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BTK Inhibitors for CLL and MCL: A Settling Storm or Just the Beginning?

  • Authors: Deborah Stephens, DO; Chan Cheah, MBBS, FRACP, FRCPA, DMSc; Barbara F. Eichhorst, MD; Nirav N. Shah, MD
  • CME / ABIM MOC Released: 12/28/2022
  • Valid for credit through: 12/28/2023, 11:59 PM EST
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    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for hematologist/oncologists and pathologists.

The goal of this activity is to enable learners to better understand the recent data on Bruton tyrosine kinase (BTK) inhibitors and how they may change practice in managing patients with B-cell malignancies (eg, chronic lymphocytic leukemia [CLL]/small lymphocytic leukemia [SLL] and mantle cell lymphoma [MCL]).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Current challenges with available BTK inhibitors in patients with B-cell malignancies
    • Emerging clinical trial data on BTK inhibitors in B-cell malignancies
  • Demonstrate greater confidence in their ability to
    • Integrate the latest data with BTK inhibitors into the treatment algorithm for patients with B-cell malignancies


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  • Deborah Stephens, DO

    Associate Professor
    CLL and Lymphoma Program
    Division of Hematology and Hematologic Malignancies
    University of Utah
    Huntsman Cancer Institute
    Salt Lake City, Utah, United States


    Deborah Stephens, DO, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie, Inc.; BeiGene (Beijing) Co., Ltd.; Bristol Myers Squibb Company; Celgene Corporation; CSL Behring; Genentech; Lilly; TG Therapeutics, Inc.
    Research funding from: Acerta; ArQule; AstraZeneca Pharmaceuticals LP; Juno Therapeutics, Inc.; Mingsight; Newave; Novartis

  • Chan Cheah, MBBS, FRACP, FRCPA, DMSc

    Consultant Hematologist
    Sir Charles Gairdner Hospital
    Perth, Australia


    Chan Cheah, MBBS, FRACP, FRCPA, DMSc, has the following relevant financial relationships:
    Consultant or advisor for: AstraZeneca Pharmaceuticals LP; BeiGene (Beijing) Co., Ltd.; Bristol Myers Squibb Company; Eli Lilly and Company; Gilead Sciences, Inc.; Janssen; Merck Sharp & Dohme; Novartis; Roche; TG Therapeutics, Inc.
    Speaker or member of speakers bureau for: AstraZeneca Pharmaceuticals LP; Roche
    Research funding from: AbbVie, Inc.; Bristol Myers Squibb Company; Eli Lilly and Company; Loxo Oncology; Merck Sharp & Dohme; Roche

  • Barbara F. Eichhorst, MD

    Associate Professor
    Consultant Hematologist
    Department for Internal Medicine
    Secretary of the German Low-Grade Lymphoma Study Group
    University Hospital of Cologne
    Cologne, Germany


    Barbara F. Eichhorst, MD, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie, Inc.; AstraZeneca Pharmaceuticals LP; BeiGene (Beijing) Co., Ltd.; Bristol Myers Squibb Company; Eli Lilly and Company; Janssen; Merck Sharp & Dohme
    Speaker or member of speakers bureau for: AbbVie, Inc.; AstraZeneca Pharmaceuticals LP; BeiGene (Beijing) Co., Ltd.; Janssen; Merck Sharp & Dohme; Roche
    Research funding from: AbbVie, Inc.; AstraZeneca Pharmaceuticals LP; BeiGene (Beijing) Co., Ltd.; Gilead Sciences, Inc.; Janssen; Roche

  • Nirav N. Shah, MD

    Associate Professor
    Medical College of Wisconsin
    Brookfield, Wisconsin, United States


    Nirav N. Shah, MD, has the following relevant financial relationships:
    Consultant or advisor for: Bristol Myers Squibb Company; Epizyme; Incyte Corporation; Kite Pharma, Inc.; Lilly Oncology; Miltenyi Biotec; Novartis; TG Therapeutics, Inc.
    Research funding from: Lilly Oncology; Miltenyi Biotec


  • Sanneke Koekkoek

    Medical Education Director, WebMD Global, LLC


    Sanneke Koekkoek has no relevant financial relationships.

