Bhavesh Shah, RPh, BCOP

 I want to talk through the future, with BTK [Bruton tyrosine kinase] inhibitors and CLL [chronic lymphocytic leukemia]. There was a lot of exciting stuff presented at ASH [American Society of Hematology Annual Meeting]. Maybe you can talk about 1 or 2 things that you’re excited about for CLL in the next year or so.

 I think 2022 is going be a very active year in CLL and new approvals. I’m excited about having additional options for existing targets. Zanubrutinib is going to be a clear 1 that will likely become available. I’m very interested in seeing that ALPINE study that we referenced, and the head-to-head comparison of ibrutinib vs zanubrutinib in published manuscripts, so we can look at the data in detail on how those 2 drugs compare now that we have the ELEVATE-RR trial for acalabrutinib vs ibrutinib. It’s always good to have more options for our patients: that third BTK inhibitor and second-generation BTK inhibitor option. I’m hopeful that umbralisib and ublituximab will get approved as a PI3K inhibitor, anti-CD20 combination—the U2 [umbralisib, ublituximab] regimen from the UNITY-CLL study presented at ASH—to give us a better-tolerated PI3K inhibitor option.

What do we do with our existing agents? Is there a better way to treat? The obvious 1, which we’ve talked about, is combining Bruton tyrosine kinase inhibitors with venetoclax over a defined timeline. This might be a very appealing option for many patients—maybe not all, but many patients. I’m excited about that opportunity to involve both BTK and BCL2 inhibition and maybe get long-term deep remissions with a year’s worth of all oral therapy in some circumstances. That will be really neat.

In terms of new targets and options, I hope the first that will become available in 2022—at least on a limited basis for our double-refractory patients, who have progressed on BTK and BCL2—is the alternative-site BTK inhibitor pirtobrutinib. There are others in development, but that 1 appears to be the furthest along in its development. This agent has been shown to be active in patients who have progressed on BTK and have a mutation at that C481S-binding site, because it binds in a totally different way, unlike zanubrutinib, acalabrutinib, and ibrutinib, which are covalent inhibitors. Pirtobrutinib is a noncovalent inhibitor that binds at a different site on Bruton tyrosine kinase, and it’s a very specific and well-tolerated drug. That will give us an additional target option for patients, another in our growing list of different targets to have.

One that has been in development for many years in CLL and has been approved in other areas is CAR [chimeric antigen receptor] T-cell therapy. We hope can give curative results to a fraction of patients, as we’ve seen in other lymphomas. Many times, our patients with CLL are aged out of being able to get cellular therapy that’s available to them, like allogeneic stem cell transplant. The average age of a patient with CLL is 70 years old. The average age of a patient with CLL who needs treatments all the way up is 74 years old, and that’s just first line. When we run out of our convenient options, we’re left with not much that we can do for these older patients. Having a CAR T-cell therapy available for those select few who get to that point would be nice for those patients.

 Thank you for sharing that. I’m sure you saw the 

 came out with the 10-year data on a patient with CLL. It’s definitely exciting to know that there’s so much coming into pipelines for CLL.

Thank you for this opportunity to educate everyone on the changing landscape of BTK. I want to thank all our viewers and audience. I hope you found this 

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Bhavesh Shah, RPh, BCOP, and Ryan Jacobs, MD, discuss emerging agents in the pipeline and the future treatment landscape for CLL.

Future Directions for the Treatment of CLL

 We talked about some of the toxicities of managing hypertension and having the appropriate blood counts for these patients. There are even data for switching these patients. How do you utilize your pharmacist? Do you have that pharmacist support that helps you manage some of these patients who are on oral agents?

 We have great pharmacy support at Levine Cancer Institute. We round with pharmacists in the hospital, and we always have a PharmD in our lymphoma clinic. I definitely use that very helpful resource of having a pharmacist in clinic with me. It starts with them educating the patient about chemotherapy. Pharmacists are great at doing that. They know the drugs better than I do in many circumstances. It’s part of that process: we review the existing medications together to make sure there are no interactions that need to be considered in terms of potential dose reductions or switching them from certain medicine they’re on to ones that would be better taken with the BTK [Bruton tyrosine kinase] inhibitor that we’ve chosen. That’s primarily going to be a C38 coadministration issue.

