The APP’s Guide to Patient-Centered Management of BTK Inhibitor Therapy in Lymphoma

So I'm going to first talk briefly about the different types of B-cell malignancies that we use BTK inhibitors for. So we are treating patients with basically secondary B-cell lymphomas that come from the secondary lymphoid tissues and what our secondary lymphoid tissues, their organs and structures within the immune system that play a crucial role in the development and activation of lymphocytes, which are white blood cells.

So examples of secondary lymphoid tissues include the lymph nodes, the spleen, the tonsils, mucosa-associated lymphoid tissue which comes in the respiratory tract, the GI tract. And examples of these diseases would be mantle cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, and a plasma cell–based disorder coming from the bone marrow would be Waldenström’s macroglobulinemia. So these are the patients that we're treating with BTK inhibitors.

[00:11:07]

B-Cell Lymphomas: What APPs Need to Know

So when a patient presents with a new diagnosis or relapsed disease, what are some of the symptoms that they're going to experience?

So grouping together abdominal pain with an enlarged spleen or retroperitoneal enlargement of lymph nodes, that can also lead to loss of appetite, weight loss. More obvious would be swollen lymph nodes, palpable lymph nodes in the cervical chains, supraclavicular, axillary inguinal nodes, fatigue, multifactorial, including, you know, cytopenias, just active disease itself can be cause fatigue, itchy skin, so pruritus, rashes or skin lumps, so patients can have infiltration of their skin, and then fevers of unknown origin. So no infectious etiology but still having persistent fevers.

So for these patients, it's important that nurses understand the presentation what would be concerning for a B-cell malignancy, educating patients about what to watch out for. Between visits, all of a sudden, you're losing weight. You're having drenching night sweats. Give us a call. And then further on in when they're being treated, what side effects are they experiencing and how to manage them, guide them through it so that adherence and tolerability improve.

And then knowing other therapies that might be helpful in the event that somebody is not tolerating either a BTK inhibitor or another therapy. And then, complications of the disease or the therapy are important for APPs and nurses to really understand to help educate and guide patients through their treatment and diagnosis.

[00:13:14]

Covalent vs Noncovalent BTK Inhibitors

So this is important in terms of choosing BTK inhibitors. So you have covalent vs noncovalent BTK inhibitors. And just that you understand what a BTK inhibitor is, it's a Bruton tyrosine kinase inhibitor that—it's a protein that's important in B-cell proliferation.

So a covalent BTK inhibitor irreversibly binds to the BTK enzyme, and it plays - you know, which plays a crucial role in signaling B-cell signaling. Examples of this would be ibrutinib, zanubrutinib, acalabrutinib. And then on the other side, noncovalent BTK inhibitors bind reversibly. Therefore, you know, they're able to go around any sort of mutations that patients get from the covalent BTK inhibitors.

[00:14:21]

Kinase Selectivity of Irreversible Covalent BTK Inhibitors

So selectivity is really important. So when you have a covalent BTK inhibitor, there you're at risk for the highest number of side effects. So, you know, there's off-target kinase inhibition. The highest number of side effects would be from ibrutinib, which I can get into in a little bit, which is a first-generation BTK inhibitor, and then zanubrutinib and acalabrutinib followed by that, we’ll have a less number of side effects because they're a little bit more selective.

And then furthermore, the third-generation BTK inhibitor such as pirtobrutinib is much more selective, being a noncovalent BTK inhibitor and therefore can have less undesired side effects.

[00:15:21]

Review of Current BTK Inhibitor Indications

So talking about the different types of BTK inhibitors, again, ibrutinib was a first-generation BTK inhibitor. It is less frequently used due to side effects, and then with the second-generation BTK inhibitors acalabrutinib and zanubrutinib being a little bit more tolerable in terms of side effects. Ibrutinib has sort of fallen out of favor.

That being said, I have patients that are still on ibrutinib because it's controlling their disease and they also are tolerating the medication. So we don't need to switch at this time. So ibrutinib is approved for patients with CLL or SLL, so chronic lymphocytic leukemia or small lymphocytic lymphoma and Waldenström’s. So this is daily dosing which also can be helpful for patients remembering to take an evening dose.

