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CE

Optimizing Care of Patients With Chronic Lymphocytic Leukemia: Clinical Pearls for Nurses and Pharmacists

  • Authors: Amy L. Goodrich, RN, MSN, CRNP-AC; Kirollos S. Hanna, PharmD, BCPS, BCOP
  • CE Released: 8/26/2022
  • Valid for credit through: 8/26/2023
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  • Credits Available

    Nurses - 0.50 ANCC Contact Hour(s) (0.5 contact hours are in the area of pharmacology)

    Pharmacists - 0.50 Knowledge-based ACPE (0.050 CEUs)

    IPCE: 0.50 Interprofessional Continuing Education (IPCE) credit

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Target Audience and Goal Statement

This activity is intended for community-based nurses, nurse practitioners, pharmacists, and other clinicians caring for patients with chronic lymphocytic leukemia (CLL).

The goal of this activity is that learners will be better able to understand CLL treatment regimens and manage adverse events (AEs) as an interprofessional team.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Monitoring recommendations for CLL therapies
    • AEs associated with CLL therapies
  • Have greater competence related to
    • Managing AEs of CLL treatment regimens
  • Demonstrate greater confidence in their ability to
    • Work as an interprofessional team to optimize care of patients with CLL


Disclosures

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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Amy L. Goodrich, RN, MSN, CRNP-AC

    Research Associate
    The Johns Hopkins School of Medicine
    Nurse Practitioner
    The Sidney Kimmel Cancer Center at Johns Hopkins
    Baltimore, Maryland

    Disclosures

    Participation by Dr Goodrich does not constitute or imply endorsement by the Johns Hopkins University or the Johns Hopkins Hospital and Health System.

    Amy L. Goodrich, RN, MSN, CRNP-AC, has no relevant financial relationships.

  • Kirollos S. Hanna, PharmD, BCPS, BCOP

    Oncology Pharmacy Manager
    M Health Fairview
    Maple Grove, Minnesota
    Assistant Professor of Pharmacy
    Mayo Clinic College of Medicine
    Rochester, Minnesota

    Disclosures

    Kirollos S. Hanna, PharmD, BCPS, BCOP, has the following relevant financial relationships:
    Consultant or advisor for: Abbvie; Beigene; Seagen Inc., formerly Seattle Genetics, Inc.
    Speaker or member of speakers bureau for: Abbvie; Beigene; Bristol Myers Squibb; Exelixis; G1 Therapeutics; GlaxoSmithKline; Rigel; Seagen Inc., formerly Seattle Genetics, Inc.

Editor

  • Megan Whitney, DMD

    Medical Education Director, Medscape, LLC  

    Disclosures

    Megan Whitney, DMD, has no relevant financial relationships.  

Compliance Reviewer/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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This activity was planned by and for the healthcare team, and learners will receive 0.50 Interprofessional Continuing Education (IPCE) credit for learning and change.

    For Nurses

  • Awarded 0.50 contact hour(s) of nursing continuing professional development for RNs and APNs; 0.50 contact hours are in the area of pharmacology.

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    For Pharmacists

  • Medscape designates this continuing education activity for 0.50 contact hour(s) (0.050 CEUs) (Universal Activity Number: JA0007105-0000-22-223-H01-P).

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CE

Optimizing Care of Patients With Chronic Lymphocytic Leukemia: Clinical Pearls for Nurses and Pharmacists

Authors: Amy L. Goodrich, RN, MSN, CRNP-AC; Kirollos S. Hanna, PharmD, BCPS, BCOPFaculty and Disclosures

CE Released: 8/26/2022

Valid for credit through: 8/26/2023

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Activity Transcript

Amy L. Goodrich, RN, MSN, CRNP-AC: Welcome to this program titled, "Optimizing Care of Patients with CLL: Clinical Pearls for Nurses and Pharmacists." I'm Amy Goodrich. I'm a nurse practitioner at Johns Hopkins in Baltimore. Joining me today is Kirollos Hanna, PharmD, an oncology pharmacy manager at M Health Fairview, Maple Grove, Minnesota and assistant professor of pharmacy at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Let's start by just giving a brief overview of chronic lymphocytic leukemia (CLL). Those of you who see these patients know that this is a chronic incurable neoplasm of mature B cells. In this day and age, it is often diagnosed on routine blood work with just all of the labs that our patients have drawn nowadays.