  • Chii Shyang Fong, PhD

    Scientific Content Manager, WebMD Global, LLC


    Chii Shyang Fong, PhD, has no relevant financial relationships.

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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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BTK Inhibitors for CLL and MCL: A Settling Storm or Just the Beginning?

Authors: Deborah Stephens, DO; Chan Cheah, MBBS, FRACP, FRCPA, DMSc; Barbara F. Eichhorst, MD; Nirav N. Shah, MDFaculty and Disclosures

CME / ABIM MOC Released: 12/28/2022

Valid for credit through: 12/28/2023, 11:59 PM EST


Activity Transcript

Deborah Stephens, DO: Hello, and welcome. I'm Debbie Stevens, and I'm from the Huntsman Cancer Institute at the University of Utah. Thanks for joining us today for "BTK Inhibitors for CLL and Mantle Cell Lymphoma: A Settling Storm, or Just the Beginning?" We're very lucky today to have 3 additional expert speakers here, Dr Chan Cheah from Australia, Dr Barbara Eichhorst from Germany, and Dr Nirav Shah from Medical College of Wisconsin in the United States.

In this program, we're going to be focusing on the following items, the current challenges with the available BTK inhibitors in patients with CLL and mantle cell lymphoma, take a look at emerging clinical data on BTK inhibitors coming out of American Society of Hematology (ASH) 2022 [conference], and the majority of the time, we'll spend doing a panel discussion on the clinical implications of the new data presented at ASH.

As a way of introduction, I'd like to give just a brief review of the mechanism of action and the difference between covalent vs noncovalent BTK inhibitors. When we talk about covalent inhibitors, these are irreversible drugs that bind specifically to a drug target and form a permanent bond with their target. When we talk about noncovalent inhibitors, these are reversible drugs which are in equilibrium with their target, continually binding, unbinding, and rebinding.

Specifically in this session, we are going to talk about some selected BTK inhibitors, and so covalent, again, these are the ones that bind irreversibly to BTK in a C481-dependent manner. Those are the drugs, ibrutinib, acalabrutinib, and zanubrutinib. And when we talk about noncovalent inhibitors, again, these are the ones that bind reversibly to BTK in a C481-independent manner. We're going to focus on pirtobrutinib and nemtabrutinib today.

So our group has selected some key abstracts regarding covalent and noncovalent BTK inhibitors in CLL and mantle cell lymphoma presented at ASH 2022. So let's do a quick round and ask for a brief summary of data. So let's start with the covalent BTK inhibitors in CLL. Barbara?

Barbara F. Eichhorst, MD: So yeah, thank you very much, Debbie. As you all know, we have these 3 covalent-binding BTK inhibitors which are approved, or at least zanubrutinib is now approved by the European Medicines Agency (EMA) in Europe. And so the new BTK inhibitors, at least acalabrutinib, are not so new anymore. We selected here, or we want to discuss an abstract with now 4 years follow-up of our phase 1/2 study. And in that study, more than 130 patients who were relapsed or refractory to CLL were included. And the data from the study also reflect quite nicely the similar progression-free survival rates as observed in the ASCEND study.

They also indicate that, again, or confirming that the rates of atrial fibrillation as well as the rates of major bleeding are really low, and mostly follow-up time of up to 7.4 years. So confirming that, with respect to the side effect profile, acalabrutinib has advantages over ibrutinib.

As we have seen that, for example, in the ELEVATE-RR study, and this is the next abstract I want to discuss. This was a poster presented by John Seymour from Melbourne. And the approach they took in the abstract, I think it's quite relevant for all patients being on continuous treatment, because normally, we just calculate incidence rates of side effects. But, of course for a patient, even grade 1 or 2 side effects which are lasting for a long time can be a big problem. And many of those patients on continuous treatment stopped, not so much because of the severe side effects, but also because of the grade 1 and 2 side effects.