But then we have acalabrutinib and zanubrutinib, again, more in favor at this time just because they're more selective but being irreversible, they're going to still have some off-target side effects.

Acalabrutinib is approved for patients with mantle cell lymphoma who have received a previous therapy, and then patients with untreated mantle cell lymphoma in combination therapy with bendamustine and rituximab. So this is twice-daily dosing.

Zanubrutinib again is selective, potent, but again irreversible at the binding site. So having some unwanted side effects but less so than ibrutinib. So patients with CLL, again Waldenström's, mantle cell lymphoma, marginal zone lymphoma can be receiving this in combination therapy. And again, you can do daily dosing or twice a day dosing.

And then pirtobrutinib would be the third-generation. This being a noncovalent BTK inhibitor, so therefore reversible and having, you know, less off-target side effects is actually approved for mantle cell lymphoma after at least 2 lines of previous therapy. We also are giving it in CLL for patients who have received at least 2 lines of therapy, including a BTK inhibitor.

So that means you can't be treating someone with obinutuzumab and venetoclax. They progress and start them on pirtobrutinib. They have to have progressed on acalabrutinib, zanubrutinib previously.

[00:18:21]

Insights on the Current Role of Nurses in Lymphoma Patient Care: Current Drivers of Healthcare Inequities

So thinking about our patients and current drivers of healthcare inequities. What, as APPs, nurses can we do to help our patients that they're able to come to clinic, we're able to help them through their side effects, and be available to them to increase compliance, and again, tolerability?

So I know we all work in various locations. Some patients are coming to the city and from far distances, and lack of transportation is an issue or the cost of transportation. So identifying resources. So I know at Mass General, we have a transportation specialist trying to get patients to the ride and discounted parking and things like that to try to help them make it easier for them to come to clinic, especially if they don't have a caregiver to drive them.

And then again, patients do feel burdened when they're traveling a far distance. So trying to reduce frequency of visits. Local labs are helpful, you know, and virtual check-ins, if possible. And then again, the cost of receiving noncovered care. So these medications are very expensive. So working with either drug companies or with your pharmacy staff, case managers trying to get prior authorizations, copay assistance, really trying to minimize the expenses for patients.

And social workers can also be very, very helpful patient navigators. You know, the Leukemia Lymphoma Society has funds for certain patients that can help cover costs of either whatever they need, whether it's transportation or, again, paying for some of the medications.

And then it's also helpful just to have staff available for patients to call in and talk through side effects or, you know, we use messaging systems a lot that patients write in questions and we can manage a lot of these things from home that patients don't need to come in for a visit or just to allow them to ask questions openly, without feeling like they, you know, need to come make an appointment because sometimes patients will avoid contacting us if they think we're going to make them come in.

[00:20:54]

An APP-Driven Approach to Selecting BTKi Therapy in CLL

Okay. So what's the APP-driven approach to selecting a BTK inhibitor in CLL?

[00:21:02]

Treatment Algorithm for Newly Diagnosed CLL/SLL

So here's the treatment algorithm for newly diagnosed CLL. And just talking about some of the cell markers as to why patients are at higher risk, lower risk. So you have the TP53 status or deletion 17p. So deletion of 17p or P53 mutated disease would indicate higher risk disease. So that would help with selection of treatment.

So if somebody is without a deletion 17p or P53, you're going to also look at the IGH mutational status, again to pick, you know, the poor prognosis. So if somebody is relatively healthy, they don't have any of these cell markers, then you're going to start with either a combination of a BCL2 inhibitor and a CD20 antibody like venetoclax and obinutuzumab, or you can use combination therapy, including a BTK inhibitor. So venetoclax with acalabrutinib plus/minus obinutuzumab or zanubrutinib—you can use monotherapy zanubrutinib.

And a lot of patients, an open discussion of what works for your lifestyle. So with BTK inhibitor, you're going to continue therapy until progression or intolerance, where selection of venetoclax and obinutuzumab is, generally speaking, a time-limited therapy, usually about a year. So that is part of the decision making as well as what their disease looks like.

