Krish Patel: Hello everyone, I’m Krish Patel from the Sarah Cannon Research Institute and I’m joined by my colleagues here, Dr Craig Patel and Tycel Phillips for a discussion about the role of BTK inhibitors in mantle cell lymphoma. We’re going to be talking about both the use of BTK inhibitors in frontline as well as in relapsed/refractory settings. And so we’ll kick it off with a discussion about how do we think about patients in the frontline setting.
So maybe I’ll start with you, Dr Phillips, can you give me a sense of when you’re seeing a patient with mantle cell lymphoma, what are some of the key factors that you think about that are going to guide your treatment decision making?

Tycel Phillips: Yeah. I think one of the first things is a patient symptomatic or not because that’s determined whether to discuss treatment. Patients’ age and fitness, and I think we’ve gotten more details now about some of the molecular characteristics that may predispose to indicating poor risk with just chemoimmunotherapy. So looking at cytogenetics, p53 mutation, other mutational cohorts, I’m sure we all have molecular sequencing that we can send out from our institution just to grab that sort of information. Blastoid or pleomorphic variant, Ki-67, things of that nature, just to sort of get a key of, hey, is this somebody I should probably treat with something a little bit more, as we would say in the topic of BTK inhibitor, or is this just somebody with a standard risk mantle cell lymphoma where you have a lot more options on the table?

Krish Patel: And Dr Portell, can you share with us kind of when you’re putting together those clinical factors, what are some of those characteristics that might lead you to think about treating a patient in the frontline with a BTK-based treatment regimen?

Craig Portell: Well, yeah, there’s been a lot of data that has come out in the past year and two, around two years that’s really incorporated various different BTK inhibitors and to both chemo immunotherapy and then kind of done some non-chemotherapy approaches also. So like, Dr Phillips mentioned, you know, one of the first things to consider is should we include chemotherapy, is that a reasonable choice? And some of the higher risk features that really push me away from chemotherapy are really the p53 mutation status. As of right now, I think that’s the one that really kind of highlights in my mind whether or not I really want to consider a non-chemotherapy approach for patients and just do like a BOVen, which is a zanubrutinib-venetoclax-obinutuzumab based approach out of Memorial, which would be kind of my non-chemotherapy approach. You know, the other thing to think about though, is, there was a retrospective study at ASH that really kind of highlight – they took all patients that had both p53 mutations and non-p53 mutations and limited patients that had actually had the test done. And maybe it’s not as bad as we once thought, so I think there’s some other clinical features that may kind of push me in that direction. You know, somebody who has classic mantle cell on histology with the moderate Ki-67 but still has a p53 mutation, maybe I will try the chemotherapy with the BTK inhibitor approach. But maybe, you know, someone with a little bit higher proliferation rate, I may try to not to do that. But to be honest with you, for most of my news starts, I’m incorporating a BTK inhibitor with chemotherapy, even in the more classic variants. Given data from ECHO and TRIANGLE now, and 4181 that just was released at ASH. So that’s kind of kind of my approach for most patients nowadays.
Krish Patel: Yeah. Thank you. You highlighted a lot of important data that’s come out. So we have this approach of so-called chemo-free BTK therapies, perhaps we’re thinking about p53-aberrant patients. But as you pointed out, we have this swath of classic mantle cell lymphoma patients where there’s a lot of heterogeneity, where perhaps BTK with chemotherapy is a good option. Dr Phillips, anything to add there? And when thinking about how you select between BTK inhibitors that you’re using in the frontline option, we heard a little bit about zanubritinib-based therapy, a little bit about acalabrutinib-based therapy. Can you tell us more?

Tycel Phillips: Yeah. I mean, it’s, so as Dr Portell sort of mentioned, you know, with the most recent ASH meeting, it was a lot of data that came out, specifically more updated data with TRIANGLE, which as we know uses ibrutinib of as a BTK inhibitor. I think within the US, obviously, we tilted more toward the second generation BTK inhibitors acalabrutinib or zanubritinib just for improved tolerance and toxicity, and obviously for the simple fact that ibrutinib is no longer necessarily indicated in patients with mantle cell lymphoma. Not that we can’t get it, but ideally, if the company pulls back the sort of indication, it’s sort of – some say that again, the other two drugs, not for efficacy reason, but more for safety and toxicities would be better choices for our patients, especially if you’re combining them with chemoimmunotherapy. Given what we saw with SHINE, with increased toxicity and deaths, likely attributed to those, the combination of those two medications and not sort of seeing that same picture readout in ECHO, I would strongly lean to either acalabrutinib or zanubritinib, and that’ll really come down to personal preference. I mean, are you a Coke patient or do you like Pepsi? So I think in that situation it’s really a fair game.