And therefore, on that poster they addressed the burden of adverse events, and they confirmed with that method, calculating on severity, but also the duration of some side effects, that confirming that cardiac comorbidities were more frequent as well as muscle pain, or also arthralgia with ibrutinib. On the other hand, the known side effect of headache is significantly higher with acalabrutinib, also with respect to the adverse event burden. And in addition to that, diarrhea, which was at least for me some surprise, but grade 1 and 2 diarrhea tendency was associated with a higher adverse event burden.

And then last but not least, we had a late-breaking abstract on zanubrutinib in the relapsed setting within the ALPINE study, compared head-to-head in a nonblinded manner to ibrutinib. And here in the late-breaking abstract, Jennifer Brown showed that after the first primary endpoint was already shown a year ago, with respect to overall response rate, which was superior with zanubrutinib over ibrutinib. Now, they tested the next step for the progression-free survival, noninferiority, and then this test was also showing noninferiority. They tested for superiority, and this is the first study with the head-to-head comparison showing also superiority of one of the BTK inhibitors over the other one. And there are also some aspects with regard to subgroups, also with regard to the ibrutinib to which I'm very much looking forward to discussing with you.

Dr Stevens: Yeah. Thank you very much. That was a great overview. I'm going to move into the noncovalent BTK inhibitors in CLL, and there were some important and exciting data shared at ASH 2022.

And pirtobrutinib, there were several abstracts that were, I think very key abstracts to discuss. And one of them is the extended follow-up from the phase 1/2 BRUIN study, and this is for patients with relapsed or refractory CLL. And they specifically looked at that cohort. It's a subset of a bigger phase 1. With more than 2 years of additional follow-up data, pirtobrutinib continues to demonstrate clinically meaningful and durable efficacy in these CLL patients, especially notable in these patients previously treated with the covalent BTK inhibitors.

And favorable efficacy was observed regardless of BTK C481 mutation, status, age, TP53 and or del(17P) mutation status, and those with many prior lines of therapy. And again, I think this is just specifically notable in the patients who previously were treated with covalent BTK inhibitors and a BCL-2 inhibitor. Really consistent, high overall response rates across all of these subgroups. And of course, one of the shining parts of this drug is the low rate of toxicity, and really low grade ≥ 3 AEs, low discontinuation rates due to drug-related toxicity.

So, expanding the group, looking at all the B-cell malignancies who were previously treated with pirtobrutinib on the phase 1/2 BRUIN study, this particular abstract showed that pirtobrutinib monotherapy was safe, well tolerated in these patients. They analyzed a subset of patients who had intolerance to prior BTK inhibitor therapy, and this included patients who were on anticoagulation with prior and or active atrial fibrillation. And most of these patients did not experience a high-grade recurrence of AEs that led to the discontinuation of the initial BTK inhibitor that they were on. And among those who did, none actually discontinued pirtobrutinib because of that AE. And so this is just a really good abstract that shows pirtobrutinib being effective in patients intolerant to a prior BTK inhibitor.

And then something a little bit different, switching to Richter's transformation. This was a really great abstract that looked at patients who are heavily pretreated with Richter's transformation. Of course, this is a group that has an extremely poor prognosis, and pirtobrutinib, just a monotherapy demonstrated really promising preliminary efficacy. And including patients who had prior chemoimmunotherapy and covalent BTK inhibitors. There were 50 patients on this study who were available for response at this time point. Overall response rate was 54%, which is great in this population. And I think even more notably, there were 5 complete responses (CRs) with a monotherapy BTK inhibitor, which is really great for this patient population.

So now, still relatively short follow-up, median duration of response was about 8 months. Median overall survival was 13 months, so still not perfect news for these patients. But, there were 6 patients on study who electively discontinued pirtobrutinib to go on to allogeneic stem cell transplant. So maybe this could be a drug that we can bridge those patients and get them into response. And again, this was just really well tolerated for these patients.