And then so somebody who's fit, you can—and good prognostics. Those are the options. And then if somebody has a little bit more of an aggressive disease with the deletion 17 or P53, so higher risk of disease, you can use the same agents like venetoclax and obinutuzumab, and then the BTK inhibitors. But, you know, there's decisions to make when somebody is finished, you know, venetoclax-obinutuzumab. Are we going to keep them on the venetoclax or, you know, is something better like zanubrutinib, where they're going to be on something continuously rather than the time-limited therapy?

But things to think about with BTK inhibitors is a lot of the cardiac comorbidities patients come in with. So do they have a history of arrhythmias, particularly atrial fibrillation? Are they on anticoagulation? Or do they have difficult to control hypertension? And I'll get into the side effects a little bit. But a lot of these cardiac side effects are something to consider. But it doesn't prohibit you from choosing this as an option, but we'll get more into that in a little bit.

[00:24:24]

Expert’s Algorithm: Therapy for R/R CLL/SLL

So relapsed/refractory chronic lymphocytic leukemia. So just because somebody relapses or, you know, you see progression of their disease in their CBC, their lymphocyte count is rising, but they don't have cytopenias there, they don't have bulky adenopathy. That doesn't mean you don't have to treat those people. They can be watch-and-wait. You know, you can see them every 3 months to trend their CBC, talk about their symptoms of their disease.

And then, you know, if they remain stable for multiple 3-month visits, you can space it out to a little bit longer, 4 months, 6 months, depending on how they're doing but educating the patients of some of the symptoms of progression of disease that we discussed earlier, night sweats, weight loss, you know, their adenopathy is increasing in size rather than waxing and waning and overall small. But that doesn't mean that they need treatment right away just because they relapsed. So indication treatment.

They're symptomatic of their disease. They have cytopenias that are worsening. They have bulky adenopathy with end-organ damage, kidney dysfunction and such. How do you pick treatment?

So they've had a prior covalent BTK inhibitor. So they've had acalabrutinib or zanubrutinib. You can consider pirtobrutinib, so prior BCL2 inhibitor, so such as venetoclax and obinutuzumab, you can switch to a BTK inhibitor. Prior chemotherapy, again, a BTK inhibitor or a BCL2 inhibitor plus obinutuzumab would be an option.

And then if they've had a prior covalent BTK inhibitor and a BCL2 inhibitor, so refractory, they can get the third-generation BTK inhibitor and/or go to CAR T therapy. So we've had plenty of patients who we've bridged with pirtobrutinib to try to get them have a response. And then we will send them to CAR T.

[00:26:45]

BTK Resistance Mutations and Their Consequences

So BTK resistant mutations and their consequences.

[00:26:49]

Acquired Resistance to Covalent BTK Inhibitors Is Generally Driven by Mutations in BTK at C481

So acquired resistant to covalent BTK inhibitors is driven by where the BTK inhibitor binds at C481. So what happens is, you know, because it irreversibly binds to that, the disease can kind of go around that and mutate, making them not responsive to the treatment anymore. So that would be, you know, what drugs, you know, can cause this resistance. So the first/second-generation BTK inhibitors, acalabrutinib, ibrutinib, zanubrutinib.

So when this resistance occurs, that's when you can have progression of disease. And because there's less efficacy, and that's when a third-generation BTK inhibitor would be considered because they're able to inhibit that BTK C40 - 481 mutation, go around that binding site and continue to work.

[00:28:01]

Potential Treatment Sequencing Scenarios in CLL/SLL

So here's some more potential sequencing for scenarios in CLL. And again, we've talked about this that, you know, you have your venetoclax-obinutuzumab. And then you have a continuous BTK inhibitor. And then have they had a covalent BTK inhibitor and then they progress on that. So it's a little bit more information about, you know, thinking through what treatment have they had and what treatment to do next.

[00:28:37]

Patient Case #1

So here's a case for you. So Mr. Green is a 72-year-old man diagnosed with CLL 5 years ago. He was originally treated with a BCL2 inhibitor and CD20 antibody, and he's currently on surveillance. He comes into you with increasing fatigue, shortness of breath, unintentional weight loss, and progressive lymphadenopathy.

On exam, he has multiple palpable lymph nodes in the cervical, axillary and inguinal chains. And then there's a mildly enlarged spleen, so splenomegaly on exam.

