Welcome to Unscripted the AMCP podcast, a look inside managed care pharmacy. Listen in as experts explore the challenges, innovations, and opportunities shaping healthcare for millions of patients. Welcome everyone to this episode of Unscripted, the AMCP podcast that's sponsored by AbbVie, where they work to find answers that make life better for patients in the world.
Now we're gonna talk a lot about things like the 2026 NCCN guidelines for chronic lymphocytic leukemia, or you'll hear us call it as CLL because they now recommend several therapies. If you've seen the guidelines, you know, you know, and especially several therapies that have oral fixed duration approaches for our patients as preferred frontline treatment. In this episode, we'll discuss the impact of these changes. With my amazing panelist, Kirollos Hanna, PharmD.
Kirollos is the director of pharmacy for Minnesota Oncology and an assistant professor of pharmacy at the Mayo Clinic College of Medicine. So welcome Kirollos to the podcast. Thanks, Laura. I'm really glad to be here and happy to talk about this. Amazing. Let's jump right into it. Holy moly. So the evolution of treatment for CLL Chronic Lymphocytic leukemia has really evolved lately. And now again, we wanna talk about these oral fixed duration regimens that we have in the first line setting.
So, Kirollos, I'm really curious, can you give our audience an overview of what fixed duration treatments are available in the first line setting for CLL? Also, how widely are they used? Sure. No, and that's a great question. And I think, you know, the evolution that we have seen over time in CLL has really been something that I think is very exciting for patients. Laura, back in the day, you know, decades ago we were using FCR and chemo immunotherapy to treat a lot of these patients. Right?
And I would say probably 10 to 12 years ago, your BTK inhibitors came to this space. Really revolutionize what we do in CLL. We learned that B-cell signaling, B-cell targeting, um, is really the way to control this indolent disease in the grand scheme of things. And we've seen drugs like ibrutinib, zanubrutinib, acalabrutinib really make a significant impact and push chemoimmunotherapy kind of along the side, right? Whether you, even if you had IGHV mutations or not.
Uh, whether or not you were deletion 17 p, but then I would say over the past couple of years, right, we hadn't done the introduction of BCL-2 inhibition and CLL with venetoclax based therapies. And when you look at the NCCN guidelines, just the updates that have gotten to effect over the last 3, 4, 5 months, um, the, the options that you can combine with venetoclax, um, are quite significant at this point. You know, I would say for the last several years. We had two critical studies.
We had CLL 14 and Murano, and out of these studies we probably have seven to eight years worth of data from both of these studies. And what we learned from CLL 14 and Murano was that we can combine BCL-2 inhibition with a CD 20 monoclonal antibody, whether it's obinutuzumab or rituximab, your frontline or relapse CLL patients. And when that concept was first introduced. You know, I, I think there was a lot of people who, uh, may have been hesitant to get patients off of therapy, right?
Because we got so used to BTK inhibition being a continuous treatment until progression or toxicity, and then we continued to follow CLL 14 and Murano, looking at MRD, negativity and various things. And then here we are today. But to take it even a step further, so since we've learned that Ven plus CD 20 is working could Ven in combination with BTK-I a BTK inhibitor or even a BTK-I, as well as a CD 20 monoclonal antibody. Get patients to that more durable remission.
Can we get more patients to MRD negativity? So when you look at the NCCN guidelines, now, there are multiple, multiple combinations regardless of the presence or absence of deletion 17 P, but a couple of combinations that I think are worth to call out, we have veneta, we have the AVO combination, which is venetoclax acala. With or without obinutuzumab, we also have various other combinations with ven ibrutinib, uh, we also have ven zanubrutinib.
So there's a lot of exciting combinations, a lot of different cocktails I would say you can kind of mix up for your patients. And we're getting to this point where we can treat CLL, let's say for a year and get patients off, and they're doing really, really well. So it's something very exciting. Absolutely. And for those fixed duration treatments, I love how you pointed out that it brings a option for patients where they can stop therapy at just over a year.
Versus continuous BTK inhibitor therapy in which we were used to seeing patients on just constant therapy waiting until disease progression. So that time off treatment is really valuable for patients. But I wanna hone in on something you mentioned. MRD, so minimal residual disease. If you look in NCCN guidelines, they mention that there's a few frontline CLL regimens that can be used to treat the patient until minimal residual disease or MRD. So I'm really curious, are you guys doing this?