There's a very variable disease course. This is not a cookie cutter. Different patients have very different disease courses. The median age at diagnosis, this is an older crew of patients in general, 70 is about the median age, although all of us have much younger patients than that in our clinics. In 2022, there were about 21,000 estimated new cases and only about 4400 deaths. And with that a 5-year relative survival of 87%, we do have large numbers of these patients in our clinics because they do so well and live so long.

Making the diagnosis of CLL is typically done on peripheral blood flow cytometry, and what we're really looking for are patients with greater than 5000 monoclonal B lymphocytes or circulating lymphocytes in their peripheral blood. Typically, on flow cytometry these are CD5, CD23, and CD19 positive.

Once you make the diagnosis, it is important to do some prognostic testing to try to figure out what type of course a patient will have. Fluorescence in situ hybridization (FISH) studies are commonly done at diagnosis. Those are recommended. If a patient has a normal FISH or trisomy 12, they sort of have a middle-of-the-road course of CLL. Our good risk indicator is 13q. Those patients tend to have a more indolent course. They respond better to treatment. Those folks definitely do the best overall. An 11q deletion is a negative finding, but really our highest risk finding is this 17p deletion. So those patients are expected to have more rapid progression and respond less well to therapy. Although with our newer treatments, which Kirollos will talk about, that's not necessarily the case anymore.

Karyotyping is important, and the more complex findings on karyotyping, the higher risk the patient is projected to be. In addition, TP53 sequencing is important, especially if your 17p deletion is not there. If patients don’t have these -- they don’t have to go hand in hand TP53 sequencing and 17p deletions -- so it’s good to do both.

And then your immunoglobulin heavy chain gene (IGHV) mutational status. That is another prognostic indicator that patients with mutated status have a better outcome than those with unmutated. And then, really, peripheral blood flow cytometry is adequate to make a diagnosis. We used to do lots of bone marrow biopsies on these patients, but really don’t anymore outside of clinical trials.

So, our CLL patients are spending a lot of their time in observation or active surveillance. If a patient doesn’t have an indication for treatment, we will observe them. Those indications for treatment include cytopenias, very large or rapidly enlarging lymph nodes or spleens that are causing symptoms, as well as symptoms such as fatigue, weight loss, fevers, night sweats; in my practice, very few patients with CLL develop these symptoms.

Refractory autoimmune conditions can occur, and those are typically autoimmune hemolytic anemia and autoimmune thrombocytopenia. And if a patient has lymphocyte doubling time of less than 6 months that is also an indication for therapy or can be. And this doesn't mean going from 20,000 to 40,000. This is more like going from 100,000 to 150,000 or 200,000 to 300,000. Big numbers making big jumps. So, those are the indications for therapy, and there is no magic white blood cell (WBC) count number for treating these folks.

Kirollos, let's talk about once a patient is deemed to require therapy, what are we thinking about? What are we talking to patients about? What are options for our patients today?

Kirollos Hanna, PharmD, BCPS, BCOP: When we look at the National Comprehensive Cancer Network (NCCN) guidelines, regardless of the frailty or comorbidities of our patient or their age or the presence or absence of IGHV mutations as well as deletion 17p, I really think that the majority of us will see that BTK inhibition has very strong recommendations in numerous areas, category 1 level of evidence in terms of utilizing BTK inhibition.

In the previous couple of years, we've even had our BCL2 inhibitor venetoclax move into this space and now have strong data that has continued to read out. And really the key thing that we look at when we're initiating a patient on a potential BTK inhibitor or a BCL2-containing regimen is really the concept of finite treatment duration. I'll get more in depth with regards to that. But the majority of our CLL patients, if you're going the BTK route, will be on therapy indefinitely. So, you don't get them off of a BTK inhibitor unless the patient has progression or unacceptable toxicity.

So, we'll talk a little bit about that. And then we have one of the newer BTK inhibitors move into NCCN guidelines, which is zanubrutinib. We've had acalabrutinib and ibrutinib for quite some time now, but even zanubrutinib, based on some data that was reported out is now in the NCCN, although it does not hold an FDA indication at this moment.