Laboratory studies show a white count of 125,000, a hemoglobin of 9.8. And the big thing to note from that is that there's been a decrease from a hemoglobin of 11.2. Platelets again down trending from 130,000 to 95,000. The LDH with the upper limit of normal being 210 is elevated. This is a nonspecific marker for lymphoma. But the patient has a diagnosis and it's been a change and an increase showing that there's more cell turnover. And then the patient does have a TP53 mutation.

[00:30:01]

Patient Case #1 (cont’d): Treatment Decision

So he has relapsed CLL with high-risk features being that P53 mutation. Chemotherapy-based options are unlikely to be effective with this relapse. And then targeted therapies will be the preferred options. So BTK inhibitors are going to be considered because they're highly effective with patients with a P53 mutation and with 17p deletion, where traditional chemotherapy often will not work.

So compared to ibrutinib, zanubrutinib and acalabrutinib are more selective with fewer off-target effects, and particularly with respect to the cardiac side effects like AFib and bleeding complications, which can be a concern in older patients if they're on anticoagulation or they're high risk for falls and their skin is a little bit more friable. So, you know, ibrutinib would be less favorable for those reasons.

And then Mr. Green has a history of hypertension and chronic kidney disease. So the lower risk of cardiac side effects is a major advantage. So while his kidney function isn't prohibiting him from the choice of a BTK inhibitor, his history of hypertension, is it controlled, is it not controlled is important. And then again, avoiding ibrutinib due to the higher risk of off-target side effects.

[00:31:42]

CCO Online Treatment Decision Support Tool for CLL

So just a brief helpful tool that you can use. You can use this CCO Online Treatment Decision Support Tool. You can type in your patient's information, and then it can help guide you in what to treat them with if they have newly diagnosed CLL, relapsed, what their prior agents were, etc.

[00:32:13]

MCL: Current and Emerging Roles of BTK Inhibitors         

So switching to mantle cell lymphoma and the use of BTK inhibitors.

[00:32:18]

Guideline Recommendations for R/R MCL

So guidelines for relapsed/refractory mantle cell lymphoma. It's usually a second-line therapy and beyond. We would start with a covalent BTK inhibitor. You can also use rituximab and lenalidomide as an option. And then again, not really a first choice therapy but ibrutinib and rituximab are possible.

I do want to say there's—you know, there is a first-line treatment based on the TRIANGLE study, where patients do receive ibrutinib as part of a combination chemotherapy. But again, it's not used upon, you know, outside of that ibrutinib that is.

So under certain circumstances patients might receive rituximab-bendamustine if, you know, they haven't received chemoimmunotherapy in the past. If they're, you know, can't tolerate a BTK inhibitor due to, you know, uncontrolled hypertension, AFib, etc.

And then if they've had a prior covalent BTK inhibitor, again, you can consider the third-generation BTK inhibitor, the noncovalent pirtobrutinib, and then CAR T, as well as bispecific glofitamab.

[00:33:52]

Covalent BTK Inhibitors in R/R MCL: Summary

So covalent BTK inhibitors in relapsed/refractory mantle cell lymphoma. So combination therapy is not been proven to have a benefit due to increased toxicity and financial burden. So using, you know, single agent or monotherapy with acalabrutinib or zanubrutinib is helpful. And again, ibrutinib, just using with the TRIANGLE study with R-CHOP/R-DHAP plus ibrutinib is a first-line option. But again ibrutinib as monotherapy is not.

Acalabrutinib has an overall survival rate of 81%. And then 84% was zanubrutinib. With acalabrutinib, headaches are very common, but knowing that this is usually time limited and patients will, you know, end up becoming more comfortable with the medication with time, it usually lasts 2 to 3 months. Caffeine, hydration are helpful.

And then with zanubrutinib, there is a higher rate of neutropenia. But you can treat through that.

[00:35:19]

Guideline Recommendations for MCL Induction Therapy

So recommending therapy for mantle cell. Again, we're talking about the importance of BTK inhibitors. You can use acalabrutinib with bendamustine-rituximab. You can use acalabrutinib, again, continuous with rituximab alone and not with bendamustine. So patients without P53. So wild-type, so less aggressive disease.