Krish Patel: Yeah, and maybe to speak to what you highlighted, Dr Phillips, tell us a little bit about the toxicity differences for second generation BTK inhibitors compared to first generation ibrutinib.

Tycel Phillips: Yeah. I mean I think across the board, I mean we do see like typical we see rash, we see GI side effects, all will have some impact on heart rhythm. So some linked to atrial fibrillation and bleeding. But to the point is the rates of those things were just significantly higher, especially AFib, late onset hypertension, and unexplained cardiac deaths were highly more prevalent with ibrutinib than what we see with acalabrutinib and zanubritinib. And I bet a lot of the information we have from those second generation drugs, as far as long-term toxicities are really coming from the CLL patient population, where these patients are on drugs forever, but it gives us insight to what we expect to see. And then again, not to sort of dump water on SHINE completely.
But again, I assume a lot of us presume that a lot of those unexplained deaths that they couldn’t sort of pinpoint weren’t people getting hit by cars, but probably having, again, unexplained and undocumented cardiac events leading to some deaths, with a long-term use of ibrutinib. And so, with the second-generation drugs, I think the biggest thing we worry about in the front term is acalabrutinib causes some headaches, you drink coffee, as Dr Portell is drinking, it helps with the headaches quite a bit. And the headaches are self-limiting, with zanubrutinib we may see some increased risk of neutropenia. But again, it didn’t really seem to sort of hint to an increased infection risk as compared to acalabrutinib. So all in all, both the drugs will probably lead to some increase in blood pressure, again, some bleeding risk. But an apples to apples comparison, much, much less than what we saw with ibrutinib. And as you know, the old sort of saying goes [inaudible] there are options, so if ibrutnib was the only BTK inhibitor, I’m sure we’d manage AFib and everything else, but it’s not. And so, I mean, we were able to move on for our patients to safer drugs.

Krish Patel: Great, thanks for that summary, that was really helpful. So maybe shifting a little bit into the relapsed/refractory setting, as you both highlighted, we’ve had covalent BTK inhibitors for a long time in that space often used as monotherapy. What do you see as the role for BTK inhibition, kind of how is that changing in the relapsed/refractory setting as we think about moving these up into earlier lines? So Dr Portell, maybe you could give us some insights there.

Craig Portell: Yeah. So, we’re essentially moving our favorite second-line therapy to the frontline setting, and how do we manage that? And it’s a little bit hard to know now because we, I think this paradigm has really changed in the last 2 to 3 years. So not many of our patients have really progressed, and if they have progressed, they’ve progressed on a BTK inhibitor. And that would probably limit our use of a covalent BTK inhibitor at least at second line. You know, I think that kind of gets into what else we have available and what the patient’s seen before. So, I would try to get a patient like that on a clinical trial. There are some trials that are open specifically for these types of patients. So I think that’s an important space that we don’t quite understand yet well. So if they fail a BTK inhibitor, I probably would not go to a covalent BTK inhibitor again, I may consider sending a BTK mutation analysis to get a sense of what the mutational status of BTK is, and consider a non-covalent BTK inhibitor like pirtobrutinib which is on the market, those other ones nemtabrutinib, etc. that are in development. Bispecific antibodies, CAR T-cell therapy, these are all choices also depending on what the patient’s had and functional status and kind of what the status of the progression is. Is it a rapid progression, is it a slow progression? You can still watch a slow progression, I think very carefully. But you can watch that very, very carefully.

Krish Patel: That’s really helpful. So recognizing that one option may be to stay within the BTK class, we have these new agents emerging, non-covalent BTK inhibitors, one approved some others potentially coming down the pipeline. Dr Phillips, could you maybe tell us a little bit about what should we expect in terms of toxicities with non-covalent inhibitors and maybe what are some of the strategies that you see in clinical trials that look promising for those patients who have progressed after a covalent BTK inhibitor?