There are a couple of factors that we have to consider as a care team where we're initiating therapy. We're going to look at patient-specific comorbidities. We want to know: does my patient have cardiac arrhythmias? Is my patient on antiplatelet or anticoagulation therapy? How do those things impact my potential treatment option for the patient? Does my patient have preexisting hypertension? And all those are going to be things we're looking at because it will help us dictate how we're going to monitor and follow up in terms of our patients. We do need to review their medications, their supplements, their diets. On top of that too, we know that sometimes certain medications can actually impact absorption of our therapeutics.

We're also going to have to talk about access. Is my patient going to experience some type of financial toxicity? How easy is it going to be for my patient to potentially come into the clinic to receive their rituximab or their obinutuzumab infusions if they're on venetoclax-based regimens? Do we have access to hospitalize this patient if they are at high risk for developing tumor lysis syndrome (TLS)? These are all going to be things that we're going to consider as we're initiating potential treatments for our patients.

We're also going to look at the infectious risk for our patients. Has my patient had a long history of infections? What does their lifestyle look like? And in certain patients, we might have to use infectious prophylaxis.

It's very, very important that when we are initiating therapy for our patients, that there's some type of shared decision-making process or conversation in place. What is the patient looking for in terms of what they're going to get out of their therapy? As Amy has highlighted, CLL is an indolent disease. But it is a chronic disease. We're not going to cure our patients.

Now we have options where I can treat my patient with an oral pill indefinitely and they do just fine for years. I think we now have 7- or 8-year data readouts from something like ibrutinib. But we also have finite treatment durations. Things like venetoclax as I mentioned. What does the patient want? What do they want to get out of their therapy in terms of their lifestyle and controlling their disease? Again, the finances always going to be a certain conversation that we have and weighing all these risks and benefits of therapeutics are going to be very important.

And while CLL is at a very, very good spot right now with the therapeutic regimens that we have and 5-year survival rates look great, select patients could still benefit from clinical trial enrollment.

Now for BTK inhibitors, it's important for us to highlight that there are some key considerations. They're all administered orally. For the most part, they're given 1 or 2 times a day depending on which drug you have. Things like ibrutinib have one of the easiest dosing schedules in terms of adherence and compliance: 1 tablet once a day, for the most part. And it has a different tablet strength for any dose reductions. Something like zanubrutinib is an 80 mg capsule and patients could take it once a day or twice a day, but it's a total of 4 capsules in 1 day. So, it's either 2 capsules twice a day or 4 capsules once a day. So, there's some pill burden there, but you have to keep that in mind, but also the benefit of something like zanubrutinib is you don't have to worry about a dose-exchange program. If you have a certain tablet strength, you can just tell your patient to potentially take less.

Drug-drug interactions have already been highlighted, but all these are tyrosine kinase inhibitors. They end in -nib: ibrutinib, zanubrutinib, acalabrutinib. They are going to go through the CYP3A and 3A4 pathway. So, if you have strong or moderate inhibitors, you are going to have to dose reduce or potentially avoid co-administration. If you have inducers, for the most part we try to avoid those altogether. I've already highlighted as well our proton pump inhibitor (PPI) interaction with acalabrutinib. It's only acalabrutinib-specific, but on top of PPIs also H2 receptor antagonists and antacids can also impact the acidity of the gastrointestinal (GI) tract and impact absorption.

These drugs, we have to keep in mind, can lead to cardiovascular (CV) side effects, bleeding events, GI side effects such as diarrhea, nausea, vomiting. There are other symptoms: fatigue, myalgia, arthralgia, headaches -- and again, the infectious aspect of these drugs we have to consider and keep in mind.

In terms of the evidence that we have, ibrutinib is a first-generation BTK inhibitor. It has some of the longest readouts we have. We have numerous trials with ibrutinib that have over the years has looked at deletion 17p patients, older patients, younger patients, IGHV mutations. And consistently, across the board, ibrutinib-treated patients do better than chemoimmunotherapy, regardless of age or any of those cytogenetic aberrations. RESONATE trial, E1912, RESONATE-2: all those clinical trials have really established and solidified ibrutinib for this patient population.

Being a first-generation, it does have more off-target kinase activity, which translates into a different side effect profile or different tolerability that we do see with ibrutinib. I'll get more into that but we can see things like hypertension, bleeding, atrial fibrillation (AF), and the aches and pains.