Then I make sure the patient knows to give us a call anytime they start a new treatment so we can run that same interaction. Then I have a separate pharmacist in our specialty pharmacy who is very attuned to seeking out philanthropic support for co-pay assistance, and that’s been such a wonderful resource to have for patients who maybe get quoted high co-pays for medicines that are expensive. The overwhelming majority of patients out there can have co-pay assist students engaged, and they get their drug at a very reasonable co-pay.

 We have a similar model. We have the same up-front education for patients, and we know these patients are going to be on them for the long term. As you mentioned, there are data out 50 months and beyond in these patients. It’s amazing how when we looked at the CML [chronic myeloid leukemia] data, there was always this drop-off in adherence, and we knew that it was directly tied to overall survival and a lot of the clinical outcomes that these patients have. Even though these patients are on stable therapy and have stable adverse effects, there’s always going to be new therapies, as you said, and we need to make sure that there are no drug interactions. Knowing that hypertension can happen at such a long time frame beyond 12 months, there’s definitely this oversight that you need to have for patients to have that extra hand to make sure there are no adherence issues and that the toxicities are being monitored on a frequent basis.

You’re absolutely right in terms of having that pharmacist support in managing patients on oral therapy. A lot of times with what we see in a clinical trial, it’s hard to see the same outcomes in real-world evidence. Even with a lot of the companies I’ve spoken to aren’t able to see the same persistence even in different types of models. For patients who have to go to another specialty pharmacy vs their own health system or specialty pharmacy, there’s definitely difference in management that happens for patients. I feel like we’ve seen much better adherence, better persistence, and better outcomes. It’s important to have that model and to have a pharmacist involved in the care of these patients who are on oral therapy.

Ryan Jacobs, MD, and Bhavesh Shah, RPh, BCOP, comment on the role of pharmacists in clinical practice for managing patients with CLL.

Role of Pharmacists in the Management of CLL

 That brings me to talking about how there are also data in terms of patients who are intolerant to 1 BTK [Bruton tyrosine kinase] inhibitor and switching them to another. We’ve seen that with ibrutinib to acalabrutinib, and there are some data emerging on ibrutinib to zanubrutinib. I want to get your perspective on that. And if somebody has been on a BTK for a long time and then you’re switching them over, would you be concerned about any mutations they may have from switching from 1 drug to another?

 To answer your first question, it’s been interesting how the utility of these next-generation BTK inhibitors has evolved over time. With initial approval, I was using acalabrutinib. It was the first second-generation BTK inhibitor to become available. I was using it almost exclusively as a switch from ibrutinib patients who were having adverse-effect issues to acalabrutinib. My clinical experience mirrored what Farrukh Awan was able to show in his small study, which looked at patients treated in that manner because of toxicities: 75% of patients were able to be switched to acalabrutinib and either have the toxicity not recur at all or recur at a significantly lower grade. Those patients were able to be maintained on BTK inhibition. That’s primarily how I was using next-generation BTK inhibitors initially, and it was great to have that option for patients. Over time, with more data that have come to light, I’ve been primarily starting new treatment with next-generation BTK inhibitors.

Back to the question about mutations, because the treatments zanubrutinib, acalabrutinib, and ibrutinib are all covalent binders of BTK at the C481S side, I don’t think switching 1 from the other is going to necessarily increase rates of resistant mutations. To the CLL [chronic lymphocytic leukemia] cell, it’s seeing the same inhibition. The occupancy rates might vary, but those tend to be in favor of next-generation BTK inhibitors.