Are you seeing this? How do you really view the role of MRD testing in guiding treatment decisions? Are you doing that in practice today or are you leaning more towards a fixed duration and not as much of the MRD testing? Yeah, I mean, MRD is becoming more and more popular and I, I would say it's even now more popular just given that ASH was about a month ago, a month and a half ago. Um, we've continued to see a, a more expanded role within CLL.
When we kind of go back and talk just about BTK inhibition, MRD negativity was a moot point. You don't really get MRD negativity when patients are on monotherapy, BTK inhibition. The role of MRD negativity really started to to make sense here when. You, you look at a lot of these clinical trials, right?
The, the fixed duration combinations and when you trend how patients are doing, whether you're looking at their progression-free survival or their overall survival trend, whether or not it's reached, you know, and we know the median at this point, but the trends across the board, and even again going back to CLL 14 and Murano, the groups of patients who achieved MRD negativity with a BCL-2 inhibitors.
They actually had and trended to have better progression-free survival as well as response rates. So it's becoming more and more popular, especially. Now in CLL, even when you look at the NCCN guidelines, some of the callouts that NCCN tells you is MRD guided, right? So you will find that in the NCCN tables, um, and by MRD guidance, depending on which regimen we're actually talking about, it allows you to potentially discontinue the BTK inhibitor or maybe the CD 20 at some point.
So based on MRD guidance on how quickly your patient can can get to that point, um, we can start to take some therapies off or even maybe extend their in in interval a little bit longer. So I, we're definitely seeing it a lot more in practice. I would say it's that, uh, the standard of care across the board and I think there's still opportunity for education amongst some hcp's. Maybe within the community setting.
Uh, but we will continue to see this evolution and impact of MRD negativity as we continue to navigate CLL and start getting patients off of treatment. Wow. So that's a lot. The, and the reason I say it's a lot. Is because from the payer world, can you imagine a payer trying to understand this and how treatment is stopping perhaps because the patient is becoming now MRD negative?
It can be really confusing because that learning curve, uh, while it might be high on your end, it's extremely steep on the payer world and in the AMCP community to understand how this is working and how therapy is perhaps being stopped because MRD negativity. So I give a lot of kudos there and I'll be leaning on you as my clinician to, to help the patients out with that because that's extremely complex.
So let's switch gears a little bit and tell me about the benefits of fixed duration first line CLL treatment versus continuous BTK inhibitor therapy. What are you seeing there for benefits? In general, just the management of these patients tends to be better. Now, when I think about CLL as a whole, whether we're talking about BTK, BCL-2 inhibition, finite treatment duration, continuous, whichever combination as a cancer.
We have made significant strides in CLL, just with the introduction of BTKis in this space To begin with, decades ago or a decade ago, you look at the five-year survival for CLL, and it's over 90%. So when I look at the disease state, I, I'd like to think that we've made it right. We are making a significant impact for patient. Many patients with CLL at this point are not succumbing to their disease. They're succumbing to older age comorbidities and may be toxicity of treatment.
So as we weigh the benefits, we certainly have learned over the years, continuous BTK inhibition is associated with toxicity. Whether you want to talk about first generation, second generation. Covalent, non-covalent binding. We know hypertension is real. We know cardiovascular toxicities are real, and with the cumulative exposure, we do see an increase there. That's not to say the most appropriate modality is always gonna be finite treatment duration. Right? Because if you combine.
A BCL-2 BTK inhibitor, for example, and maybe a CD 20. We're going to see profound neutropenias. We're going to see infections early on, um, in that patient's management. So I think you have to be able to balance those aspects. Does the patient want to come to the infusion center or be on an all oral regimen? Those are all considerations.
And then when I think about though, the other benefits that come from this A BTK inhibitor, if your patient is gonna be on it, you're expecting them to be on it for 5, 6, 7, 8 plus years, right? I mean, these, these patients get on it, stay on it, but there is an added overall cost to, you know, to the patient. So there's financial toxicity potentially to the patient, to the payer. Uh, you know, we're covering these BTKs for seven, eight plus years.
