Amy Goodrich: Hello, and welcome to JADPRO's roundtable discussion titled “A Case-Based Discussion of BTK Inhibition in CLL.” I'm Amy Goodrich. I'm a nurse practitioner at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Joining me are two of my colleagues, Jill Miller and Mollie Moran. Jill and Mollie, I'll let both of you introduce yourselves. Jill, why don't you go first?
Jill Miller: Sure. I'm Jill Miller. I'm a physician associate at MD Anderson in Houston, Texas, and I am part of the outpatient leukemia APP team there. Been there for almost 18 years.
Amy Goodrich: Great. How about you, Mol?
Mollie Moran: I'm Mollie Moran. I'm a nurse practitioner at the James Cancer Hospital at The Ohio State University in Columbus, Ohio, and I am one of the many nurse practitioners in the CLL group.
Amy Goodrich: Great. Thank you, to both of you, for joining me today. So in this first round table video, we will be focusing on high-risk CLL in initial therapy, and this is my case.
Ladies, this is Betty. She is a 72-year-old female. Her past medical history includes GERD and osteoarthritis. She takes daily ranitidine, just over-the-counter ranitidine, she watches her diet, and she takes acetaminophen as needed for her mild osteoarthritis discomfort.
She works part-time as a payroll specialist doing office work, and she watches grandchildren two days a week before and after school. She's active, she walks, she's a pickleball lady. She is divorced, she lives alone. She's got two kids locally, she's got a good support system, so she's just an older lady with a really good support system and very healthy otherwise.
So she is incidentally noted to have lymphocytosis on routine labs with her primary care provider. At that time, her white count was 45. Absolute lymphocyte counts were 44. Hemoglobin was 12.1, platelets 152. She gets referred to an oncologist, she gets some flow cytometry done, and this is typical CLL. She has her prognostic testing done. And she does have a TP53 mutation as well as a 17p deletion. Her IGHV status is unmutated. She does not have a complex karyotype. So she's got high-risk CLL, but she's asymptomatic. She's got no adenopathy. She's got no organomegaly on exam.
And so the decision was made to observe her. She is educated that she's got these high-risk features, and as we all know who see these patients, just because they have high-risk features, doesn't mean we're automatically treating folks. You can get a good watch-and-wait period out of these folks as well. So, she's followed every three months with labs and physical exam.
At each visit, we're talking to her about therapy options, so that when it is time for her to get treated, she is aware of options. And so we're talking to her about continuous BTK inhibitor therapy, and we're talking to her about a host of time-limited options as well, with or without continuous or covalent BTK inhibitors, with or without BCL-2 and/or anti-CD20 therapy, but also talking to her about BCL-2 inhibitors with anti-CD20s. We're talking to her about the schedules, the lab monitoring, the visits, the toxicities.
And so about 18 months after her diagnosis, her white count has drifted up to 128,000 with mostly lymphocytes. Her hemoglobin is now 9.9, platelets are 95. We can feel her spleen tip. She still has no adenopathy on exam. The most alarming thing is she's now not able to be as active. She's not exercising routinely because she's getting winded easily. She's just tired. And so really, it is getting time for her to need therapy.
And so we're making sure that she's meeting our international working group on CLL indications for treatment. And clearly, her hemoglobin is less than 10 at this point, her platelets are less than 100,000. And those are really her current indications for treatment. So we're prepping this lady because, consistently, these things have been heading in the right direction.
In thinking about getting her ready for treatment, what are you ladies doing in terms of repeating testing? So she's a lady with unmutated IGHV, she's got high-risk features on FISH. Are you repeating any of those? Are you repeating her TP53? Are you repeating her karyotyping? Some, none, all?
Jill, let's start with you. Do you think this lady needs more prognostic testing? Because we know that people, those can change, but she's high-risk to start out. How would you be approaching her knowing that she's getting close to needing treatment?
Jill Miller: Right. I mean, as you said, Amy, we already know that she's high-risk, so we certainly could repeat FISH and a molecular panel to see if she's acquired any new mutations. But her IGHV status is not going to change, so there's no need to repeat that test.
