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

Jill Miller: Hello, I am Jill Miller, physician assistant at MD Anderson Cancer Center in Houston, Texas, where I've been taking care of leukemia patients for the past 17 years. So just glad to be a part of this group today.

Mollie Moran: Hi, I'm Mollie Moran. I'm a nurse practitioner at the James Cancer Hospital at The Ohio State University in Columbus, Ohio. And I've been working with cancer patients for the last 23 years.

Amy Goodrich: Well, thank you both for joining me today. In this video roundtable, we will be focusing on a case study in CLL, so let's dive into our case study.

So Mike is a 62-year-old with lymphocytosis noted on routine annual labs, and you can see there his white count is just modestly elevated. His hemoglobin and his platelets are normal. His lymphocyte count is over 5,000. He feels completely well. His only past medical history is notable for well-controlled hypertension. He's on lisinopril. He works as an accountant. He's married. He's active. He bikes for exercise. He's got two children. He's got some little grandchildren. He is seen in your clinic, and his peripheral blood flow cytometry gets sent and is consistent with typical CLL. His prognostic testing reveals an unmutated IGHV status. He has a 13q deletion, no complex karyotype. Indications for therapy are discussed, and the plan is to observe. So Jill, how often is this the patient that walks into your clinic?

Jill Miller: Very often. This is a typical patient. Now that more and more patients are doing routine labs as a part of their annual physicals, we're seeing more of these incidental diagnoses come up. So this is a pretty typical patient, and the last thing they want to hear is, "Oh, you have cancer, but we're not going to do anything about it." So having to walk them through the rationale behind observation is always a challenging conversation initially.

Amy Goodrich: Right. So over the next several years, he has slowly increasing lymphocytosis. He develops palpable lymphadenopathy. So 3 years after diagnosis, his white blood cell count is up to 112, which there's no magic white count for treating, but his hemoglobin is now 10. His platelets are 99,000. He's got some splenomegaly, and he's got nodes up to 5 cm on exam. He's starting to get fatigued, continues to work full-time, but he's not able to exercise full tilt like he used to. He's now age 65. He's on two antihypertensives. So Mollie, what are you talking to him about? What concerns do you have about him at this point?

Mollie Moran: So he's heading into that arena of frontline therapy, and so having the discussions about what are goals of therapy. Obviously everybody wants to go into remission. That's the number-one goal. But how undisruptively we can be to his lifestyle, his current activities, and get him back to his baseline activities. We talk about fixed duration, we talk about what's available frontline, and then we look at his comorbidities. And the only one that he has is hypertension, and so it would not be a deterrent from starting frontline therapy, but it may jump us down in the BTK lineup.

Amy Goodrich: So prognostic testing is repeated and remains unchanged. He returns in 3 months. His white count's a little higher, but his more anemic, and his platelet count is dropping. And so what other testing are you thinking about for this guy before you start therapy? Jill, do you want to talk about other things you're thinking about?

Jill Miller:Yes, so we know that he does have some pretty bulky adenopathy, so we might want to draw an LDH just to make sure that this is not turning into a more aggressive type of disease picture. So imaging is also important as a baseline to know the bulk of the disease as well as to get a baseline for any tumor lysis, prophylaxis planning. And then immunoglobulins to help us get a picture of what his immune system status is and how concerned we need to be about the potential for infections.

Amy Goodrich: Yeah, great. And so after these extensive discussions, he's talking about, he's working full-time, he wants to continue working full-time. His wife is busy with grandchildren, helps with them several days a week. He doesn't live very far away, but he really doesn't want to interrupt his life or his wife's life or the schedule that they have with their grandchildren. So he opts for a BTK inhibitor. And so Mollie, once a patient decides that they want a certain therapy, especially a BTK inhibitor, how is a specific agent chosen in your practice?

Mollie Moran: Again, based on the comorbidities. So if someone has a history of migraines, you steer closer towards zanubrutinib. If they have a history of a DVT or something that requires them to be on anticoagulation, we would lean further down in the BTK roundup as well. And then we have to see what unfortunately their insurance is going to take.

Amy Goodrich: Got it. So this gentleman is starting treatment with acalabrutinib twice daily. So he initially has rapid reductions in his nodes, in his spleen, and he develops lymphocytosis, which we all know is a potential with patients starting BTK inhibitors, where there's redistribution of the lymphocytes. He develops mild nausea. He's using ondansetron. He has mild headaches. He's using acetaminophen, and those are being well-controlled. That lymphocytosis trends down. His CBC normalizes, he remains on full-dose acalabrutinib with good response and good adherence. And so, Jill, how long do you think he's going to remain on acalabrutinib? He asks you how long he's going to be on this therapy. What are you going to tell him?

Jill Miller: Well, of course we don't have access to a crystal ball. But given his prognostic features, we would expect a pretty good stable response for a number of years.