You can be giving some of these chemo-immunotherapies, the TRIANGLE regimen with ibrutinib in it. And then with P53-mutated disease, patients can receive zanubrutinib, obinutuzumab, venetoclax, again, the TRIANGLE study or TRIANGLE regimen since it's been proven.

And then BTK inhibitors are, you know, useful in all types of mantle cell lymphoma, whether it's, you know, initial treatment or relapsed/refractory.

[00:36:32]

Follicular Lymphoma: Current and Emerging Role of BTK Inhibitors

So follicular lymphoma, current and emerging role of BTK inhibitors.

[00:36:37]

ROSEWOOD: Next-Generation BTK Inhibitor Zanubrutinib With Obinutuzumab in R/R FL

So ROSEWOOD study looked at next-generation BTK inhibitor zanubrutinib. So the second generation in combination with obinutuzumab. So this is sort of the first combination for follicular lymphoma with a BTK inhibitor. And so this overall it is FDA approved now, and had improved survival rate, relapsed/refractory follicular lymphoma with greater than or equal to prior lines of therapy.

So a great option for our patients who have had at least 2 lines of therapy and have relapsed follicular.

[00:37:26]

ROSEWOOD: Response

So here are the data points of the ROSEWOOD study. The response rate being 69%, patients in complete remission, 57%, compared to, you know, with obinutuzumab alone, 46% and 14%. So a significant improvement in their response rate. So a great option again for your follicular patients for longer durable remissions.

[00:38:04]

APP Strategies to Manage BTK Inhibitor-Associated AEs

So I think the biggest thing for APPs and nurses in this is not—I mean, obviously selection of the BTK inhibitor is important in choosing, you know, what's their disease, how are we treating it? But really the side effects.

[00:38:23]

Let’s Vote!

And I'm going to just switch over to Amy and do another poll before we get into it.

[00:38:33]

Poll 3

Amy Goodrich: Oh, sorry. I was muted. Sorry. Which BTK-associated adverse event do you find the most challenging to manage? Is it:

1. AFib and cardiac arrhythmias;
2. Bruising and hemorrhage;
3. GI toxicities;
4. Infection; or
5. Other.

So if you have another, please submit that in the Q&A. So which of these is most challenging? Okay, great.

[00:39:19]

Poll 4

And let's move on to our next question. So a 58-year-old woman with mantle cell treated with zanubrutinib for 10 months comes to clinic and she's having intermittent melena, so bleeding in her GI system and a symptomatic anemia. Her hemoglobin is 8.5. Platelets are normal, so are her PT/INR. What is the best option for a patient experiencing grade 3 bleeding while on a BTK inhibitor?

1. Do you consider changing to an alternative BTK inhibitor;
2. Do you hold to allow the patient to recover and then restart at the same dose;
3. Do you abandon BTK inhibitor therapy; or
4. Do you dose reduce BTK inhibitor therapy.

And I'll give you a couple seconds to wrap your head around all those options.

All right. Wonderful. And let's get back to our presentation.

[00:40:31]

Common AEs of Available BTK Inhibitors

Thank you again, Amy. So common adverse events with available BTK inhibitors. So I sort of like to talk about this with patients with the risk of arrhythmias, with the risk of infection, with the risk of hypertension, bleeding being the most common. And again, ibrutinib sort of falling out of favor, having the most adverse events just due to not being as highly selective as acalabrutinib and zanubrutinib.

That being said, with the second and third generation, you're still going to have cytopenias. That's why you're monitoring patients counts. With neutropenia, we can treat through that to some extent, depending on the grade and if it, you know, is associated with infection. So growth factor is really helpful to help support patients and kind of keep them on therapy.

And, you know, we do have patients receiving growth factor, you know, monthly or, you know, periodically depending on, you know, how severe it is or if another cause, like, they're infected or something has dropped it down. Thrombocytopenia is, you know, 7% to 11% depending on the drug here and, again, higher with ibrutinib. But I'm going to focus on the second, third generation.

