of mixed….It looks like maybe more participants prefer a venetoclax plus obinutuzumab approach for their patients mostly in an upfront setting.

MEHTA: I can give my perspective. I work in a satellite of Dana-Farber Cancer Institute, but in our practice we have an on-site pharmacist and chemotherapy teaching is done by the outpatient dispensing pharmacy. But in this specific situation, all the discussion about the AEs is mostly done by me, because it plays into the decision about which route to go. The discussion is pretty much all about AEs on this vs the other regimen, so there is barely anything left beyond my discussion that the patient would learn from the teaching session.

I would like to just mention about the hypertension and atrial fibrillation issues. I feel that with acalabrutinib I faced much [fewer] of those in my personal experience and, yes, the PPI issue is always brought up. We get messaged by the pharmacist if we overlooked it. But most of the patients can then switch over from a PPI to a famotidine [Pepcid]-type regimen. Occasionally, they are not able to, and then that does play a role in terms of the BTK choice. But it’s mostly manageable. And believe it or not, a lot of times these [patients] are on PPIs without knowing why they are on it, for years. It’s not uncommon.

ALLAN: It’s sometimes tough to get them off once you try. I think you speak for the group that, obviously, it’s part of the informed consent, talking about these AEs, etc. We’re probably doing a lot of it, honestly, with our patients. I have missed carvedilol [Coreg], and some other medications that venetoclax and some of these other agents that can increase the levels, [only to be] notified by our pharmacist and specialty pharmacy. It’s nice to have them double-checking things, as well.

CERNY: I am in a university practice. I have the benefit of having a cardio-oncologist to work with, but I would say these issues are far too easy to manage for him. He helps me with more complex decisions. Because it is part of the consenting process and discussion about which route we go, I discuss the AEs with patients, as well. Many times, [patients] ask, “What is it that I can do”? I often leave them with, “You need to control your blood pressure better and either work with your PCP or you must work with us.” Because, ultimately, patients tend to see us more often than their PCPs and cardio-oncologists. I have also the benefit of having great pharmacists. They will catch some of the omissions, so it’s great to have a great team taking care of these patients.

ALLAN: I echo those points. I manage a lot of hypertension [in patients], and because we see them so often, they’re frequently asking me to refill their medications….It’s my name that gets on that last script, and suddenly I’m the one who’s prescribing it. It’s fine, I do feel comfortable doing it. Obviously, if they get to 2 or 3 agents, for example there are 2 agents that are maxed and I’m thinking about a third agent, I start to get our nephrologists involved. We have a hypertension specialist if you’re talking about clonidine [Catapres] and things along those lines and other significant calcium channel blockers. That’s where I need some help. I draw the line at starting to max out on 2 hypertensives.

KADDIS: I use different strategies based on the patient’s age, their comorbidities, frailty, and, of course, the prognostic factors such as IGHV mutations and del(17p), because there is evidence that some of those high-risk patients respond better to certain strategies than others.

It’s very specific to the patient. The other think I wanted to say, too, is that a lot of my younger patients in their 50s and 60s want finite treatment. These days, though, we are shying away from CD20 inhibitors such as obinutuzumab because of the slight increased risk of COVID-19 infections and decreased response to the vaccines. In the pandemic era, I know a lot of these studies are just maturing and coming out now, but it’s also a little limiting. I have a couple of patients on obinutuzumab plus venetoclax, but there are several others who we’ve chosen not to start on that treatment, specifically because they’re worried about COVID-19 infections and risks.

ALLAN: Are you mostly using BTK inhibitors for these types of patients, then? And, in general, most patients? Or do you still use chemoimmunotherapy for these low-risk patients in your practice?

KADDIS: [I use it] for the younger patients. [I had] 2 in the past year who were under the age of 65 years, were healthy, [had] good performance status, and they were on FCR [fludarabine (Fludara), cyclophosphamide (Cytoxan), rituximab (Rituxan)]. But otherwise, for most of my patients who were not starting obinutuzumab plus venetoclax, I have started on a BTK inhibitor and I’ve had various levels of success and various complications, including atrial fibrillations and arthralgias. I’m still trying to navigate that.

ALLAN: Are you using the molecular factors to help steer you toward those patients you want to use FCR for?

KADDIS: Yes. I certainly don’t use FCR for some of the higher-risk patients with mutated IGHV or del(17p).

ALLAN: Dr Shparber, what are your thoughts? What do you think is the standard of care, and what approaches are you using for which patients?

SHPARBER: Until recently, I used exclusively BTK inhibitors. The last patient was on venetoclax and obinutuzumab. It went well for a year and, based on clinical grounds, he seems to have achieved a complete remission….I don’t do much [molecular testing]. From what I understand it’s a great tool, but I don’t think it guides treatment, as best as I can tell. Nor did it, in my mind, indicate that overall survival [OS] has improved. But I could be wrong.

ALLAN: Are you sending for a lot of these molecular features that help dictate your choices for patients?

SHPARBER: I do. I don’t use much NGS [next-generation sequencing]. I’m not sure how good they are. But I do, at least, IGHV [testing] and FISH and chromosome analysis on diagnosis. Also, [I do them] after treatments when [patients] develop additional mutations. IGHV doesn’t change, usually, so I don’t bother repeating it.

ALLAN: It sounds as though you’re not using chemoimmunotherapy in your practice, typically, for the most part. It sounds as though you use BTK inhibitors.

