Navigating BTK Inhibitors in Mantle Cell Lymphoma: Safety, Sequencing, and Evolving Pharmacist Roles

As Bruton tyrosine kinase (BTK) inhibitors continue to reshape mantle cell lymphoma care, pharmacists play a pivotal role in guiding therapy selection, counseling on toxicity risks, and anticipating resistance patterns. In this discussion, Grace Baek, PharmD, BCOP, explores how differences in BTK inhibitor selectivity influence safety, how to navigate drug-drug interactions and cardiovascular risks, and what pharmacists should consider when sequencing treatments or preparing patients for advanced therapies such as chimeric antigen receptor (CAR) T cell or bispecific antibodies.

Q: With multiple BTK inhibitors now available, what pharmacological and patient-specific factors should guide a pharmacist’s recommendation when these agents are being incorporated into frontline regimens, and how do differences in BTK selectivity translate into clinically meaningful safety distinctions?

Grace Baek, PharmD, BCOP: Yes, so we do have a number of agents in the BTK inhibitor space. We have our first-generation inhibitor ibrutinib (Imbruvica; Pharmacyclics LLC/Janssen Biotech, Inc), which has a little bit more promiscuous binding, including binding to the Tec family of kinases, which can, downstream, lead to things like increased risk of atrial fibrillation and some other toxicities. The implication of that, of course, is that it can potentially decrease adherence due to some toxicities, which has implications potentially for things like progression-free survival.

So with our next-generation Bruton tyrosine kinase inhibitors like zanubrutinib (Brukinsa; BeOne Medicines USA, Inc), acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP), and pirtobrutinib (Jaypirca; Eli Lilly and Company), even further generation, we have the potential for decreased [adverse] effects, better efficacy, and potentially even survival benefits down the line.

Q: BTK inhibitors have well-characterized toxicities such as atrial fibrillation, bleeding risk, and hypertension. As these agents move into the frontline setting, where patients may have fewer prior comorbidities, how should pharmacists counsel patients and collaborate with the care team on monitoring parameters, dose modifications, and managing potentially significant drug-drug interactions, particularly with anticoagulants or CYP3A4 modulators?

Baek: Yes…those pieces are definitely important. I think we’re looking at the who, what, when, and why. “Who” being [that] we want to ensure that patient selection is optimized and that folks who are coming in with baseline cardiovascular comorbidities are being counseled about that risk, as BTK inhibitors can cause exacerbation of cardiovascular conditions as well as new-onset cardiovascular conditions.

We also want to assess for drug-drug interactions as well, so looking at counseling folks on how to take the medication—when to take the medication, to take with food or on an empty stomach, et cetera—but also counseling on drug-drug interactions. [We also need to determine whether] we need to modify either the BTK inhibitor in terms of empiric dose reductions or the concomitant medications.

The “when,” of course, would be the onset and expected median resolution based on data that we have for resolution of toxicities. And then the “why” would be why do these toxicities occur, and what interventions or preventive measures can we take to hopefully prevent some of these toxicities or watch more closely for them.

Q: Pirtobrutinib and other noncovalent BTK inhibitors have shown activity in patients who have progressed on covalent BTK inhibitors. From a pharmacist’s standpoint, what do we know about the resistance mechanisms driving covalent BTK inhibitor failure, and how does the binding pharmacology of noncovalent agents potentially overcome these mechanisms?

Baek: Resistance to BTK inhibitors in mantle cell lymphoma (MCL) is slightly different [from that] in chronic lymphocytic leukemia (CLL). We have the potential for primary resistance medications with MCL that can be…higher than in CLL. So the implication [is] that…someone who starts on a BTK inhibitor may not get as much mileage out of the BTK inhibitor in mantle cell as opposed to CLL. Of course, there are differences [between] combination vs monotherapy—that’s a separate topic.

Now, we know that with secondary or acquired resistance to BTK inhibitors, that’s also a slightly different picture. In MCL, as opposed to disease states like CLL, we don’t see as [many] C481S mutations or PLCγ2 mutations, for instance. However, we can see other pathways that can cause this acquired resistance. So there aren’t any guidelines for when to test for mutations or any specific ones to test for in MCL as of now. But we are always on the lookout…. Is a patient still continuing to respond to a BTK inhibitor–based therapy? Is it time to move on to something else?

Q: Given the growing number of active agents in relapsed/refractory MCL, how should pharmacists think about optimal treatment sequencing—particularly regarding how prior BTK inhibitor exposure may affect eligibility, response, or lymphodepletion strategy for patients being considered for CAR T-cell therapy or bispecific antibodies?

Baek: The understanding of optimal treatment sequencing in MCL is certainly growing. There’s a lot of new evidence coming out with novel agents and combinatory agents, so that’s really exciting to see. I think some of the factors that pharmacists are looking at and should look at are the efficacy outcomes. We don’t have too many head-to-head trials, but [we could look] at cross-trial comparisons, for instance, and…at the duration of response as well.

We know in MCL that with each relapse, we may get a shorter and shorter time on each treatment. So we want to certainly watch out for that, as well as factors like progression-free and overall survival, and potentially some proxy outcomes; …time to next treatment [has] been an area of growing interest.

Of course, we need to also include safety in the conversation…, so [we need to watch] out for any toxicities and [compare them] to patients’ prior experience with other agents and regimens. Do they have comorbidities that might make them a better candidate for one regimen over another? So safety and efficacy are the name of the game.

Q: Many pivotal trials in MCL enrolled highly selected patient populations. What efficacy and safety outcomes are immediately actionable for pharmacists in community or academic settings, and where do you see the greatest gaps between trial results and real-world MCL management?

Baek: In induction therapy in MCL, we've seen in the past few years an interest in incorporating BTK inhibitors into induction, whether or not patients down the line receive autologous stem cell transplant. An example would be [the] TRIANGLE [trial, (NCT02858258)] in a high-intensity…approach, and ECHO [NCT02972840] in more of a low-intensity approach for [patients with] mantle cell lymphoma. So with the results of TRIANGLE and ECHO, I think we’ll see more BTK inhibitors used up front in the first-line setting for [patients with] MCL. Of course, we need to consider the cardiovascular, myelosuppression, and other safety concerns associated with these agents. So that’s important to counsel on.

One gap I think we are still working on in MCL is understanding how and when to use minimal residual disease [MRD] data. We do have a more established role of MRD assays—including frequency, when do we get it, who do we get it for, and do we assay peripheral blood, bone marrow, or both—in some other disease states, but in MCL, that’s a growing area of interest. So I’m excited to see additional data coming out in that area.