Amy Goodrich: Hello, and welcome to JADPRO's roundtable discussion on Updates in the Use of BTK Inhibitors in CLL. I'm Amy Goodrich. I'm a nurse practitioner at Johns Hopkins in Baltimore. Joining me today are two of my colleagues in the field, Jill Miller and Mollie Moran. I'll let both of you introduce yourselves.
Jill Miller: All right. Hello. I am Jill Miller, physician assistant at MD Anderson Cancer Center in Houston, Texas, and I have been taking care of leukemia patients for the past 17 years, and very happy to be a part of this group today.
Mollie Moran: I'm Mollie Moran, and I'm a nurse practitioner at the James Cancer Hospital at The Ohio State University Medical Center. I've been working with CLL patients for the last 23 years, and thank you for having me as this group.
Amy Goodrich: Great. Thank you both for joining me today. In this video roundtable, we will be focusing on treatment of relapsed/refractory CLL. So let's dive in.
So let's look at the NCCN guidelines, a CliffsNotes version of those, in the current treatment landscape of CLL. So on top are the first-line therapies, and on the bottom are our second-line therapies. And you can see that, with or without 17p deletions or TP53 abnormalities, our preferred second- and third-line treatment options are acalabrutinib, zanubrutinib, and venetoclax with rituximab. And if you look at the first-line therapies, they're very similar. And so essentially, what you didn't use first line, you're using second line. And then our other regimens that are used in second or third line, we can use ibrutinib. We've got our alemtuzumab, duvelisib, lenalidomide with or without rituximab. But this is where some of our newer agents, pirtobrutinib, which is our non-covalent BTK inhibitor, and liso-cel, our CAR-T product that has been approved in CLL, come into play.
And so the indication for therapy does not change based on the line of therapy. You continue to use the iwCLL criteria to initiate therapy. And then if patients do not have high-risk features, if they don't have a 17p deletion or a TP53 abnormality or complex karyotype, those should be repeated prior to each line of therapy. That IGHV status does not change and does not need to be repeated. That just is recommended at initial diagnosis.
And so if we look at our BTK inhibitors, we've got first-, second-, and third-generation BTK inhibitors. Our first- and second-generation BTK inhibitors are our covalent BTK inhibitors. Ibrutinib is our first generation. Acalabrutinib and zanubrutinib are our second-generation covalent BTK inhibitors. Pirtobrutinib is our third-generation BTK inhibitor. It's a non-covalent BTK inhibitor, and we'll talk about this in a second. And you can see there the FDA approvals and the dosing of all of those agents.
And so why do we need all these BTK inhibitors? So on the left you can see where our covalent BTK inhibitors, ibrutinib, acalabrutinib, zanubrutinib, they bind to C481, and that C481 binding pocket needs to be normal for them to attach to the cell. And so when that binding pocket, when BTK C481 mutates, resistance occurs, and patients will be resistant to all non-covalent BTK inhibitors. And then on the right, you can see where our non-covalent BTK inhibitors, and pirtobrutinib is our FDA-approved drug and nemtabrutinib is in trials. The C481 binding pocket can be normal or abnormal because those are binding to a spot outside of that C481 binding pocket. So regardless of that mutate, whether it's mutated or not, the non-covalent BTK inhibitors can bind to the cell.
And so what are some of the implications in terms of side effects? And so one of the things that happens with our first, second and then third generation is that they have less off-target effects with each generation that have been developed. And so you can see ibrutinib has the most off-target effects, and then those get less as each iteration occurs. And so some of those potential side effects, so TEC is felt to be responsible, although not clearly understood, the bleeding and cardiac toxicity, and we'll talk about that in a second. EGFR, for those of you who are more familiar with solid tumor patients, you know the EGFR-related rashes, diarrhea, arthralgia. Those are seen with our BTK inhibitors too, and those are off-target effects.
So if you look at some of our toxicities, they're listed here. And so Mollie, why don't you tell us what you most commonly see as toxicity when starting a patient on a BTK inhibitor?
Mollie Moran: The most common side effect is – fatigue is always in there. And so that's kind of common across CLL patients, and it's hard to tease out whether that's attributable to the BTK inhibitor or if it's attributable to the disease or the age or some other process. So you rule everything organically out with that, and that's a tough one to tease out. But I think the most common one that we see is bruising, and patients equate that with the bleeding. And it's not always that they're having internal bleeding, it's just that their skin is friable. The platelets aren't as sticky as they should be, and it doesn't take much to cause a bruise. So I think those are the most common ones. I think the harder ones to manage tend to be in the – rashes are always hard to manage for me.
Amy Goodrich: And Jill, what is the most difficult to manage or the most challenging? What are the challenging toxicities that you see?