 That’s the future of talking about the next-generation BTKs that we’ll be seeing. It’s focused on those patients in the relapse setting and having specifically…

Key opinion leaders in hematology-oncology share recommendations on switching from first-generation BTK inhibitors to next-generation BTK inhibitors for the management of patients with CLL.

BTK Inhibitors: Switching Therapies in CLL

 There have obviously been some head-to-head trials with zanubrutinib and ibrutinib, specifically in Waldenström [macroglobulinemia]. Of course, there are ongoing clinical trials. There was 1 presented at ASH [American Society of Hematology Annual Meeting] that wasn’t looking at comparisons with other BTK [Bruton tyrosine kinases] inhibitors. Rather, it was looking at BR [bendamustine, rituximab] vs using a combination of zanubrutinib with venetoclax. There’s some early readout in terms of progression-free survival. I want to get your thoughts on that trial.

 I believe that was the SEQUOIA study. The cooperative group studies of ibrutinib compared with chemoimmunotherapy, like BR [bendamustine, rituximab] and FCR [fludarabine, cyclophosphamide, rituximab], show BTK superiority in the frontline setting. So I don’t think anybody is surprised to see a zanubrutinib-based treatment showing superiority to bendamustine-rituximab. It’s almost like checking a box to get approval. Moving beyond the single-agent BTK, combining BTK inhibition with BCL2 therapy over a defined time period, has a lot of interest. It’s going to be an evolving topic that I believe is going to gain even more traction in 2022.

 It’s interesting to see the toxicity profile. Compared with ibrutinib, there’s definitely a higher toxicity profile, but what is that difference with zanubrutinib? As a pharmacist, I’m involved in managing these patients. We help get their CBCs [complete blood counts] monthly, coordinate a lot of the labs, and then monitor for hypertension and bleeding. If you look at the JNC 8 [Eighth Joint National Committee] guidelines, grade 3 hypertension is pretty close to the goal for patients who live at that blood pressure. It’s 150/90 from the JNC 8 for older patients. It’s 160/100 for grade 3 hypertension. Sometimes these patients live at this blood pressure. We know that there’s this time to incidence that increases with some of the BTKs. I don’t know if you’ve seen that: where a patient’s blood pressure is fine for 12 months and then suddenly you start to see it creep up. Do you see that in practice? How do you manage that?

 When we were treating patients with ibrutinib originally, and they were doing well and able to stay on the drug for many years, obviously the concern was that they were going to accumulate toxicities over time. Luckily, by and large, that’s not what the data have borne out. The 1 exception is hypertension. That seems to accumulate over time with ibrutinib treatment. Personally, I haven’t had to take many patients off ibrutinib. In fact, I’ve only had to do intermittent holds and not necessarily had to permanently discontinue a patient because of hypertension. The hypertension is generally manageable. There are some data that show it’s probably being undertreated in our long-term ibrutinib patients and potentially making them more at risk for other cardiac complications. The next-generation BTK inhibitors, specifically acalabrutinib, showed head-to-head lower rates of hypertension and, of course, atrial fibrillation. In general, they’re shown to be safer from a cardiac standpoint. Before we had these second-generation options, I was usually able to medically manage the hypertension. I had to put on my internist hat and prescribe hydrochlorothiazide in many circumstances, or amlodipine.

Dr Ryan Jacobs, MD, leads a review of the phase 3 SEQUOIA trial presented at ASH 2021 evaluating the use of zanubrutinib for previously untreated CLL and discusses the management of adverse events with BTK inhibitors.

Phase 3 SEQUOIA Study: Zanubrutinib in Treatment-Naïve CLL

 Getting back to our discussion about BTK [Bruton tyrosine kinase] inhibitors, we have these first-generation BTK inhibitors, which believe it or not, I still do see a lot of ibrutinib [Imbruvica] being prescribed, and then now we’re seeing more of the second generation BTK inhibitors being more prominent, such as acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. I just want to understand, for those patients for which you are considering a BTK inhibitor, how do you decide on which BTK inhibitor you’re going to start with?