The thing with thrombocytopenia is, you know, maybe overall mild in terms of numbers. But there's some alteration in the, you know, platelet function. So monitoring for bleeding outside of thrombocytopenia is really important, like to educate patients that bruising is very common. Whether aware of it or not, we're bumping into things all the time. So women are carrying bags on their arms or we're all carrying groceries on their arms. So and again, if you're older, more friable, frail skin, you're going to have some bruising on your arms, your legs. But excessive bruising is something to really watch out for.

And then anemia, you know, again, should be minimal and something to keep an eye on. But generally, patients are not requiring transfusion support. One thing I do like to mention to patients when we're starting a BTK inhibitor is that your counts can often look worse before they look better. You know, you have these diseases that are infiltrating your bone marrow causing cytopenias. And then as the drug is working, it's getting that out into the periphery. So your white count can go up, your platelets can go down, your anemia can worsen.

I liken it to a cleaning out a messy closet. You make a mess of your room before you put it all back together. And I think that helps explain it to patients when they see all of a sudden, their counts are super high 2 weeks after starting the BTK inhibitors.

So other side effects, infections. So again, this being listed as grade 3, you are immune compromised. You can be neutropenic. Calling with the fever is super important, so 100.4. And then being vaccinated for flu, COVID, pneumonia, shingles, etc. is important to really protect yourself because we're suppressing those lymphocytes.

Other notable, adverse events. Specifically with acalabrutinib, the headaches, but again time-limited, supporting patients through that with hydration, caffeine, and saying, you know, this should be a time-limited side effect.

Diarrhea. With any of them, you're going to rule out infection first. And then we can support with Imodium or other antidiarrheals. Fatigue, and again, that could be from cytopenias, or just, you know, as your body is getting rid of your disease, you're going to be tired, your disease is active, and hopefully that improves with time.

Bruising. Again, we'll get more to bleeding, but nausea is a possible, not super common. And then again, diarrhea or on the other side you can have some constipation. So really a bowel regimen can be helpful.

[00:45:17]

Managing Bruising and Hemorrhage

Okay. So really important is bruising and hemorrhage. So again, this is very common to see bruising. It's important to educate patients that you're going to bruise more frequently. It has a mild anticoagulant property. But bleeding is something we need to be aware of. So patients should be asked in every visit, are you having nosebleeds, blood in your urine, blood in your stool, coughing up blood? Any unusual bleeding?

You know, if somebody comes in, say, with some melena, what are you going to do? You're going to hold the medication. You obviously want to figure out the etiology of the bleed. You know, should we get an endoscopy, a colonoscopy? You know, PPIs are important, etc. But it's also important to hold the medication, see if it improves. And if it improves, then we're going to restart that drug because we want to get the maximum benefit if possible. So we're going to restart at the same dose once it's back to grade 1 or back to baseline.

And then if it happens again, that's when you're going to hold the dose and then consider dose reduction. And then again if it happens again and again fourth occurrence, then we're going to discontinue treatment. But really the goal is to fix the underlying cause while holding the medication and then resuming it at the same dose.

It's also important that if patients are having a procedure, you know, a tooth pulled or major surgery, we're going to hold your medication. So if somebody is having a Mohs procedure, maybe we're going to hold for 3 days before or after. If they're having surgery for some reason, a shoulder repair, abdominal surgery, we're going to hold for at least 7 days before and after just due to that increased bleeding risk.

So reminding patients, you know, if something's being done, something's being cut, call us. We have patients come in and be like, oh, I had my tooth pulled and I didn't tell anyone, and it bled. So really just reminding them at every visit.

[00:47:42]

Managing Atrial Fibrillation and Cardiac Arrhythmias

The cardiac side effects are, you know, AFib, uncontrolled hypertension. So you're making sure patients know if you're having palpitations, you're having palpitations with shortness of breath, any chest pain. I mean, you're going in the emergency room, but it's important for you to call us. And then we're monitoring patient's blood pressures in clinic.

If somebody has hypertension, you know, working with their primary care providers or their cardiologists to say this is a potential side effect. Can we control this blood pressure with medication? Then we can keep treating them with the BTK inhibitors.

Somebody in AFib, that doesn't mean you can't give them a BTK inhibitor. If they are rate controlled, even if they're on an anticoagulant, it doesn't mean that they can't get the medication. It's, you know, educating them about the bleeding risk with the combination of a BTK inhibitor and an anticoagulant or really, if we're able to manage these things, the AFib, the hypertension, then we can treat them with a BTK inhibitor, for sure.

