Best Practices in the Use of BTK Inhibitors in CLL

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 the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Joining me today are my two colleagues in the field, Mollie Moran and Jill Miller. I'll let both of you introduce yourselves.

Mollie Moran: Go ahead, Jill.

Jill Miller: All right. I'm Jill Miller. I'm a physician assistant at MD Anderson Cancer Center in Houston, Texas, where I've been for the past 17 years working in leukemia, focusing primarily on chronic lymphocytic leukemia. I'm glad to be here today.

Mollie Moran: I'm Mollie Moran. I'm at James Cancer Hospital at The Ohio State University in Columbus, Ohio, and I've been working with CLL for the last 25 years.

Amy Goodrich: Great. Well, thanks to both of you for joining me today. In this first video roundtable, we will be focusing on CLL diagnosis, prognostics, and initial therapy option, including BTK inhibitors.

So let's start with an overview of CLL and SLL. This is the most common leukemia in the Western world. It is a chronic, incurable mature B-cell neoplasm. And under the microscope, the lymphocytes appear mature, but they are functionally immature. And most patients in this day and age are on the older side. They're in their 60s and 70s, typically diagnosed on routine blood work, and are asymptomatic. So the majority of patients have an observation period before requiring therapy.

Treatment is required for symptom management, cytopenia, bulky adenopathy, and we'll look at that in a minute. But the new cases per year in the United States are somewhere a little over 20,000. Deaths are about just under 4,500. And with all of the advances in therapies that we'll be talking about, that 5-year survival is now around 88%.

So to diagnose CLL, it is typically diagnosed on peripheral blood flow cytometry, and you will see CD5, CD23, and CD19 positivity. The diagnosis of CLL requires greater than 5,000 clonal lymphocytes in the peripheral blood. It is an identical disease to SLL—small lymphocytic lymphoma—which is mainly adenopathy and splenomegaly without those 5,000 or more clonal lymphocytes in the peripheral blood.

We have a number of prognostic factors, and we're going to look at this in a second as well. Unfavorable prognostics, essentially no matter what disease you're talking about, that TP53 mutation and 17p deletions are always unfavorable. Unmutated IGHV status is also unfavorable. Our most favorable prognostics are a mutated IGHV status and deletion of 13q. Those are the most common ones we think of when we think of favorable prognostics. And then neutral are normal cytogenetics or trisomy 12 on FISH.

Staging of CLL, we have two staging systems. We tend to use the Rai staging system in the United States, and in Europe they tend to use the Binet system. And you can see here that patients with count abnormalities and significant lymphadenopathy have higher-stage disease. And in both of these models, the survival is clearly improved or better with early-stage disease, and then survival is less favorable as you develop more advanced-stage disease or are diagnosed with more advanced-stage disease.

So let's dive into a little bit of the pathophysiology. One of the biggest issues with CLL is figuring out that IGHV status, and so this is a critical prognostic test in CLL, that immunoglobulin heavy chain variable region gene. And this caricature is showing you that – I like to start at the bottom of this caricature so that when patients have a mutated version of CLL, meaning the malignant hit occurs in those mutated CLL cells, all that means is that these cells have been in a lymph node, they have interacted with T cells, and they have been exposed to more parts of the immune system, and they are mutated after they come out of that lymph node after doing their work.

Versus at the top, those cells are, in some way, a little less mature. They've not been around the block quite as much. And I think that we all understand that, in malignancies in general, the less well-developed a cell is when the malignancy occurs, the higher the risk and the poorer the prognosis. And this is really what's happening here in this slide is that an unmutated CLL cell really has not been in a lymph node, has not been around the immune system block the way the mutated ones have been. That's how I wrap my head around that.

And it matters because when we look at survival of these patients, you can see the unmutated patients are in the darker color, and mutated is in the lighter gray color, and the overall survival is very different. So for patients with unmutated disease, their survival is about 117 months, whereas the mutated IGHV status folks are living double that for sure at 293 months.

And so the other prognostic that we tend to do are FISH studies, and again, the 17p deletion patients are that darkest blue, and our 13q is the lighter blue at the top. And you can see in the grid at the bottom that overall survival is better for those better-risk patients. And I do want to point out that this predates our new therapies that we're going to be talking about, but it is still important to get these prognostic tests done, and we'll be talking about this as we go on.

So indications for therapy for CLL is really primarily using the iwCLL criteria, where we're looking for marrow failure, things like anemia, thrombocytopenia, looking for organomegaly, massive lymph nodes, rapid lymphocyte doubling time, autoimmune complications as well. And then of course, symptomatic disease or disease-related symptoms, those fevers, night sweats, weight loss of unclear etiology.

I want to talk a little about CLL complications here. Infections are always an issue with our CLL patients. Hypogammaglobulinemia can be present in up to 40% of patients for several years prior to their CLL diagnosis. And this is something that we're monitoring all the time, and many patients will require IgG replacement therapy. There's also immune dysfunction related to the disease itself. Remember, we talked about those lymphocytes appearing to be mature, but being functionally immature. And then treatment effects for sure. Those can be immediate, they can be cumulative, and we're always thinking about prophylactic anti-infectives based on the immunoglobulin levels, the treatment history, infection histories. And vaccines are really critical in this patient population to try to prevent any infections humanly possible. The other events here that are complications are autoimmune issues, autoimmune hemolytic anemia, autoimmune thrombocytopenia. Jill, do you have any thoughts about these complications? You have any pearls of wisdom for the audience?