 I want to just start out by saying it was really ibrutinib that led the way in this small molecule inhibitor-based renaissance that we’ve seen in treating CLL [chronic lymphocytic leukemia]. It is a great treatment. It has benefited so many patients, and it should be recognized as such, but now we do have other options. In terms of FDA [Food and Drug Administration]-approved options at this point in time, we have 1 other option that’s a second generation BTK inhibitor if you will: acalabrutinib. Early on we just had the kinome trees that we like to look at, and we could see that acalabrutinib had much less off-target kinase inhibition and just seemed like a cleaner drug. Then, clinically, we were maybe seeing less toxicities or lower grade toxicities in general in our clinics. We had these cross-trial comparisons that we could draw between the 2 and the matched, adjusted, integrated comparisons. Now, thankfully, we were able to—in manuscript form—just recently have the publication of the ELEVATE-RR [clinical trial] data, which compared ibrutinib versus acalabrutinib head-to-head in a high-risk relapsed CLL patient population. I feel like the conclusions that we drew from that study corroborated what we were thinking, which is that toxicities were lower with acalabrutinib, and discontinuation rates due to toxicities were lower. Specifically, atrial fibrillation, which was 1 of the secondary end points, was lower. Now, I think it’s reasonable to refer to acalabrutinib as a better-tolerated BTK inhibitor. When I talk about BTK inhibitors, I always say, it’s important to understand how these drugs are similar and how they’re different when making treatment decisions because how they’re similar is how they treat the CLL and their covalent inhibitors of Bruton tyrosine kinase. They do that by binding at the same 

binding moiety. That’s why on this ELEVATE-RR study, which was a non-inferiority trial and that was the primary end point, it showed non-inferiority between the 2. You don’t efficacy-wise necessarily expect 1 to be superior to the other. Certainly, if you had a patient that had progressed on ibrutinib, I would not consider acalabrutinib as a treatment option for them because they should be resistant to acalabrutinib as well and most likely have a mutation at that 

binding sign. Now we have head-to-head data to say definitively there are lower incidences of discontinuations due to adverse events with acalabrutinib, specifically lower rates of cardiac toxicity. I think it is reasonable at this point, and this is what I’m doing in my clinic, that if I’ve decided the patient’s going to be treated with a BTK inhibitor, then I start the conversation with acalabrutinib at this point. However, there are still situations where you might need another option other than acalabrutinib. The most obvious is the contraindication of taking a proton pump inhibitor with acalabrutinib. There are some patients that just really need their proton pump inhibitor. They can’t be downgraded to an H2 [histamine 2]-receptor antagonist, so ibrutinib is a great option to have for those patients. Sometimes you’ll run into situations, it has come up a few times for me, where there’s a contraindication like that to acalabrutinib, and maybe they’ve already been treated on ibrutinib and had a toxicity problem, and I’m looking for another option. That’s where it’s nice to have, in an off-label format, the ability to use zanabrutinib, which has had some data reported at this point about its efficacy in CLL and its tolerability. It’s not technically FDA approved yet, but it is now on the NCCN [National Comprehensive Cancer Network] guidelines, so I’ve been able to get it approved off-label in those select circumstances where I’ve needed it.

 I couldn’t agree with you more. I think really emphasizing the off-target impact of 

 [Janus kinase 3] and R2, which really kind of bring to light some of these toxicities that you were talking about, such as atrial fibrillation, bleeding, and hypertension. It’s like we’re making these agents better and better to where we have more choices for patients. It’s amazing what some of the companies are doing, like acalabrutinib manufacturers reformulating acalabrutinib to actually be given with the PPI [proton pump inhibitor], because currently, you can’t. They developed the formulation, which is a maleate tablet formulation that actually you can give through a nasogastric tube or with a PPI, so it’ll be really interesting to get rid of the interaction that providers are always concerned about. I think it’s amazing for a manufacturer to go through lengths like that to actually reformulate because they know it’s such an important impact to patients on these medications. It seems like you’re definitely moving towards acalabrutinib, and if there are concerns about drug interactions, then zanabrutinib is kind of your other choice.