[00:48:59]

Monitoring and Managing Covalent BTKi-Related AEs

So with the AFib risk, they can develop it on treatment, but they can also have it as a, you know, preexisting comorbidity. So you're monitoring for AFib. You're monitoring for rapid AFib. They can be on anticoagulants. But if they're, you know, having frequent and rapid AFib with RVR, then you would have to stop the medication. Again, just to review for bleeding risk, you're going to monitor for bleeding, hold BTK inhibitors before procedures, and then hold the medication and resume at the same dose once that improves or dose reduce if it is a recurrent event.

Diarrhea, antidiarrheals. And then headache, again with acalabrutinib, specifically caffeine, acetaminophen. We do try to tell patients to avoid NSAIDs just due to that increased bleeding risk.

So infection risk. We talked about just vaccines, hypertension, antihypertensives, working with their primary care. Muscle pain, arthralgias, we can treat with acetaminophen, dose reduce if necessary.

Neutropenia. We talked about thrombocytopenia.

[00:50:25]

Switch BTK Inhibitor to Mitigate AEs

And then you can always consider a switching from one BTK inhibitor to another. If somebody is on ibrutinib and they're having a lot of bleeding risks or infection risks, they've been on it for a while, let's try a second generation, or the headaches with acalabrutinib are intolerable, then we can switch to an alternate, you know, zanubrutinib.

[00:50:47]

Patient and Caregiver Discussions: What AEs to Expect/Monitor While Taking BTK Inhibitors

So educating patients is really important, about the bleeding risk there, calling us, they're calling and talking through some of their side effects, letting their primary care know about things, like the risk of hypertension. Again, vaccines are recommended. No live vaccines with these medications. So really just the MMR. Really just having them calling us.

[00:51:20]

Empowering APPs to Promote Adherence to and Persistence With BTK Inhibitor Therapy      

Understanding Challenges Related to Adherence to and Persistence With Oral BTK Inhibitors

And then how are we going to help them? We're going to help with their financial burden, referring to social work, referring for grants, toxicities, not understanding. Sitting with the patients. We do that all—that's the bread and butter of what we do. Educate, educate, educate. Have them call us, talk them through it.

And then helping, you know, older patients or forgetful patients, you know, pill diaries or charts or alarms on their phones to remember to take it. And then having them involved in their care. You know, what do you think will work for you, this continuous treatment or time-limited therapy? That's really just the bread and butter of what we do.

[00:52:01]

BTKi Clinical Trials

And then, so clinical trials, you know, what's their diagnosis, what's their prior measurable disease, what's their performance status? You know, if they've had an MI, we're not going to start in on clopidogrel. We're not going to start a BTK inhibitor.

[00:52:16]

Addressing Misconceptions About Clinical Trials

And then addressing misconceptions about clinical trials. Fear of unknown risks. Really again, talking through these things. I know we're running out of time, so I just want to say, you know, continue to educate, limit the number of side effects, talk about how you're more important than any clinical trial. We can remove you from the trial, and then helping with the financial and travel burden.

[00:52:42]

Let's Vote!

Okay. So I think we're doing some more polls.

[00:52:46]

Posttest 1

Amy Goodrich: Great. So let's vote. So we asked these questions before. We're asking them again. All of the following are important patient comorbidities to consider when recommending a BTK inhibitor, except. So

1. That history of anticoagulation;
2. History of AFib;
3. Diminished creatinine clearance; or
4. Difficult to control hypertension.

Okay.

[00:53:27]

Posttest 1: Rationale

And so, Emily, do you want to talk about this?

Emily Patterson: Yes. So I think we sort of reviewed that it's the cardiac side effects of BTK inhibitor is super important. So they're associated with bleeding, AFib, uncontrolled hypertension. So those are the primary ones. And diminished creatine clearance is not—it's safe for patients with mild to moderate renal impairment.

Amy Goodrich: Great. Thank you.