Shifting gears just slightly to nemtabrutinib, which is another noncovalent BTK inhibitor, and the extended and updated analysis of the phase 1/2 Bellwave-001 study, where nemtabrutinib was used at the recommended phase 2 doses of 65 milligrams daily. This drug also continues to show really promising and durable antitumor activity with a manageable AE profile. Again, this was tested in a really heavily pretreated patient population who had treatments with other novel therapies, including BTK and BCL-2 inhibitors. Saw similar overall response rates across these key high-risk subgroups, people who had prior BTK, prior BCL-2, C481S-mutated BTK, del(17P), immunoglobulin heavy-chain variable region gene (IGHV)-unmutated status. And again, we saw a really low rate of treatment related AE discontinuation, only 13% in this study.

So I'd like to switch gears a little bit from CLL to mantle cell lymphoma. Chan, can you give us an update on the covalent BTK inhibitor scene?

Chan Cheah, MBBS, FRACP, FRCPA, DMSc: Yeah, sure, Debbie, thanks. So there were a few interesting abstracts presented around covalent BTK inhibitors in mantle cell lymphoma. And one of them was a study coming from the Peter MacCallum Cancer Center in Melbourne, using a combination of time-limited ibrutinib in combination with tisagenlecleucel in patients with primarily BTK inhibitor refractory mantle cell lymphoma. So as you know, the management of patients with covalent BTK inhibitor refractory mantle cell lymphoma remains a challenge. There is 1 approved CAR T construct brexu-cel, however, there remains a need for development of more therapies. So in this abstract, ibrutinib was used as a way of, number 1, providing disease control around the time of leukopheresis, and while CAR T-cell manufacture was occurring. And secondly, as a hypothetical way of improving CAR T-cell fitness to potentially improve efficacy.

So around 20 patients were enrolled on this study. It was a reasonably small study. However, the efficacy was quite impressive. At 4 months, the CR rate was 80%, and a minority of patients experienced disease progression. The response rate among patients who were BTK naive was 90% CR rate. Numerically slightly lower among the Bruton tyrosine kinase inhibitor (BTKi)-exposed group, but that was not statistically significant. And I think the reassuring thing, given that these are patients with frequently high-risk biology, such as TP53 mutations, high Ki67, and other genomic aberrations conferring adverse biology, those patients all seem to have reassuringly high CR rates. Again, which provides a good support for the use of tisagenlecleucel and ibrutinib in this population.

There was also some nice correlative work done with this study, looking at the correlation between chimeric antigen receptor (CAR)-T-cell expansion and T-cell exhaustion markers, showing that those did correlate with response.

There was also another abstract presented with ibrutinib in combination using a ROR1 antibody-drug conjugate called zilovertamab vedotin (ZV). Zilovertamab vedotin is an interesting molecule actually. It also has activity in CLL, as you know. And in this particular study there were both patients with mantle cell lymphoma and CLL included. And essentially, the zilovertamab is given as an infusion. The safety profile of ZV in combination with ibrutinib did not seem to add substantially to the toxicity in this combination.

However, it did appear to improve the efficacy. We know that for single-agent ibrutinib in a population of mantle cell lymphoma patients who are relapsed and refractory, you would expect to see a complete response rate of maybe 30%, 40% with ibrutinib, something like that, if you use positron emission tomography (PET) to assess. I think that the overall response rate and CR rate that we saw in this study were encouraging, and probably maybe a little bit higher than what you would expect. But more impressive was the median duration of response, which we observed for the mantle cell lymphoma cohort, which is about 34 months. If you think back to some of the phase 2 studies with ibrutinib and acalabrutinib monotherapy in mantle cell lymphoma, you would probably expect it to be a little bit shorter than that, maybe around about 2 years or so. And these data serve as the basis for an ongoing phase 3 study, which is enrolling.

Dr Stevens: That's great. So Nirav, what about the noncovalent BTK inhibitors in mantle cell?

