Additional Efforts Needed to Optimize Treatment With BTK Inhibitors in MCL

Bijal Shah, MD, MS

Emerging data are reinforcing the benefit of BTK inhibitors for patients with mantle cell lymphoma (MCL), according to Bijal Shah, MD, MS. Although these advancements are exciting, investigators are still working to determine which BTK is right for which patient, and when to trade 1 BTK for another.

“We care a lot about grade 3 adverse effects because [they influence] what we do acutely,” Shah said. “But you must keep in mind that, for the year and a half or 2 and a half year, or whatever you get in terms of your benefit with these drugs, if you have chronic grade 1 or grade 2 toxicity, that’s not going to be a fun journey for the patient. With that background, if I'm seeing toxicity and I start with 1 BTK, I don't hesitate to switch to a different BTK [because] that’s very easy.”

In an interview with OncLive^®, Shah, associate member of the Department of Malignant Hematology at Moffitt Cancer Center, further discusses the evolving role of BTK inhibitors in MCL, how to choose among the variety of agents, and the safety concerns that affect treatment decisions.

OncLive^®: Could you highlight some of the key points that emerged from the workshop?

Shah: We had an in-depth workshop focusing on the role of BTK [inhibitors] specifically in MCL. We [discussed] what it means to have 3 BTKs to pick from, ibrutinib [Imbruvica], zanubrutinib [Brukinsa], and acalabrutinib [Calquence]. Then we talked about what [role BTK inhibitors will have] as we develop the therapeutic space of MCL. What [should] the position be for these therapies—front line, second line, [or] third line—and how to begin thinking about rational combinations? We’ve begun exploring what it means to combine BTKs with monoclonal [antibodies] in smaller trials with lenalidomide [Revlimid], venetoclax [Venclexta], and others. The question is, where is this non-chemotherapeutic approach to MCL—or, more broadly, BTK-based therapeutic approach—going [given that] BTKs certainly could conceivably be combined with chemo as well?

In terms of conclusions, we all acknowledge that BTKs have unquestionably changed the treatment landscape for MCL. We now have a pill therapy that functions in many respects as well, if not better than, chemotherapy in the same space. The problem we run into is [that] there are still high-risk subsets that don't benefit from the BTKs. These are the same high-risk subsets that don't benefit from chemo either. It’s a struggle now that [there are] 3 drugs that have entered clinical use, but it’s still the same population: typically, p53 mutated, very proliferative, with Ki-67 in excess of 50%, with blastoid or pleomorphic morphology. How do we approach this patient in 2021?

Without head-to-head comparative data on the 3 BTK inhibitors you highlighted, how are you selecting between them?

I hate to say it, but insurance usually declares which [BTK inhibitor] we’re going to use before we make that decision. Certainly, we [have] found that sometimes one BTK is covered, and another is not. Therefore, before the physician judgment even kicks in, we must keep in mind that not all BTKs are created equal.

This happened to me just this week. We had a patient who was progressing, and we wanted to move into a BTK a couple of years ago, but his copay with ibrutinib was going to be prohibitive, so it didn’t work. We tried acalabrutinib, but we ran into the same issue. We’ve been able to string [the patient] along the best we can, but with ongoing progression we suggested [trying] zanubrutinib if it’s the new kid on the block and, lo and behold, he has a $0 copay. [The patient’s expenses went] from several $100/month now to $0/month. That’s obviously a game changer for the patient and it’s going to make my life much easier as well, knowing that it's not a battle that I have to fight. That’s the first fundamental, unspoken truth.

The second thing, [for] patients who have been on ibrutinib and are tolerating [the agent], you don’t need to make any changes. When you’re deciding to start the BTK, predicting who’s going to do well long term is more based on anecdotal experience than it is on randomized data. However, we will find looking back at our own internal data that somewhere between 30% and 40% of patients are stopping ibrutinib for side effects, [which is] a pretty big number.

What do you do when a patient can’t tolerate an agent?

It’s always important to characterize what we mean by that. [If a patient experience] atrial fibrillation, I don't mind combining BTK with anticoagulation, I certainly have seen bleeds, I don’t want to imply that that doesn’t happen, but they’re rarely spontaneous. The bleeds that we see are typically occurring in the context of trauma. In a [patient] who falls and hits their head, rather than seeing a focal subdural hematoma, you may see a multifocal hematoma or a more significant hematoma. Those are the things that you must be cognizant of when you're combining a BTK with some form of anticoagulation. However, we’re talking about treating folks with a median age of 68 at diagnosis, so by the time they’re coming on to therapy a few years into their diagnosis, most of these patients will at least be on a baby aspirin and potentially something more potent than that if they develop atrial fibrillation. Therefore, to argue that that we must move forward without any anticoagulation, I don't think that's going to be terribly feasible.