[00:53:57]

Posttest 2

And so posttest number 2. A newly diagnosed patient with mantle cell. Which of the following biomarkers would make this patient a possible candidate for zanubrutinib, obinutuzumab, and venetoclax. Is this that:

1. TP53 mutation;
2. IGHV;
3. A Ki-67 of greater than 30%; or
4. Having a double hit with a MYC and BCL6.

And I'm sorry if you can hear my dog barking. We're getting a delivery. I'm sorry about that. I'm so sorry. He's a Great Dane. He's very loud. Sorry.

Okay. Emily?

[00:54:45]

Posttest 2: Rationale

Emily Patterson: Okay. So P53 mutation with somebody with mantle cell lymphoma indicates a poor prognostic factor. And therefore triplet therapy would be helpful. You know, IGHV, Ki-67 and MYC/BCL6 double hit are not used to identify, you know, patients with MCL as candidates for BTK inhibitor. It's really that P53 mutation makes them higher risk and important to treat more aggressively.

[00:55:24]

Posttest 3

Amy Goodrich: Okay, great. And then our next question. So now that you've had this presentation, please rate your confidence on educating patients with B-cell lymphomas on the pros and cons of different BTK treatment options to improve shared decision-making and patient adherence. So from not confident to very confident.

[00:55:55]

Poll 5

Okay. And then poll 5. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No; or
3. Uncertain.

Okay. Wonderful.

[00:56:15]

Poll 6

Poll 6. So please take a moment to enter one key change you plan to make in your clinical practice based on this education. I'm going to give you a couple seconds to click things in here. Okay. So Emily, do you want to go through slide?

[00:56:47]

Patient Communication Checklist

Emily Patterson: Yeah. So there's this communication checklist for patients to help. It's a downloadable resource for them. You know, it helps them understand why they need a BTK inhibitor, what the side effects are, and then how to manage them. So it's a great resource for patients.

[00:57:17]

Q&A

Amy Goodrich: Okay, great. And then here our question and answer. And we do have a few minutes for questions. Emily, so when we asked the question about which were the most challenging toxicities, someone talks about myalgias. Do you want to talk about those very, very, very difficult arthralgias and myalgias that we see with these BTK inhibitors?

Emily Patterson: Yes. So they are challenging, because patients really can't be taking NSAIDs regularly, just due to that increased bleeding risk. It is something to consider, you know, dose reduction for. So if it's interfering with their quality of life, it's beyond a grade 1 where they're noticing it, and they're not able to manage it with something like acetaminophen. I would dose reduce those patients.

Amy Goodrich: Great. Thank you. And I agree, that's really a tough - that's a tough one. And then someone else asks, is there a test to look for the C481 mutation?

Emily Patterson: Not that I'm aware of.

Amy Goodrich: Right. So some places do have the ability to send this testing off. It's done widely on clinical trials. But, you know, really if a patient is adherent and they're progressing, C481 is not the only mutation that patients can have, as you know, Emily. So, you know, if somebody is compliant and they're progressing, even if you don't have access to this testing, you can assume that they are, you know, developing some mutation. Do you agree with that?

Emily Patterson: I completely.

Amy Goodrich: Yeah. Yeah. And then someone is clarifying the hold for BTK inhibitors for procedures is for 3-7 days before and 3-7 days after. Is that the case?

Emily Patterson: Yes. That's correct. I mean, there's certain things that you'll modify it for, but generally speaking, it’s before and after.

Amy Goodrich: Perfect. And then someone is asking what your challenges have been with the side effects of specifically ibrutinib.

Emily Patterson: Just more of the cardiac and the bleeding risks. So more AFib, more uncontrolled hypertension and then more bleeding. I've also seen patients with more frequent or severe infections. So if that's the case, there are, you know, second-generation agents that are better in terms of their side effect profile.

So again, when we talk about, you know, why you would switch. So yes, progression, but intolerability would be a reason. So, you know, if somebody has poorly controlled AFib and their disease is well controlled, maybe you can trial them off therapy for a bit. And if they progress, then I would - I would consider a second-generation agent after that.

Amy Goodrich: And then Emily, are you switching patients who are and have been on ibrutinib for years and tolerating it, or are you leaving them on ibrutinib?

Emily Patterson: We are leaving them on it, although it's a small number of our patients, but we are leaving them on it.