Nirav N. Shah, MD: This is a noncovalent or reversible BTK inhibitor, and this was actually presented as an abstract by Dr Wang, and then group at MD Anderson and colleagues, looking at the efficacy in those patients with relapsed refractory mantle cell lymphoma. And this is really a large cohort of patients, a now extended follow-up from the phase 1/2 BRUIN study. And within this, the majority of patients that were treated were actually covalent BTK inhibitor exposed. And so that's an interesting population. And so the question is, can a noncovalent work in this patient population?

And so what's interesting is that the overall response rate in the prior covalent BTKi exposed was 57.8%. And not surprisingly, in the small group of patients that were actually BTK inhibitor naive, it was much higher, at 85.7%. But we know that those patients who failed covalent BTK inhibitors have few options, and this looks like a promising strategy. The median duration of response was 22 months, but the median follow-up was 12 months. Eventually, the number 1 reason that patients did ultimately discontinue was due to disease progression.

And, as previously noted among the other pirtobrutinib trials, the safety profile seems to be in line with all the other histologies, with low rates of discontinuation due to drug-related toxicities, at 2%. And it seems to have a slightly different toxicity profile than our covalent BTK inhibitors. And I think that comes back to the mechanism of action that you described, Debbie.

Dr Stevens: No, this is great. There are so many good abstracts on this topic, and so we need to talk about what this actually means for our patients, or how do we use this in clinic? So how do you guys choose between what BTK inhibitor to use right now? Barbara?

Dr Eichhorst: Yeah.

Dr Stevens: Any thoughts on that?

Dr Eichhorst: Yeah, I mean that's, I think to be discussed with every patient individually. There is a big discussion about if there is still a role at all for ibrutinib as continuous therapy, not within the combination, but as continuous therapy, due to the better toxicity profile in comparison to acalabrutinib. However, my argument, because I still use ibrutinib in younger and fit patients without comorbidities is that the E1912 study was so far the only study showing benefit for overall survival on ibrutinib. And we do not yet have these data in the young patients with acalabrutinib (acala). So there was, in the ELEVATE-TN study, a benefit for overall survival, but this was in comparison to chlorambucil plus obinutuzumab. And I think there is still a role for ibrutinib.

And of course, acalabrutinib is an excellent drug for patients with hypertension. And now with zanubrutinib (zanu) showing superiority to ibrutinib, I think it's difficult now to make a decision between zanu or acalabrutinib, because we don't have a head-to-head comparison here. And I think we won't also have a head-to-head comparison.

So my choice, or talking with the patient would be, if he has a higher risk, if it's more important for him that he really responds for a long time. So maybe rather the young and fit patients, I would choose zanu for them, and acala more for the elderly patients with comorbidities.

Dr Stevens: Got it. Is it any different in mantle cell lymphoma? Or, how do you choose a mantle cell which drug to use?

Dr Shah: Sure. So I think that ultimately we try to make decisions based on the individual patient. And what I try to think about is what toxicity may affect this patient the most. And so we know, based on the data we talked about, that there's unique toxicities of all of these agents. And some of this is driven by approval. We're lucky in the US, we have all 3 covalent BTK inhibitors approved for mantle cell lymphoma, but I really try to individualize it to the patient and their needs.

Probably using a little bit more second generation, acalabrutinib, zanubrutinib. And honestly, we're getting this data extrapolated from CLL patients, mainly because we don't have that head-to-head comparison in mantle cell. But extrapolating some of the safety data, thinking about mantle cell patients who tend to be a little bit older, have accumulated more comorbid conditions. I try to take that into account with my decisions. What do you think, Chan?

Dr Cheah: Yeah, so it's an interesting one, isn't it? I have to say I agree with you in that I am predominantly using second-generation covalent BTK inhibitors now for my relapse/refractory mantle cell lymphoma patients, more so than ibrutinib. Because, like you in Australia, we're fortunate to have the choice of all 3 agents. We don't have any direct phase 3 data to really make that comparison, but I do think it's reasonable to extrapolate the safety data from trials in CLL and Waldenstrom macroglobulinemia, for that matter. And so for that reason, I'm pretty comfortable preferencing acalabrutinib and zanubrutinib over ibrutinib.