Amy Goodrich: Okay. So he remains on acalabrutinib for 4 years, and he comes in, and his white count is rising. His lymphocyte count is rising as well. Hemoglobin is okay. It's sort of marginal. Platelets are okay. He continues with good adherence. So Mollie, what else are you thinking about? So this guy walks in, and it looks like he's progressing on therapy. What else do you want to know about what's happening with him?

Mollie Moran: So one of the first things we would evaluate is, does he indeed have a resistance mutation? Has he developed a TP53 or another mutation? And then we would start thinking about the Richter's possibility as well. He doesn't sort of present like a Richter's. A typical Richter's, they usually feel lousy, they usually have a big lymph adenopathy burst, and he doesn't have those, but it's certainly something you want to rule out. But the quick and dirty ways to look for resistance mutations.

Amy Goodrich: Yes, absolutely. But you're talking about adenopathy. Is his spleen enlarged? Has he had illnesses recently? What's his LDH doing? Is he having symptoms? Does he have new comorbidities? So it's clear that this guy is progressing on a BTK inhibitor at this point because there are no other red flags. He has no new or worsening comorbidities, remains active. And so when you're discussing next therapy with him, Jill, do you want to talk about how you're talking about other therapy and how progression on a BTK inhibitor is handled versus progression on other agents?

Jill Miller: Sure. So we talked about the possibility of a resistance mutation. If that is in fact confirmed, then you have to either go to a non-covalent BTK inhibitor, such as pirtobrutinib, or switch to a completely different mechanism of action because we know they're not going to continue to respond to BTK inhibitors. Another thing that's important to keep in mind is you don't want to take them off therapy at this point. They need to remain on the acalabrutinib until that next treatment is lined up and ready for them because you don't want to give the disease an opportunity to flare.

Amy Goodrich: Right. And so that's that rapid disease progression that we can see. Yep, that's great. And so now this guy is now nearing age 70. He's retired. His grandchildren are, they're only helping after school. So he remains on acalabrutinib, and we're going to start him on venetoclax with rituximab. His C481 mutation is confirmed, so he tolerates his venetoclax ramp up, and the acalabrutinib gets discontinued. And then he starts his rituximab per the regimen outlined in the MURANO trial. His counts normalize. His exam normalizes. We did imaging on him, and that normalizes. And so he completes his venetoclax and rituximab, and he has undetectable measurable disease.

So he remains in a complete remission for 5 years, and then he comes in with new palpable adenopathy. His white count's heading up. He's slightly anemic, not profoundly by any means. His platelet count is okay. He feels well. He's got no new medical problems. He gets observed for another year until he meets criteria for therapy due to increasing adenopathy, splenomegaly, thrombocytopenia. He now has a 17p deletion and TP53 mutation and complex karyotype. So clearly this guy's disease is becoming more aggressive.
And so Mollie, do you want to talk about his treatment options? He's now progressed on a covalent BTK inhibitor. He's got a confirmed C481 mutation. He has progressed on venetoclax with an anti-CD20. What are you thinking about for him now?

Mollie Moran: The non-covalent BTK inhibitor, pirtobrutinib, is a great option for him, despite the more complex karyotype. Also, with CAR-T, you want to have a little bit better control over the disease before you send him into CAR-T. And then certainly we look at clinical trials, but he has options both on and off clinical trials is the good point of it. That's one of the take-home points of working with CLL patients is that you're going to have these periods of quiescence and treatment and quiescence and treatment. And what you're trying to get is bigger gaps between the treatment in terms of not requiring therapy and so pressing along this trajectory. And it can be a tough road to haul, but we've got things we can do.

Amy Goodrich: Yes. So Mike opts to start pirtobrutinib. He really feels positive about BTK inhibitors. He tolerated his acalabrutinib well. He just has a good feeling about pirtobrutinib. He likes the convenience of the BTK inhibitor therapy, and so he starts pirtobrutinib. And so Jill, can you talk a little about what education he needs, what monitoring he can expect, and then a little about that shared decision making that is just so critical in these patients?

Jill Miller: Sure. So clearly at this point, he now has very high-risk disease. He has relapsed disease, so he needs to have a realistic expectation of how long he will maintain a response on pirtobrutinib and the possibility of developing progressive disease. So he needs to be monitoring for any return of symptoms, palpable enthesopathy. We need to be following his labs very closely as well as watching for any toxicities associated with it, either initially or as he progresses through treatment. But primarily being realistic about, now that he's on his third salvage therapy, the definite risk of developing disease progression at some point.

Amy Goodrich: Yes. And then shared decision-making here I think is really, really critical that we rely on these folks to take their oral drugs and to come when they're supposed to come. And we know that, if they're part of the team, they're more invested.

So at this point, that concludes our discussion on our case study in 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.