But then when you look at the finite treatment duration option, most of the time it's gonna be a combination of things, right? It's not single agent venetoclax. And we kind of move on with that. So you also have to be considerate there that the patient is going to have increased pill burden, potentially if you're doing then BTKi combination. So adherence and compliance and proper education is critical there.
You're gonna have potentially a CD 20, so they're coming in for their infusions for however many months of that CD 20. And then from a payer lens, while there's gonna be a big spend upfront, right, you're covering a doublet now or a triplet regimen. Versus a single agent. I think one thing that we should be doing to partner with our payer partners is let's start to dig at this data, right?
And while we might have a heavier cost during that first year of treatment, what does that look like if then the patient is off of treatment for five additional years beyond and kind of try to model those out of continuous BTKi. Combination therapies, but finite duration, uh, and just trying to see the impact on the payer lens as well as the total healthcare spend.
Absolutely. And I love where your brain's going, and I love your perspectives from perhaps the payer lens as well, because when we're thinking about covering these therapies, one for Medicare members coverage is a no-brainer. If it is FDA indicated or follows NCCN guidelines, category one or two a. Then when you're saying, is a payer going to prefer one therapy over another? Are they going to say prefer fixation, acalabrutinib, venetoclax, over single agent BTK inhibitor first line therapy.
Now, to be honest, data payer is going to be as bold to say, I'm gonna prefer the fixation and do step therapy here. Something aggressive or wild, even though we do perceive that the fixed duration, perhaps acalabrutinib and venetoclax might be more cost effective then like he mentioned, whoa, four or five years of a single agent, BTK inhibitor. But a payer also would want to protect that discussion between a provider and a patient for what is the patient's will.
I think that you might see payers more interested, like you're talking about looking at the data. Doing maybe value-based care programs with the providers. Sometimes perhaps pathways and incentivizing, maybe the fixed duration therapy, the acalabrutinib and the venetoclax. But I doubt you're gonna see big hurdles in access to either of the different treatment options, because the patient really does have a lot to weigh here.
So with that being said, talk to me about what you're hearing from a patient's perspective on what they're preferring. Yeah, no, and, and those are all excellent points. And I, and I, and I love to hear that too, Laura, from, from your payer lens side of things. And that's really what I've, I've been seeing in clinical practice, um, when our physicians are sitting with patients to discuss their CLL diagnosis.
Right. You know, Hey, Bob, you've, you, you know, we, you've been under active surveillance for five years, but you're now getting infections. You are. You know, you're having toxicity. It's time for us to start treatment. It's always a shared decision making approach. You know, putting it on the table. To your point, the physicians will, will put out there, Hey, we can put you on this, this great, let's say second generation, BTKi.
It works really well, and you'll be on it for, you know, indefinitely until you have toxicity or progression of your disease. And then the a, the other aspect is they're putting that finite treatment duration, right? And walking the patients through it. What it means. There's obviously a little bit more. I would say burden on the patient during that combination finite treatment duration approach. So there are things that we have to take into consideration. How far does this patient live? Right?
What is this patient age and comorbidities? If my patient's 80, maybe some of my physicians may be more prone to do single agent BTKi than the whole venetoclax ramp up acala or ibrutinib or whatever you do in combination or a CD 20. The availability of a caregiver, right? Uh, affordability as well. Making sure that all of these can be covered by insurance, and it really comes down to that. And we do see a bucket of patients that.
Like to do, to go down that route of finite treatment duration and then the other bucket kind of sticking with the BTKis. It's very hard for me right now to say that it's a 50 50 split between, between all of this, right? I'd still say a large portion of the market share in CLL is on BTK continuous, uh, treatment. Uh, that's simply because of where the data was a couple of years ago. It was all BTK. So I still think that some of that, um, is straggling into where we are today.
And if it's working, our physicians are not going to automatically switch them to one alternatives, but that'll be something in our back pockets. So I do see that with time as this data continues to evolve and report out, that we will start to see maybe more of a shift. But that's kind of where we are. And, and it's, but it is that shared decision making with the patient, their caregivers, and their provider in terms of how they wanna approach it. Absolutely.