Dr Stevens: Yeah, that's great. And I think a good message is, we have a lot of great drugs for our patients, so it's nice to have different choices. Now, Barbara, I'm interested in the ALPINE data that you presented, and I would love to hear your thoughts on how do you think this benefit in progression-free survival of zanubrutinib over ibrutinib is going to impact the field?

Dr Eichhorst: Yeah, I mean the interesting thing is when we just look at the ibrutinib arm, it seems that the progression-free survival there is doing a little bit worse than we have seen in the past, for example, the RESONATE study. And so the patients in the RESONATE study were even more heavily pretreated.

I think there is, at least to my knowledge, no clear explanation that patients in the ALPINE study were, in tendency a little bit older. I think one would have to look in detail into the data if they also had more comorbidities, because obviously the key is that the patients stay on the BTK inhibitor because there is a 14% difference in stopping treatment favoring zanubrutinib. And that probably would be my assumption, the key that patients also have gotten a better response. So maybe it was just the patients, which were included with respect to the comorbidities. Maybe, I think what also has changed with all these different BTK inhibitors we have available right now, that of course patients know about that, they tend not to tolerate side effects so well as at the beginning.

Dr Stevens: They know they have options.

Dr Eichhorst: They have options. At first, ibrutinib, everyone wanted to stay on the drug, and so now it's different.

Dr Stevens: Yeah, no, I agree with that. And how about the management of these side effects? So Chan, are there certain side effects you think are particularly bothersome to manage on these BTK inhibitors? And how do you deal with them? Do you dose reduce? Do you change people over a class of drugs? What do you do?

Dr Cheah: Yeah, that's a great question you asked, Debbie. I think that it depends on side effects. So there are certain side effects which you know are going to be short term, during the first month or 2 of treatment. For instance, the headache with acalabrutinib. And if you counsel patients about how to, often caffeine helps for that, so that works pretty well. And if patients know that it's going to be for a brief period of time, you can usually push through it.

So other things can be more troublesome. So, if patients have atrial fibrillation, then sometimes that requires more thought, involvement of a cardio-oncologist, making sure that you've covered off appropriate rate control, if necessary. And then considering whether or not a patient needs to have anticoagulation, because of course patients with CLL mantle cell lymphoma are often elderly. They often have a higher CHF, hypertension, age ≥ 75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65 to 74 years, sex category (CHA2DS2-VASc) score. And if they get AF, then you need to think about whether you need to put them on anticoagulation or not. And then how that plays into the fact that their BTK inhibitor also is potentially going to cause an increased rate of bleeding. So there are a few considerations. Fortunately, it doesn't happen to the majority of patients who were treated, but it is something that does take up quite a bit of time in the initial consult, when you're starting someone with BTK inhibitor. Right?

Dr Stevens: I think that that helps so much, that initial conversation, just letting the patients know what side effects to watch out for, and things like encouraging them already, that there are ones that are going to get better if they just stick it out on the drug for a while. So Nirav, what do you think? Are there side effects that you would prefer to switch class altogether, as opposed to try dose reduction, or switch to a different BTK inhibitor?

Dr Shah: Yeah, I think the greatest long-term concern is the cardiovascular toxicities, right?

Dr Stevens: Yeah.

Dr Shah: I mean, so there's data coming out. There's been some posters, some papers talking about ventricular arrhythmias, atrial fibrillation, that increases your risk of stroke and other complications. And so we are seeing lower rates of atrial fibrillation. And I think the data we talked about in both the second-generation covalent, and even the noncovalent, which obviously is not available at this point in any of our countries. But I think, when it comes to that cardiovascular toxicity, there's short-term and long-term risk. And ultimately, our goal is for patients to be able to stay on these medications, take them with fidelity, which we know it's going to affect their progression-free survival. And that's a situation where I will consider switching to a different agent.