Tycel Phillips: Yeah, so I think one of the shocking things I shouldn’t say shocking. One of the good things that came out of the BRUIN study is how well tolerated pirtobrutinib was. So not to quote Dr Michael Wang, but, you know, the patients were saying that they weren’t taking anything at all. And so I think the toxicity profile, as we sort of evolved with these BTK inhibitors, has improved. And to that point, again, I think pirtobrutinib is very well tolerated, now with nemtabrutinib, not necessarily sure of the mechanism, but it did appear that nemtabrutinib had a bit more toxicities in what we saw with pirtobrutinib, specifically with rash. And so I’m not sure if it’s hitting something else or if it’s more aligned with what we saw with some of the covalent BTK inhibitors as far as AE profile, but pirtobrutinib, which is approved to appear to be quite safe and tolerable. Dr Portell alluded to, obviously, it did show some benefit. I do think, you know, to a sense, there are some patients who have very good responses to pirtobrutinib, but unfortunately, you see in the mantle cell lymphoma space, most of our patients don’t have mutations in the BTK receptors. So why these patients are sort of failing new drugs, I think is still a big mystery for most of our patients. So, it does bring up light some of these other treatments, such as, you know, CAR T-cell therapy, where we have two approved options, you know, brexu-cel and liso-cel, so brexucabtagene and lisocabtagene maraleucel. There are bispecific antibodies being explored in this space, so there’s glofitamab as a single agent and then we have mosunetuzumab and polatuzumab as a combination that was explored. And then there are a lot of ADCs that are in the works, which will likely include patients with mantle cell lymphoma, given, you know, obviously, unfortunately, it doesn’t look like CAR-T is curative in mantle cell lymphoma, so we’ll continually have to come up with some treatments for these patients, especially again if, as Dr Portell alluded to, we’re moving of our BTK inhibitors into the frontline space. And so until we have some clarity about what we can do, even with these time limited treatments, with their response, I think, you know, it does sort of spur the need for other ways, or maybe even new BTK inhibitors like the BTK degraders, if they have a role in this space, even though the data, you know, has been a bit limited. I think as far as reports of how patients with mantle cell lymphoma are responding to these drugs.

Krish Patel: Yeah. Thanks. A lot to be excited for in sense of, you know, potential investigational therapies that hold some promise maybe kind of drilling down on that a little bit more. Dr Portell, can you tell us a little bit about BTK degraders? And I know these are still being studied early in trials, but what might excite you about what you’ve seen so far, and what might people want to know about BTK degraders?

Craig Portell: Yeah. So, you know, I haven’t had a chance to work with them specifically, but what I do know about them is that they essentially, as opposed to inhibiting the function of BTK, kind of get rid of BTK by shuffling the protein to the proteasome and then allowing it to be degraded. There does still need to be a binding of a drug to shuffle it into the proteasome so there can still be, from my understanding, some mutations that happen that make that difficult to actually happen. But it’s a novel way of attacking BTK, it’s a novel way of attacking many of our proteins because this type of degradation can happen with many different intracellular proteins. So it’s a way of as opposed to using a drug to inhibit the function, just getting rid of the protein. So that’s kind of exciting. I haven’t seen a whole lot of clinical data about how well they work and the toxicities and things, but my understanding it’s still pretty early, but exciting nonetheless.

Krish Patel: Thank you for explaining how they work, and as you noted we haven’t seen a lot of data yet in mantle cell, we’ve seen some in CLL and what we see there is exciting. Hopefully we’ll see more and more safety and efficacy data in mantle cell and that will help us try to figure out where they might ultimately land. So before we kind of move a little bit towards how we manage toxicities that we see from BTK inhibitors, I did want to ask you both, any other clinical trials that really excite you in this space, those that you think are going to hopefully hold the potential to change how we treat mantle cell lymphoma? Dr Phillips?

Tycel Phillips: Of trials that read out this year – so, I do think at least with – Dr Portell mentioned BOVen, that’s being explored in an elderly patient population. We still have the frontline study that’s looking at zanubrutinib-rituximab versus BR. So the bendamustine – to sort of see if we can still get a decent efficacy study to read out. And then obviously there’s the Phase III study with glofitamab versus standard of care in the relapsed/refractory space as we can see how that sort of reads out in a truly sort of mantle cell driven study as we move along.

Krish Patel: So, just to summarize that: trials of combination BTK in the frontline setting, bispecifics in the relapsed setting. Dr Portell, what excites you in the clinical trial space in mantle cell?