SHPARBER: I don’t [use] chemoimmunotherapy.

ALLAN: Have you had experience with the later-generation ones, or mostly ibrutinib?

SHPARBER: No, I use acalabrutinib almost exclusively.

ALLAN: Has that been recent with the ELEVATE-RR [NCT02477696] data, or has that been your practice because you had experience with it early?

SHPARBER: Yes, it’s the latter.

MEHTA: I would say the triplet data made sense theoretically, and now [we know] that there are trials showing a similar benefit and with no cross-toxicity. Helping us to use all oral agents in the front line would be great. I think what we belabor about these chronic toxicities from BTK inhibitors may not become relevant once you use it in a time-limited fashion. To me, that’s more exciting. I think they both have very different roles, mechanistically. One works on the lymph nodes, the other one in the peripheral blood. It would make sense to use [them] together, and that’s panning out pretty well without adding any severe toxicities. How the triplet would work and how you would sequence that is still a question in our mind, or if there is even a need for a triplet and in which patients. So, those will be interesting.

[Regarding] the zanubrutinib trial [SEQUOIA; NCT03336333], I am curious why they had patients with unmutated IGHV on the BR [bendamustine (Treanda)/ rituximab] arm. How would a trial like that even be approved? Was it outside the United States?

ALLAN: I believe there were United States sites. I guess the [other question] is why they are still doing chlorambucil studies, because that’s clearly an inferior arm. But there has never been an OS benefit to these drugs in that unmutated arm yet. Technically, you’re not doing a truly harmful thing in terms of detriment to the OS survival, though. I don’t use chemoimmunotherapy in my practice, and our group has stayed away from any clinical trial that randomized to a chemoimmunotherapy arm for these reasons, because we just believe that these drugs are just so powerful and better for our patients. We avoid that kind of conundrum.

Ultimately, I think these are important studies. Chemoimmunotherapy in the United States is still used very heavily, specifically bendamustine/rituximab, so I do think it’s a true comparator of analyzing outcome and efficacy. It’s a registrational study, and one could argue they are always done in an ethical way, but I think it is better than a chlorambucil comparator arm, for sure.

KOCH: One of the things I would be interested in knowing more about is the MAJIC trial [NCT05057494] that [has] venetoclax plus or minus acalabrutinib. It would be interesting to see the results of that trial. I think there’s also a trial [NCT03740529] with pirtobrutinib [LOXO-305] in patients who have failed first-line therapy with BTK inhibitors. I think [those] data would be interesting to see once they emerge.

ALLAN: Yes, the pirtobrutinib data are very encouraging and exciting. We will potentially get access to that drug, hopefully in the relatively near future. Those combination studies are being done. You mentioned the MAJIC study. There’s CLL17 [NCT04608318], which is ibrutinib vs venetoclax plus obinutuzumab vs ibrutinib plus venetoclax, a 3-arm study. There’s another by AstraZeneca [NCT03836261] that’s acalabrutinib, venetoclax, obinutuzumab vs [acalabrutinib, venetoclax, and chemoimmunotherapy]. There are the ALLIANCE [NCT02414022] and E1912 [NCT02048813] studies in older and younger patients, a triplet vs ibrutinib plus obinutuzumab. [There are] a lot of big phase 3 studies that are going to be maturing and reporting in the next 3 to 5 years, probably.

There isn’t a perfect study, yet, because…[it doesn’t] have that triplet arm. They’re always missing one of these arms that a single study might be able to answer, and so we’re going to have to compare some of these and use baseline comparators, phasing analyses, and things like that to try to understand what’s going on.

GEORGES: I know we’re using all those combinations of small molecules, but we’ve got to think about financial toxicity, too. Those regimens are going to be super expensive, and what are we achieving? Are we curing CLL, is that the goal, to deepen the response to keep the patients off therapy longer? I think those are a lot of questions that need to be answered before we jump on those super expensive regimens, the triplets, and so on and so forth.

ALLAN: I think the cost analyses need to be done. I guess the one advantage, and the counter to it, is that it is designed to be of a fixed duration and to get a patient off therapy. Because we know 50% of patients are on ibrutinib at $100,000 a year for 7-plus years, or even longer. There’s a potential that as those data mature they may get off the drug, and there are benefits there.

GEORGES: I have a patient who was on ibrutinib for [approximately] 4 or 5 years and then developed neutropenia, so we took him off the drug. It took a while for the neutropenia to get better [From the Data²]. Eventually he got better. I almost did a bone marrow [transplant], but he refused and then his neutropenia resolved and he refused to go back on ibrutinib. It’s been almost 3 years off therapy, and he is still in remission.

ALLAN: Yes, we do see that phenomenon, and who is the right patient to do that? It’s tough. The paradigm is to continue it, but yes, I think you’re right. You can come off these, and E1912 showed us the patients who came off for toxicity, who’d been on [ibrutinib plus rituximab] for a median of 1.5 years, had a median PFS of 2 years.³ Half of them had longer than that before they had a progression. So you can have these very meaningful remissions, [even] if you’ve been on the drug for some time, especially with low-risk disease that’s not going to clonally grow back quickly.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 2.2022. Accessed May 19, 2022. https://bit.ly/3sKDLCB}

_{2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x}

_{3. Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. Published online April 15, 2022. doi:10.1182/blood.2021014960}