Acalabrutinib and zanubrutinib are more selective second-generation BTK inhibitors. With acalabrutinib, we have a couple of clinical trials as well. We have ELEVATE-TN for treatment-naive, ELEVATE-RR for the relapsed/refractory setting. And all these trials now have significant benefit in terms of readouts, whether we're comparing it to chemoimmunotherapy.

Interestingly enough, acalabrutinib and ibrutinib were actually compared in a clinical trial and both had very, very similar efficacy profile, but we did see differences in terms of the tolerability. Now, certainly with acalabrutinib, we do see lower risk of CV events. But also unique to acalabrutinib, we see patients have higher incidences of headaches and sometimes that's problematic and patients can't tolerate it.

Zanubrutinib, again, although not yet FDA approved, has 2 pivotal trials in CLL. We have ALPINE as well as the SEQUOIA trial. And it's really, really interesting. As a matter of fact, zanubrutinib in the second-line setting compared to ibrutinib actually had an improvement in outcomes for patients in terms of the responses. So, it's interesting to see there are some differences as well that weren't observed in the frontline setting in terms of zanubrutinib. It was pretty comparable with both drugs.

But again, lower incidences of CV events, bleeding events, etc., vs our first-generation. Now there are numerous other pipeline BTK inhibitors, one of which is pirtobrutinib. They bind to CLL cells a little bit differently. They're noncovalent binders, potentially have a better tolerability profile. So, it's likely that we're also going to see the BTK inhibitor class continue to become more and more crowded.

Now in terms of AF, we don't really know the exact mechanism, but it's probably due to something around EGFR or HER2 inhibition, which again are the off-target kinases that are hit by these BTK inhibitors. We certainly know that ibrutinib has some of the highest incidences, anywhere from 10% to 15%, whereas acalabrutinib and zanubrutinib probably sits somewhere right around 3% to 5% or 6% or so. Generally, the risk is highest at the first half of the year when a patient is on therapy, although it could still occur anytime throughout the patient's treatment course. There's actually been some data that shows us ibrutinib AEs around hypertension and AF get worse over time, vs with something like zanubrutinib, they tend to level off and it's experienced generally early.

Now, if you do have a patient with preexisting AF, it's not a contraindication. These are going to be patients that we want cardiology on board. We want to make sure they're under good rhythm and rate control. That their therapies are optimized. There are no significant drug interactions. And then we can generally safely address and treat these patients.

Hypertension: another side effect, an off-target kinase activity. Again, we haven't seen any impact in terms of the dose a patient may on. It does increase over time as well in terms of incidence. There hasn't been any 1 antihypertensive medication that's actually shown to be better at managing the hypertension. So, for the most part, clinicians really prescribe whatever they are more familiar with and accustomed to, but also keeping in mind there could be some interactions there.

Now we also can see bleeding with BTK inhibitors. Oftentimes things like ITK. That's an off-target kinase that can impact platelet aggregation. They can impact the collagen pathways, the von Willebrand factors, within our body. And you can see increased risk of bleeding.

Again, you want to monitor patients more closely if they're on antiplatelet / anticoagulation therapy for any other comorbidity or AF or whatever it may be from based on their history if they're coming to you. But again, certainly not contraindications to use.

Now, venetoclax is also another very important drug we have to talk about. With venetoclax, oftentimes in CLL there's a 5-week ramp-up schedule that we have to follow. In acute myeloid leukemia (AML) and other malignancies, there's a different ramp-up schedule, but in CLL it's 5 weeks, whether you're using it in the frontline setting with obinutuzumab or whether you're using it in the second-line setting and beyond with rituximab. Still CYP3A4 pathway is going to be an important thing to consider for drug interactions. And we do see some of the side effects we see with venetoclax. Myelosuppression, GI side effects and the TLS, which I'll highlight here just shortly but ultimately why we do the ramp up.

Two pivotal trials, CLL14 and MURANO. CLL14 is front-line. MURANO is relapsed/refractory. One looked at obinutuzumab in frontline combinations. One looked at rituximab combinations in second line. Great thing is in the frontline setting, we treated people for 1 year. After that year they get off of therapy. We watch them. And many of these patients continue to benefit. In the second-line setting with rituximab we used it for 2 years. We got patients off of therapy, monitored them, and they continue to do well off of therapy.

