The Role of BTK Inhibition in the Management of Patients With CLL
Chapter 1: CLL Overview: Prognostics and Pathways
Amy Goodrich, MSN, CRNP-AC
Johns Hopkins Kimmel Cancer Center
Jill Miller, MS, PA-C
MD Anderson Cancer Center
Kristen Battiato, MSN, RN, AGNP-C
Memorial Sloan Kettering Cancer Center
Welcome to this virtual roundtable titled “The Role of BTK Inhibition in the Management of Patients with CLL.” I'm Amy Goodrich. I'm a nurse practitioner at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Joining me today for this discussion are two of my colleagues, Jill Miller and Kristen Battiato. Jill is a physician assistant and APP manager in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. And Kristen is a nurse practitioner from Memorial Sloan Kettering Cancer Center in New York City. Jill and Kristen, thank you so much for joining me today.
So first, an overview of CLL. CLL is the most commonly diagnosed leukemia in the Western world. It is a chronic and incurable mature B-cell neoplasm. The median age at diagnosis is around age 70, a little less than 20,000 new cases are expected in 2023 and about 4,500 deaths will occur. Fortunately, the five-year survival rate is about 87%. Most patients are diagnosed incidentally during routine blood work. Fortunately, most are asymptomatic and do not require immediate treatment. Treatment is reserved for those with symptomatic disease. CLL pathophysiology, as those of you who take care of these patients know, is a very heterogeneous disease both biologically and clinically. The B-cell receptor pathway is critical for CLL pathogenesis, but molecularly CLL is in two subgroups, mutated and unmutated. And we're talking about the immunoglobulin heavy chain variable region gene, or IGHV.
And as you can see from this caricature, I like to start with mutated on the bottom. If you follow that cell line on the bottom, that mature B-cell has gone into a lymph node, it has interacted with T-cells and then it mutates and it becomes a little more mature. I like to think of it that way, a mutated B-cell is a little more mature. It's been around the block a little bit more than the unmutated CLL cells.
If you look at the top, those mature B-cells have interacted with antigen, but they have not interacted with T-cells. They have not made that mutation, so they are unmutated. I like to think about this in terms of cell differentiation, although it's not necessarily a one-to-one, but that's how I keep track of this, that when cells are less mature or developed when the malignancy occurs, we tend to have a harder time treating them. And this is the case with unmutated CLL cells when the IGHV is unmutated, they tend to be harder to treat. That's a poor prognostic factor versus mutated CLL, which is a more favorable prognostic finding.
So again, most patients will be asymptomatic upon diagnosis. Very few patients will have B symptoms. Some of them start out with monoclonal B-cell lymphocytosis where these monoclonal B-cells are present and they can be followed for years. Not all of them progress to CLL, but some do. Forty percent or so are incidentally diagnosed on just their routine labs or imaging for some other problem or they come to medical attention because they have a lymph node that they can feel.
Spontaneous regressions are very common. Waxing and waning is very common in CLL. One single finding is not something that you act on because the next time you see that patient or do their labs, things could be headed in a different direction. Diagnosis of CLL is typically done with peripheral blood flow cytometry, bone marrow biopsies, and lymph node biopsies are not necessary to make the diagnosis. On peripheral blood flow cytometry, you will have monoclonal B-cells that are CD5, CD23, and CD19 positive typically, and this requires greater than 5,000 circulating monoclonal B lymphocytes. So these patients have to have an abnormal lymphocyte count. FISH studies are typically performed for prognostics, and I've got a slide in a little bit talking about why those are important and we have listed here some of the key prognostic factors. Karyotyping is important, TP53 sequencing and of course our IGHV mutational status.
Kristen and Jill, how do you talk to patients about these prognostic tests when you're getting the results and when you're doing these, and do you have reputable sources that you direct patients to? Do you want to start, Jill?