Dr Stevens: And Barbara, I find in my clinic hypertension is particularly bothersome. How do you deal with that, and what do you think? Sometimes I have these young patients, they're on a continuous BTK inhibitor therapy, and then you pile on another blood pressure medication, and then another. How do you deal with the hypertension?

Dr Eichhorst: Yeah, I would switch to acalabrutinib if the patient is already started with ibrutinib, and otherwise, of course when the CLL is very well controlled already, because the patient is, for example, already on the treatment for a couple of years, I would do a dose reduction, which is not so easy with acalabrutinib due to the tablet size available. Or, I think with suspect for zanubrutinib, the rates of arterial hypertension were not different in comparison to acalabrutinib, but I would first try dose reduction before I stop the treatment in those patients.

Dr Stevens: And these data are really exciting about the new drugs, and the toxicity profile is great. So I would love, Nirav, what do you think, and where do you see these noncovalent BTK inhibitors fitting in the field of mantle cell?

Dr Shah: Yeah, so I think that it's really exciting to have this class of drugs. I think that for those of us who treat mantle cell, when you fail a covalent BTKI, it's like falling off a cliff. And we try to urgently get them to CAR T, but the CAR T that's approved right now is not necessarily the easiest to tolerate, especially in a group of mantle cell where you could have 70- and 80-year-olds. So I think that the initial clinical benefit and unmet need is going to be covalent BTKI failures in mantle cell lymphoma. And so, we'll see. Having these noncovalent drugs available I think will really serve that patient population. There's a head-to-head clinical trial that's actually going to compare noncovalent to covalent in mantle cell. I think it's a very bold study, to be honest.

Dr Stevens: Agreed.

Dr Shah: But, I think it's going to give us so much information, it's going to really tell us, does a mechanism of action of a noncovalent actually lead to both better efficacy, and does it really lead to better safety? Which really you can only find out in a head-to-head study. But right now I'm really excited, and hopeful that we'll have this drug available for all of our patients, because when you fail a covalent BTKI, I don't see great options.

Dr Stevens: Yeah.

Dr Cheah: I think it's going to be a no-brainer if pirtobrutinib is approved for patients who've progressed after covalent BTK. I mean, it's a clear choice. It works really well. It's got very limited toxicity. And as you say, Nirav, many patients are not eligible for CAR T, or CAR T and brexu-cel have some toxicity, neurotoxin and the like.

I think whether it goes to BTK-naive patients is a really interesting question, right? Because then you're going to have this, almost like a PFS2 [time from randomization to progression on second-line therapy] question.

Dr Stevens: Right.

Dr Cheah: Because, if you can get 2 years and then 2 years, are you going to win so big? Do you know what I mean?

Dr Shah: Yeah, I do.

Dr Cheah: It's just like what happened with SHINE in frontline, it then becomes a question of sequencing. Yeah.

Dr Stevens: And Barbara, what do you think about these noncovalent BTK inhibitors? Where would you like to see them in CLL?

Dr Eichhorst: Yeah, it's all similar as in mantle cell, that's really the big question, because the study with a head-to-head comparison against acalabrutinib was starting. And the question is, of course when we use this rescue drug already in frontline treatment, do we really gain something from our patients? Particularly when we look at now the interesting data in resistance mutations, where probably many of the resistance mutations, or some of the resistance mutations with pirtobrutinib may also lead to resistance with the covalent binding BTK inhibitor, and vice versa as well, in some cases at least. But yeah, I think, with respect to the safety profile particularly, this is a very promising drug.

Dr Stevens: And I know, I mean you're referring to the paper in [the] New England Journal [of Medicine] that looked at the CLL resistance to pirtobrutinib. And I thought what was really interesting about that is they included that table, and they tested many different BTK inhibitors. And different drugs have different responses, and so maybe we'll get to a point where we have so many BTK inhibitors available, we can look at their genomic profile and select which one they're most likely to respond to.

So I just want to thank you guys, all. This was a really great discussion. It's great to have you here and your expertise, and thanks to the audience for participating in this activity. So please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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