So, something very unique now in CLL kind of steering away from BTK inhibition. When we talk about financial constraints and toxicities, having further readouts from CLL14 and MURANO is really exciting because now I can limit therapies to limit that financial toxicity.

I'm limiting patient's exposure to drugs, another quality-of-life benefit there, but also minimizing potential side effects. I'm using a lot less resources. So again, in the totality of evidence, there are cost comparative analyses, etc, that are definitely warranted to truly show a potential financial benefit with this new novel approach of finite treatment durations.

The neutropenia, like I mentioned, is going to happen. These patients also have a B cell malignancy so making sure we're looking at their absolute neutrophil counts. Maybe giving granulocyte colony-stimulating factor (G-CSF) when indicated. You also see this with BTK as well.

TLS is really your biggest thing. It's going to be important to look at those patients closely, especially if they have bulky disease, high tumor burden, large lymph nodes, multiple lymph nodes, any potential renal impairment, any type of uric acid that's higher than expected at baseline. We want to monitor these patients very, very closely.

Based on your tumor burden, whether it's low, medium, or high -- and that's all dictated by your lymph node size as well as your absolute lymphocyte count (ALC) and how many of those components you have -- will bucket you in a low, medium or a high bucket in terms of your TLS risk. For the most part, your high-risk patients: lymph nodes larger than 10 cm , ALCs greater than 25,000. These are probably going to be people we admit, start them on that 5-week ramp-up, doing aggressive fluid hydration, looking at labs very frequently 48, 24 hours, depending on each dose ramp-up, etc.

Whereas somebody low or medium tumor burden, depending on your resources and how well you can track and monitor these patients, those are patients that we could probably safely initiate in the outpatient setting.

There are other classes, things like PI3K inhibitors. I think for the most part because patients do so well on the majority of other therapies, our PI3K inhibitors have really fallen out of favor, but they are certainly still options for patients if they progress quickly through therapeutics and if we need to leverage these.

Again, they are targeted therapies. But the unique thing with PI3K inhibitors is a lot of the adverse events that patients may experience are going to be around inflammatory processes. They present similarly to things like immunotherapies -- diarrhea, colitis, hepatic toxicity, pneumonitis, infections. Those are going to be things that we have to keep in mind.

When we educate our patients, it's going to be very important we highlight the things we mentioned. Tell us if you have diarrhea. Monitor your blood pressure and make sure your patient knows how to monitor their blood pressure when they're at home. If they have any type of skin toxicities, they need to let us know. Any type of fevers could help us identify someone who could have an infection.

We also have to tell people in terms of any medication changes they need to let us know. We want to make sure we're limiting things like nonsteroidal anti-inflammatory drugs (NSAIDs), because obviously that could increase risk of bleeding. But again, we have to also help them in terms of supporting them for their aches and pains.

Venetoclax: the key things making sure that we adhere to that ramp-up schedule, particularly if the patient is in the outpatient setting. One thing I really value about venetoclax, especially for the 5-week ramp-up, it comes in these cartons that are color coded for each week, which makes it a little bit easier for our patients to adhere to therapy.

Making sure patients can adhere to any hydration recommendations, making sure we're clearing out their kidneys as best as we can to make sure we're washing out all that cellular junk, as I like to say, and trying to make sure we're keeping that TLS at minimum. Again, the GI side effects will be there. Maybe again the infectious recommendations. So, making sure we're asking our patients those questions and they contact us when it's appropriate.

Now as an interprofessional team and how we coordinate things, we've highlighted a lot of that for you. But again, we have to be engaged with our specialty pharmacy, with our clinicians, with our patients, particularly if everything is kind of coming from a different area. Your specialty pharmacy is doing one thing, your HCP is doing another thing, and then you have the patient who's in the middle of it all. We have to make sure that there's some type of optimized coordination there and we're navigating the system and leveraging our electronic medical records as best as we can so we can all have full insight in terms of that patient and how they're doing.

Amy, I would kind of love to hear from you. Based on everything we talked about, what are some of your pretreatment considerations and getting patients to start therapy? Does it differ between BTK vs venetoclax-obinutuzumab or venetoclax-rituximab, and what are you guys doing with your respective system?

Ms Goodrich: Right. When you talk about shared decision making, the average patient is going to have multiple options. And so it really is a matter of for most patients do they want a year of venetoclax-obinutuzumab or do they want open-ended BTK inhibitors?