Sure. I think one thing that's important for patients to understand is these markers do not change our path moving forward. It doesn't change the indications that we use to determine when they need treatment. It simply helps us predict how their CLL is going to behave and how they might respond to therapy. So, I think that’s something that’s important for them to understand. And then also helping them to understand which of these markers will change with time as the disease evolves and which would be everything except the IGHV mutational status, which is something that does not change. Helping them to understand those characteristics and the reasons that we may or may not repeat testing at points in the future.
How about you Kristen?
Yes, I agree with Jill completely. I also want to highlight that it's really important to, at diagnosis, obtain a flow cytometry to confirm the diagnosis of CLL before you do anything with the patient. That's really critical. And again, obtaining the IGHV status usually happens at diagnosis and just understanding the prognostic profile of the patient and that even though it won't help you treat sooner until they meet those International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, but it can guide your decision-making whether you're going to use a continuous flow suppression with a BTK inhibitor versus time-limited therapy with venetoclax/obinutuzumab. So, it's important information to have on hand. Often I'll refer patients to the CLL Society for more valuable information and so a lot of our patients are very educated. They come in and they've prepared, and they want to have high-level conversations, so we have to be prepared for that.
Got it. You said you're not repeating the IGHV mutational status testing, but what are you repeating and what are the intervals to repeat those?
Usually at diagnosis it depends on the practice. We at least get a flow cytometry fluorescent in situ hybridization (FISH) testing and the IGHV mutation status and we rule out a TP53, although TP53 is uncommon, it's usually evidence in more heavily treated patients, but it can occur. When the patient has disease progression on a novel agent or any kind of disease progression, it's really important to repeat this prognostic panel, except for the IGHV mutation status, to assess for any chromosome abnormalities or molecular mutations.
Is that the same thing you're doing, Jill?
Kristen brings up a good point, and that is, at disease progression, you want to see if they've acquired new mutations that would confer resistance to the BTK inhibitor that would then lead to a switch into a different mechanism of treatment.
Great, thank you. So why do we do all this testing? We know that on FISH, and if you look at the top slide, a 17p deletion or TP53 mutation is an unfavorable prognostic factor as is unmutated IGHV status as well as 11q. The green on the top graph is 17p deletion, the purple is 11q, and then the others intersect, but the red one at the top is a 17p deletion and the other two are trisomy 12 or normal FISH findings. And so favorable is 13q and mutated. And if we look at the bottom, this is showing mutated versus unmutated IGHV status and you can see that those that have mutated disease really do much better than those with unmutated disease. It's very important to get this testing upfront so that we can prepare patients for what we think is going to be their disease course and plan accordingly.
So, when do you treat CLL? First of all, there's no magic white blood cell count for treating CLL. Always, if you have a clinical trial that a patient fits, they should be offered a clinical trial even if they don't meet the rest of the criteria for therapy. If you've got an early-stage trial, that's something that we should encourage patients to do. But typically, we're treating if patients have disease-related symptoms, if an organ is in jeopardy, if they've got bulky disease, if their lymphocyte count is moving very quickly, certainly if they have cytopenias. And then when folks have this very high-risk disease, once you see them starting to move and progress, that's definitely an indication for therapy as well. Let's talk about this B-cell receptor signaling pathway. This is really the pathway through which BTK inhibitors work, but the B-cell receptor signaling pathway in our normal physiology is a critical pathway.
It plays a critical role in the survival and the development of B-cells. It plays a role in apoptosis, proliferation, differentiation, and cell signaling both within the B-cell and signaling to other parts of the immune system. When there is a defect in this B-cell receptor signaling pathway that allows CLL to grow and proliferate. We've got a number of targeted therapies for signaling the B-cell antigen receptor (BCR) pathway. Our BTK inhibitors, which is what we are focusing on here today, our PI3 kinase inhibitors which have sort of fallen out of favor and Jill will talk about, also work through the B-cell receptor signaling pathway. And venetoclax, which is not on this slide because it doesn't work through the BCR signaling pathway. This BCL2 inhibitor is another targeted therapy that we have. You can see from this caricature how and why combining these drugs is a direction that we are moving in to try to hit this abnormality from multiple directions.