Jill Miller: I think the challenging ones are the ones you have to watch out for, such as atrial fibrillation, hypertension. These can happen at any time. So a lot of the side effects, when patients start any kind of medication, will present early on, but then can creep up even months out on therapy, and it's a silent killer. So patients have to be vigilant about checking their blood pressure periodically. Same with atrial fibrillation. Patients may not be aware that they have atrial fibrillation. So just being on top of that, making sure patients are aware so that if they do begin to experience anything unusual, that they know to reach out to us and say, "Hey, could this be related to the medication I'm taking?"
Amy Goodrich: Great. Thank you, thank you. And then we've got a slide on our most common adverse events by BTK inhibitor, and we've touched on those. And then the warnings and precautions, the black box warnings. There's a lot of overlap with black box warnings: infections, hemorrhage, cytopenia, second primary malignancies. And one of the biggest issues that we've talked about here are these cardiac events. And so because of the cardiovascular risk with these drugs, there is in the NCCN guidelines recommendations that all patients have a cardiovascular risk assessment prior to starting BTK inhibitors. And I'm wondering, Jill, what are you doing? What does that mean in your practice? And then Mollie, what does that mean in your practice?
Jill Miller: So in my practice, if patients are older, so say—that threshold keeps getting younger as I get older—but older, maybe into their 50s, particularly if they have any history, then we're going to have them evaluated. If they have a cardiologist that they see outside of our institution, they can follow with that individual, or we can send them to our cardiology service for a baseline EKG and just a lot of education. For our younger patients who have no history, we may not do an extensive evaluation, other than education and making them aware of these potential risks.
Amy Goodrich: Great. Thank you. Mollie, anything different you're doing?
Mollie Moran: Ours is about the same. We were fortunate to have cardio-oncology, so we can enlist their help as well in someone who may come in with a diagnosis of some sort of cardiac abnormality, whether it's an existing atrial fibrillation, and make sure that they're evaluated there. But it's usually the New York Heart Association, and we make sure that they have low-risk disease.
Amy Goodrich: Great. Thank you. Yep, that's great. And then there are also NCCN guidance that we should not be switching from one BTK inhibitor to another based on toxicity, that we should really try to stick with the one that we're using and use dose modifications and not switching drugs over and over again. So that's on this slide as well, and I would encourage everybody to look at those guidelines and wrap their head around that guidance.
I just want to spend a minute talking about venetoclax. And so hopefully all of you are aware that venetoclax gets ramped up because of the tumor lysis syndrome risk. 20 mg for a week, then 50, 100, 200, and then at the fifth week, getting up to that 400-mg dose because of that tumor lysis risk. And then every patient should have a tumor lysis risk assessment, and then that drives the tumor lysis monitoring. All patients should have anti-hyperuricemics and also hydration. And then depending on what their risk is, that might look a little different for each patient. But this is part of why this is not the right fit for every patient because of all this tumor lysis monitoring that we need to do, whether they can make those appointments, not make those appointments.
And then other toxicities with venetoclax, neutropenia, and so monitoring for that and using growth factors. Nausea, vomiting, diarrhea, those things can happen as well. Taking with food, using over-the-counter antimotilities, and just using antiemetics typically helps. Of course that tumor lysis monitoring and patient education is really a critical point with venetoclax.
I want to jump into CAR-T. And so we've now got liso-cel for CAR-T. So side effect-wise in looking at patients progressing after BTK inhibitor therapy and venetoclax-based therapy, you can see that about 18% of patients will get into a complete response, and those are durable. And so the deeper the response, the more durable they are. Tell me, Jill, are you using much liso-cel in your CLL patients? What are you seeing in terms of responses?
Jill Miller: We are beginning to use it some, and we're seeing really good responses. It relies on having a lot of resources at hand. And so it's really, I think, limited to the major cancer centers at this point. But once we get through the initial treatment and follow up immediately afterwards, then we're actually seeing very durable responses in patients.
Amy Goodrich: Great. How about you, Mollie?
Mollie Moran: I agree with what Jill said. I have folks who've been years without any treatment for their CLL, and so we're starting to see it a bit more. Again, it's the resources and where you're located as a patient, and being able to get things done at a big center is important.
Amy Goodrich: Right, yeah. And so in conclusion, I just want to conclude here with we've now got multiple targeted agents. We now have cellular therapy options. We've got our covalent BTK inhibitors, our non-covalent BTK inhibitors. We've got venetoclax, our BCL2 inhibitor. We now have CAR-T. And one of the biggest quandaries at this point is how to sequence these and really the right patients to use our newer pirtobrutinib versus CAR-T and how we sequence them and who's going to best benefit from those newer options, and so hopefully more to come there.
So this concludes our discussion of treatment of relapsed/refractory CLL. I'd like to thank Jill and Mollie for joining me. For more information and to view our other discussions on BTK inhibitors in CLL, please visit jadpro.com.