Craig Portell: Well, you know, two studies that we heard about at ASH that we haven’t actually seen the manuscript for. So that I think is important to highlight, but I think is potentially practice changing. Both came from the ECOG group. So EA4181, which compared BR-cytarabine to BR-cytarabine-acala to BR-acala, which at least preliminarily may question the need for cytarabine in the frontline setting even for fit patients. And then 4151, which used an MRD approach to randomize patients who were MRD negative by the next generation sequencing to transplant or not, may kind of help us determine if transplant’s truly needed in mantle cell lymphoma. Honestly, I think that plus the TRIANGLE study may make transplant – I actually, I think it is probably gone in mantle cell frontline treatment in most cases. Other studies that I think are interesting, so there’s – you know, the BCL2 inhibition in mantle cell has never really taken off well, right? Outside of BOVen, there’s been other studies that incorporated BCL2, like SYMPATICO in the relapsed setting. We ran a study in PrECOG using venetoclax with BR, but hasn’t really shown a big uptake. There is a new generation of BCL2 inhibitors, sonrotoclax, which I think may kind of help us. There’s some interest in studying that in mantle cell. There’s a randomized, placebo-controlled study that’s in development through the company BeiGene incorporating it with zanubrutinib. And I’m very excited about the glofit and standard of care in relapsed patients who have been exposed to BTK inhibitors, which is ongoing now too. So a good number of trials that are accruing as well as that have accrued and are just waiting for data.

Krish Patel: Great, thank you both for summarizing those trials. I’m going to just shift for a bit to how do we manage BTK toxicity. So you mentioned we have many options within the BTK targeting space, right? First generation, second generation non-covalent, degraders. There are some class-specific toxicities we see like bruising and bleeding, hypertension appears to be one, arrhythmia. So just maybe would be helpful to kind of hear your perspective about how you manage those toxicities when they might appear.
They can be relatively rare but can be impactful to our patients. So Dr Phillips, maybe I’ll ask you to speak a little bit about bleeding and perhaps hypertension.

Tycel Phillips: Yeah, so, of those two obviously bleeding is something like, late-term, chronic use problems. So I mean, as far as the bleeding, for most patients, obviously we try to look at their concurrent medications, obviously eliminate what we can – they may also increase the increased bleeding risk, counseling these patients on just being prudent about some of the activities, you know, avoidance of things that may lead to excessive bleeding, bruising. But I think this is one of the side effects we try to just massage as much as possible without actually making these – have any severe bleeding – severe gastrointestinal bleeding, typically in these situations where, again, we may have to make dose reductions in this situation or in some cases, even stop the BTK inhibitor in general. As far as the high blood pressure, you know, ideally when this does come along, obviously working very closely along with the primary care doctor, if you can, or in most situations where we become the primary care doctor, to typically start in some blood pressure medications and seeing if we can keep it controlled in that situation, dietary evaluations, trying to limit the amount of salt intake, making sure these patients can stay as active as possible. Anything we can do in these situations, especially if they’re tolerating otherwise to keep them on the medication.

Krish Patel: Yeah. Thanks. So a lot of things that we can do to hopefully get our patients the maximum benefit while minimizing toxicity. So that’s helpful to know that many of these things are rare but potentially manageable. Dr Portell, just kind of shifting focus to the cardiovascular space. We have seen things like unexplained cardiac death, cardiac arrhythmias. So maybe could you walk us through your approach to how you might safely use BTK inhibitors in patients who have some cardiac risk factors?

Craig Portell: Yeah, so the biggest cardiac risk factors, you know, the ongoing angina and things of that nature. You know, true heart failure, sometimes we have to think, can we even use BTK inhibitors? I certainly would not use ibrutinib, the first-generation BTK inhibitor, in those situations. And those are sometimes the cases where I may skip the covalent BTK inhibitor class and just go to the non-covalent, which has not been reported to my knowledge of having significant cardiovascular toxicity. So that may be an option if I do truly need to skip the covalent BTK inhibitor class altogether. And I think it’s important is just to use the non-covalent BTK inhibitor. For those patients, dose reductions can be helpful, if these events happen and a patient’s in remission, sometimes I’ll just take them off the drug and monitor closely to use other modalities as necessary also. But, you know, these tend to be quite sick patients already. I mean, they already have fairly significant comorbidities. So our choices and therapies get somewhat limited when we have those types of therapies.

Krish Patel: That’s a really important point. There may be a subset of patients where we can’t really find a safe way to use BTK inhibitors, but many others where we may. So maybe there I will take the opportunity to thank my colleagues, Dr Craig Portell from the University of Virginia, Dr Tycel Phillips from City of Hope. Thanks for a great discussion and look forward to the next time.