What side effects make it difficult to use BTKs in this population?

The biggest thing has not been atrial fibrillation, or bruising, it's been cytopenias. That's honestly been the hardest thing to push through. It's interesting that we see, in my experience ibrutinib has a little bit more in the way of that adverse effect [AE]. With the acalabrutinib, we can see myalgias and we can see headache during the first month or so of use. [The patient] is generally [able to] push through the headache, and Fioricet or something with caffeine seems to be an effective tool for managing the headaches.

However, the myalgias are tougher with diffuse body aches. You can see the same with ibrutinib, I shouldn't imply that it's just 1 BTK. Ibrutinib [AEs] seem to come out a little later though, whereas acalabrutinib [AEs] tend to be a little earlier. Zanubrutinib tends to come with a little bit more in the way of high blood pressure in my experience. Although the trials suggested they were more in the way of cytopenias, it’s not something I’ve seen as much of in my practice.

The number 1 thing that I've seen with zanubrutinib has been worsening of pre-existing hypertension and it can be rather severe. I've had to admit a few patients to the ER for very high blood pressures, and incorporating things that I don't normally use, like clonidine, to help control some of the blood pressure fluctuations. That has been, in terms of [AEs], one of the harder things, but something that we must keep in mind.

When do you decide to go from 1 BTK to another?

[When it comes to progression], I can't think of a single scenario where we’ve been able to control disease with 1 BTK versus another. I doubt it’s going to do much, switching from ibrutinib to acalabrutinib or zanubrutinib. If a patient is showing progression in the setting of poor drug absorption, more specifically if they require chronic PPI [proton pump inhibitors] and we think that they’re not getting enough drug absorbed, that might be the 1 case where I would [suggest] switching to zanubrutinib and see if we can wrest control of this particular MCL. However, there's no good test right now for measuring BTK occupancy in the clinic.

How does your choice of BTK affect later lines of therapy?

BTKs may impact T-cells differently. If you're anticipating [chimeric antigen receptor] CAR T-cell therapy as your tool once BTK inhibitors stop working, we have data for ibrutinib suggesting that in diffuse large B-cell lymphoma that inhibition of ITK [interleukin-2-inducible T cell kinase] that comes with the [agent] may allow for the collection of a better product and that may enhance your therapeutic efficacy when you administer CAR T-cells. We don't [observe] that with acalabrutinib so our assumption is that this is an ITK effect, but we don't know.

The BTK is also present in antigen presenting cells and the very early data with BTK inhibition suggested that you could polarize towards a Th1 type antitumor T-cell that would be very useful in combating malignancy. It may be that any BTK inhibitor can do it. I will say that zanubrutinib does also have some ITK inhibitory activity. With ibrutinib and zanubrutinib, we think that if the ITK story is real, there may be some advantages to using [those] in anticipation of CAR T-cell immunotherapy. With acalabrutinib, we just must wait and see [until we] get that data. As we sort of build out the “real world experience” with the Tecartus [brexucabtagene autoleucel] product in MCL, we’ll get a better sense.

Venetoclax has shown activity in MCL, however it tends to be shorter lived when it’s used as a salvage agent. We don't know what we're going to get when we integrate venetoclax upfront. Building off Constantine S. Tam’s [MD, MBBS] data, I think that regardless [of setting] the venetoclax can impact T-cell numbers and potentially push the T-cells towards a more differentiated phenotype. That may not be good for CAR T-cell therapy. [Given that] these are all hypotheticals, we must look at and gauge what our efficacy rates look like, with and without [BTKs], but certainly that's a concern for me. If you're anticipating a short run [using] a BTK and you're thinking about combinations, you might want to think more critically about how and when you integrate these other agents.

Kami Maddox [MD] from Ohio State [will] collect T-cells first, and then integrate the venetoclax as a bridging therapy approach. If it works, great. Ride that combo as long as you can because, in general, [you] may see [overall survival of] 6 months [or more] in the very high-risk patients. Or perhaps try to consolidate at an early point with CAR T-cell immunotherapy, knowing that the T cells are a little less beaten up by the venetoclax.