Jill Miller: Yeah. I mean, one thing that comes to mind is just realizing that CLL is a very wide spectrum of disease. And you have some patients who are truly CLL, it's all in their blood, they don't have palpable adenopathy, versus those who are more SLL, who it's mostly in their nodes and very little in their blood. And you also have a diverse spectrum of complications and symptoms. Some patients can reach the point of treatment without having any symptoms whatsoever, whereas other patients, the symptoms are the driving reason for considering therapy.

The complications that we have to watch out for, as you mentioned, infection is always a big issue. We're big proponents of vaccinations, and we have those conversations with our patients at every visit and make sure that they get their annual flu shot and they're aware of the recommendations for the other vaccinations, which as you know, are changing frequently. So it's a challenge for us to keep up with those and make sure our patients are staying on top of those as well.

Amy Goodrich: Yeah. And then Mollie, do you want to talk about hypogammaglobulinemia, and what are your triggers for starting replacement therapy?

Mollie Moran: It is common. It's such a common presentation or problem with patients with CLL. We tend to watch the patients and see if you're having repeated infections, if you're on and off antibiotics. Certainly if you land yourself in the hospital with an infection, we check immunoglobulin levels, IgG, or QIMM is how it's ordered, quantitative immunoglobulins. And a lot of times, the insurance will drive whether or not you can provide immunoglobulin support, exogenous immunoglobulins.

And so we tend to start checking them in the cold and flu season. We often give patients supplemental immunoglobulins from, say, October to April to support them through those months. During the pandemic, we just did it nonstop through, and some of the patients got used to being on that supportive regimen. And again, you have to teach patients that this isn't going to keep you from getting infections. What it's going to prevent is infections that may land you in the hospital, in the ER. It keeps the severe infections at bay.

Amy Goodrich: Excellent. Thank you. And so our next slide is on mechanisms of actions of our current CLL therapies, and certainly this B-cell receptor pathway is in the middle of this caricature and is a critical pathway. This is where our BTK inhibitors are working, our covalent ibrutinib, acalabrutinib, zanubrutinib, and then our non-covalent, our FDA-approved agent, pirtobrutinib, and then our in clinical trial, nemtabrutinib. This is the pathway through which our PI3-kinase inhibitors work as well, idelalisib and duvelisib. Then as you sort of go around this circle, you can see venetoclax being our BCL2 inhibitor that induces apoptosis. Our chemotherapy, you can see where this works through just out-and-out DNA damage, and then our anti-CD20 monoclonals that work more at the cell surface level, calling in NK cells and other cells to come and attack that cell.

And so this B-cell receptor signaling pathway, and again, this is where our BTK inhibitors are working, this is a complicated slide, but you can see that this is such an important pathway in that it impacts survival, proliferation, migration, apoptosis. The breadth of activity that that pathway is responsible for is quite extensive, and so it's a great target. And so when this signaling is impaired, this allows cascades to alter all of those things, the proliferation, the survival, the differentiation of those B cells. And then ultimately what happens is those genetic insults allow malignant B-cell growth and survival. There's dysregulation in oncogenic signaling. So again, a very important pathway, and it's a great target.

And so if you look at the current landscape of treatment in CLL, we've got no 17p deletion on the left and 17p deletion on the right. And you can see that both of those, the preferred regimens are acalabrutinib with or without obinutuzumab, venetoclax with obinutuzumab, or zanubrutinib. And then if patients do not have a 17p deletion, you can see some chemotherapy options in there. The ones with a 17p deletion, you will see no chemotherapy options. And then in second line after initial therapy, we'll cover that in another section, but I just wanted the whole picture to be here. So lots of BTK inhibitors on this slide.

And so when you're thinking and talking to patients about initial therapy and those preferred regimens, when we're using our BTK inhibitors, those are continuous therapies. So you are giving those until patients progress or have toxicity. And the goals of those therapies are disease control, long progression-free survival, but there is disease measurable in almost all of these patients. There are very few complete responses, but they're durable responses versus our fixed duration therapies, our venetoclax based-therapy, that really it is deep remissions, undetectable, measurable residual disease, prolonged progression-free survival. That is the goal of that therapy. And so when you're talking to patients about whether you're going to do a BTK inhibitor frontline or venetoclax with obinutuzumab, Mollie, what are you talking to patients about when you're talking about initial therapy?

Mollie Moran: As you just explained, you try to gauge out whether they're going to be interested in a therapy that could go on for years potentially or if they're looking more at a fixed duration. And what also plays into that for me is performance status and social support, and I think we'll get into that in a bit more as well. But when I have discussions with patients about frontline therapies, a lot of times, patients come in and they're very well versed in what's available. The duration that you could be on one of the oral BTK inhibitors could be years. It could be 10+ years we have patients on the original oral inhibitors, so fixed duration is a nice prospect. What we also try to balance out is social support. How far away from us do they live? Are they going to be able to come for frequent visits in the beginning? If you use one of the CD20, CD19 antibodies, you're going to have a lot of visits in the first month no matter which pathway you take or which treatment path you take. And so there's a lot to balance out. We take a lot of input from the patients, but as you know, they always want to know what do we think is the best option for them. We look at their genetics, their mutational status, their support systems, their performance status.

Jill Miller: And also their comorbidities. As Mollie was saying, it is a discussion that is oftentimes extended over multiple visits if we have the luxury of being able to take multiple visits to arrive at a decision, but take into consideration what their goals and preferences are, and also if they have any underlying health conditions that might lead us towards or away from a particular treatment selection.

Amy Goodrich: Agree, agree. Well, thank you both. This concludes our discussion on CLL diagnosis, prognostics, and initial therapy options. I'd like to thank Jill and Mollie for joining me. And for more information and to view our other discussions on BTK inhibitors in CLL, please visit jadpro.com.