Amy Goodrich: Got it. And so, Mollie, would you do something differently than what Jill's talking about?
Mollie Moran: The only thing we might do in addition is to send something that's called clonoSEQ so that we could, if there was a question of whether we were looking for how well her response is going. When you look for minimal residual disease, it's easier to look for those kinds of things down the road. Because if you pick a frontline BTK, the probability is she's going to be on it for a long time, right?
Amy Goodrich: Exactly, yes.
Mollie Moran: But it's nice to have that data in the beginning. If you don't get it, it doesn't change the big picture of what you're doing now.
Amy Goodrich: Right. But if you're in a small community practice, this lady has high-risk disease, and really, to make treatment decisions, I think getting more prognostic testing is not necessarily mandatory. Once people have these high-risk features, you've sort of gotten what you need from a practical perspective. Great. Thank you.
So, Betty and her children have a clear understanding of these regimens and her options, and they want to review efficacy data.
When talking to patients about all of these different options in CLL, when you're talking about covalent BTK inhibitors, all of these drugs have similar efficacy as single agents in the 17p or TP53 abnormality population as they do in patients without those high-risk features, right? So those are really very effective, progression-free survivals are high, overall survivals are high for all of these agents.
The difference comes with venetoclax and obinutuzumab where we know that patients with TP53 abnormalities do not do as well as the patients without those high-risk features. Although it is still an effective regimen, the curves do separate, whereas with covalent BTK inhibitors, they're overlapping. So, we know that patients with 17p abnormalities or TP53 mutations are not going to do as well with venetoclax with obinutuzumab, although it's still an option.
And then what about combinations, right? So, we now have on our NCCN guidelines combinations of covalent BTK inhibitors with BCL-2 inhibitors. We have the SEQUOIA ArmD that zanubrutinib with venetoclax, and we have the AMPLIFY study, which uses three drugs, acalabrutinib, venetoclax and obinutuzumab. And some of them are given until measurable residual disease is negative, and there's lots of MRD testing in some of these regimens.
So, when you're talking to patients about this, and this is a 72-year-old lady, and she's healthy, and who are you thinking about for just a single-agent covalent BTK inhibitor vs. one of the combination regimens? Mollie, do you want to start? How are you thinking about this and guiding patients when you're having these discussions?
Mollie Moran: Thanks, Amy. I think when I talk, because of her age and her busy lifestyle, and we want to get her back to activity as quickly as possible, I would lean heavy on the single-agent therapies because they're well-tolerated, they are minimally disruptive to your daily life.
Whereas some of the combination therapies and time-limited therapies, they're heavy-loaded in the front end, and so that would take away time from what she's already got established. If it was someone who was maybe 20 years younger, and we were looking at a longer period of time that we needed to manage things, I think I would lean a little heavier into a combo therapy for time-limited therapy just because it would shorten. Obviously, time-limited means shortened up.
So, I think that may be beneficial for someone younger. And they don't want to be on this for the rest of their life. They want to be done with it.
Amy Goodrich: Thank you, Mollie. So Betty is very interested in finite therapy. She likes the idea of finite therapy, but she does not like the idea of infusions and frequent visits for tumor lysis monitoring. She really wants to maintain her schedule, her lifestyle. She likes the efficacy data that we talked to her about with monotherapy, covalent BTK inhibitors in this high-risk CLL population.
And so she opts for a monotherapy covalent BTK inhibitor, and after more discussion and insurance consideration, she decides to start zanubrutinib. She tolerates it very well. She has mild intermittent nausea, and she has improvement in her symptoms and her counts, and really does get back to her everyday life and her activities on zanubrutinib.
Mollie, as you talked about, that education of patients on this frontline therapy is so important, and really factoring in, in terms of the combination regimens that are available, the age, the comorbidities, their performance status, renal function. There are so many things that go into that, whether the risk benefit of that higher side effect profile is worth combination drugs.
But for this lady, a single-agent covalent BTK inhibitor was the right way for her to go, although with growing options, it's always more challenging to guide patients in the right direction and get them the right information they need.