Ryan Jacobs, MD, and Bhavesh Shah, RPh, BCOP, provide insight on considerations when choosing a BTK inhibitor for initial treatment of chronic lymphocytic leukemia. 

Treatment Selection Among BTK Inhibitors for First-Line CLL Treatment

 I know that there were some challenges that we encountered, especially during COVID-19. When having patients come into the clinic for infusions, of course, there are logistical challenges. There are infusion-related reactions that patients may be concerned about. You’re right, having an oral option where you can have a patient go in for monthly blood draws, and then you can have maybe a telemedicine visit. That definitely makes it more appealing for a patient, especially during times of COVID when you’re trying to kind of reduce the footprint, and patients may not be wanting to come in.

 I agree with you. BTK [Bruton tyrosine kinase] inhibition is a very low-touch intervention as I like to describe it to my patients, and it can almost be done completely virtually if you needed to, and so that was helpful to do during the pandemic. I used, particularly during the pandemic, BTK inhibitors as single agents. I don’t add CD20 except for a rare circumstance like concurrent severe autoimmune hemolytic anemia or ITP [immune thrombocytopenic purpura]. Of course, with venetoclax [Venclexta] the CLL14 [clinical trial]-based approach contains obinutuzumab [Gazyva], and that’s a significantly more immune-suppressive approach. We know anti-CD20 therapies are really interfering with our patients’ ability to respond to COVID vaccination. Almost 0 patients are able to mount an antibody response to COVID vaccination when they’re on an anti-CD20 therapy, maybe for up to a year after they stop. Those are considerations that have to be weighed as well depending on where we are with whichever variant of COVID is surging at the moment.

 That brings me to another perspective that we should probably talk about, which is Evusheld [tixagevimab co-packaged with cilgavimab]. I’m sure you have plenty of patients on it, and we know that they’re the tier 1 category in terms of getting pre-exposure prophylaxis. Have you had any challenges with having patients getting it, or access issues? I’m sure you’ve been using it for patients with B-cell depletion therapies and BTK inhibitors.

 Yes, certainly. I kind of went in a triaged approach of certainly, patients on active therapies particularly with anti-CD20 agents should receive Evusheld, especially those that I had documented as not having had any antibody response to COVID vaccination. I was directing them early on, and now I’ve kind of expanded my recommendations as more broadly applied, to just any of my patients on treatment. Now, I’m even letting some of my CLL [chronic lymphocytic leukemia] patients that are on observation even know about it because not all of them actually were able to respond to vaccination as well. Access to Evusheld was a little trickier earlier on. We found some clinics in my Charlotte market that were pretty good at getting patients in. Now, here at Levine Cancer Institute, Atrium Health, we’re able to give it here, and so I’ve definitely been using that as a tool for prophylaxis.

 I could tell you that we probably have, I think, at least 20 to 30 patients every week that we are doing it in; pulmonary and rheumatology oncology and renal transplant patients. It’s definitely a great option. I think one of the things that we always get questions as pharmacists is, “Do you have to hold the patient’s therapy while they’re receiving it?” We’ve been actually coordinating it on the same day as their treatment, so they don’t have to come back for another visit. The observation period is pretty simple. It’s an intramuscular injection, so you’re not really worried about those hypersensitive reactions that you see with some of the other monoclonal antibodies. We’re even thinking that we may actually reduce the observation period to 30 minutes because we haven’t seen reactions, and we know that there’s a lesser incidence of reactions for intermuscular versus IV [intravenous] infusions that patients may receive for monoclonal antibodies. I just wanted to share that pearl because I know many institutions are struggling with operationalizing this in their clinics as these patients are coming through and sharing some of that wisdom can be beneficial.

Experts in hematology/oncology discuss goals of therapy and optimal treatment selection for patients with chronic lymphocytic leukemia.

Bhavesh Shah, RPh, BCOP

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