So from a patient's perspective, it sounds like they're weighing whether they're fit enough to do the doublet therapy for fixed duration and have that time off treatment, or whether maybe single agent continuous BTK inhibitor is best fit for them. Yep. Yep. And and the other thing to mention too, Laura, that I think is important is right now CLL in terms of sequencing, right?
Even if you went down the BTK continuous, it doesn't take finite treatment duration off the table in the second line setting. And vice versa, if you went finite in that frontline setting and patient that progresses X amount of years later, you still have BTK on the table as well. So we also have great options, doubts. In that relapsed setting that are very, very effective.
And it goes back to the point that I was saying many of our patients are not succumbing due to their CLL diagnosis at this point. Right. Um, and then even beyond your first two rounds of treatment, which probably are gonna take a 10 year span, we now have other agents, like per ibrutinib. Right. A non-covalent binder. We have BTK degraders that we heard out, uh, come some data come out from ASH. So even as you go into further relapses, we have great therapeutic options for these patients too.
Ah, it's always an exciting time in oncology, right? They keep us busy, Carlos, don't they? Absolutely. So last closing question for you, if I may, what would you like our payer partners to know most about this topic? Yeah, so I mean, it, it, it's a, it's a very exciting time and, and I think I loved one thing that you said, Laura, during this was, you know, maybe value-based care arrangements and agreements.
You know, when I think about payer partners, I'm not just thinking about commercial payers. I even think about the CMS EOM program, right? We, we are part of, we're, we're an organization that's part of EOM and one of the challenges of like how data's collected and reported out and performance periods and things like that is, um, you know, CLL is certainly a disease state that does fall under, under these types of initiatives, the cost of care.
There are limitations around the cost of care evaluation if I'm using a doublet or a triplet, although overall, right, we talked about that total cost of care over the, the years balancing out. Versus continuous BTKi, for example. I think that's a challenge that we tend to see. But then also from a, from a payer lens, we all can't ignore the Inflation Reduction Act, which you know, went into effect this year. Impacting the drug that made a big impact in CLL ibrutinib, right?
Next year we're gonna see it impact acalabrutinib. So this is a disease state that it's getting impacted by multiple things. So from a payer lens, we're getting a lot of exciting therapeutic options for these patients. But how do we partner together? Also having pharma in the room or having some type of collaborations where we can have some type of support and help as we navigate this very, very dynamic space. Um, you know, ibrutinib just took a 41% haircut, right?
So, uh, on the Medicare side of things. So it's how do we work well together to control costs, uh, make sure institutions are reimbursed appropriately, and also that there's a value aspect or component to the payer arrangements. And I, I think it can make significant impact on the CLL population.
Absolutely. And I love how you know our world on the payer's side so well and who the IRA, of course, that's always a hot topic for us with AMCP and even there's a lot of discussion because payers may now have stepped therapy preferring drugs like acalabrutinib, zanubrutinib, over ibrutinib, because ibrutinib has a lot of toxicity and also efficacy has been more prolonged with some of the newer agents than ibrutinib.
Now, as you mentioned, with ibrutinib having a haircut that is so extensive under the IRA, there are perhaps thoughts that we cannot disadvantage ibrutinib for Medicare members because CMS might perceive that as disadvantaging a drug that's price negotiated.
So different ways people are looking at that formulary, but people are going to have to reevaluate their step therapy strategies, especially for their Medicare members based on all these BTK inhibitors, then becoming eligible for price negotiation like ibrutinib. So it's a wild world, isn't it? Yeah, no, absolutely. It's, it's, that's a great call out actually, and well, we'll navigate it a day at a time I say . Absolutely. Kirollos, I can't thank you enough for this amazing discussion.
You are an expert in this field. I know you are an expert in all the extreme cancers because I could never do what you do, and I find it extremely impressive to listen to you and your thoughts and how you really make this easy to understand for our audience. So thank you very much, Kirollos. Of course, Laura, thank you so much and hope it was beneficial to our audience and it was a pleasure. And uh, we hope you join us for a future event.
Absolutely, and thank you all to our audience and our listeners for this episode of Unscripted, the AMCP podcast. This episode was sponsored by AbbVie. For more information about AbbVie, go to abbvie.com. Thank you all. Have a wonderful day.