Really just talking about the pros and cons. And I think the real key for patients is that they need to understand that if they choose option A, option B doesn't go away, right?

So, most CLL patients will get a BTK inhibitor at some point and a BCL2 inhibitor at some point. But really you are thinking about coexisting conditions and their medication lists, and also their transportation issues, their social situation. There are a lot of things that go into it. But even those patients who have lots of comorbidities and lots of social challenges, they are probably going to have more than 1 option. So that shared decision making is so important.

Dr Hanna: I couldn't agree with you more. Do you want to walk us maybe a little bit through how we can kind of get all these AEs we talked about and optimizing adherence and all of that? Obviously, from the RESONATE trials, we have tons of things about adherence and compliance. I'd love to kind of hear what you guys are doing in terms of making sure that that patient is taken care of regardless of their therapy.

Ms Goodrich: Absolutely. In thinking about management and optimizing adherence, one of the first things I cover with patients is with BTK inhibitors, this anticipated lymphocytosis where the lymphocytes actually leave the lymph nodes and get pushed out into the peripheral blood. So, patients need to be prepared to see a spike in their WBC count and their ALC. If they're ready for it, it really helps. So, I tell them they'll see their nodes shrinking and that white count is going to go up. And that's just how these drugs work. And they slowly go down over time. Some patients never get resolution, but for the most part they do. And it is really important for patients to be aware that this is a normal part of how these drugs work.

You had talked, Kirollos, about hypertension management and the fact that hypertension is one of the few things that will get more prevalent over time. And so really optimizing that blood pressure control at baseline. And you had mentioned cardio-oncology and cardiology and other team members. And then I'll just highlight the fact that there really is not a one-size-fits-all approach to this. There's no preferred agent, just treating per guidelines. And I've not had any refractory hypertension, but if that happens you can use a different BTK inhibitor. So, this is just managing per standard of care.

Another issue with BTK inhibitors is bleeding and, Kirollos, you had talked about bleeding being an issue with BTK inhibitors and up to 50% of patients will have some bleeding. It's typically grade 1 or 2. It's bruising. It's bleeding gums with brushing teeth or flossing. We typically are not holding or dose reducing for grade 1 or 2, but definitely monitoring more closely.

If patients do have grade 3 or 4, definitely holding, consider transfusing, and then resuming at a dose reduction. Then you talked about procedures and holding for procedures, holding BTK inhibitors to reduce the risk of bleeding. For minor procedures it's 3 days plus-minus: 3 days before, 3 days after. For major procedures it's 7 days. That's a really critical teaching point.

Kirollos, you also talked a little bit about AF management and the incidence of AF. And so definitely getting cardiology involved. You're, of course, going to hold your BTK inhibitor. And you really you are doing rate control per your standard of care. If we are having difficulty, if it's mild or patients are asymptomatic, really using beta blockers, calcium channel blockers. If patients require anticoagulation for cardioversion there is risk of bleeding there.

And really the most important thing in this area for me is that our CHA2DS2VASc scoring is not validated in this patient population. If you do have to use anticoagulation, really try to avoid warfarin and use one of our newer and smarter drugs in multiple categories for anticoagulation for these folks.

Some other common side effects are rashes, and to use topical steroids, oral antihistamines. Just symptomatically manage those patients. They can have nail and hair changes. You can use some biotin supplements or oils on nails.

Kirollos, you had talked a little bit about diarrhea, using loperamide. Of course, making sure patients are hydrated. And one of the things for GI toxicity I find is that this bedtime dosing really does make a difference if patients have diarrhea or nausea. To do bedtime dosing, especially with the once daily options. It doesn't help so much with the twice daily options.

And then, of course, using antiemetics. I often have patients premed with antiemetics if they're having nausea. For arthralgia and myalgias, exercising always helps that. Avoiding NSAIDs because of that bleeding risk. Headaches, this is most common with acalabrutinib, caffeine and acetaminophen, and again, avoiding NSAIDs or aspirin-containing products.

Kirollos, you had talked a little bit about infection, that this is a risk with all of these agents. There are no recommendations for prophylaxis. So, this is something you're going to customize to the patient in front of you. Drug-drug interactions with antifungals, azoles, and then hold your BTK inhibitor if patients have severe infections.

For venetoclax, aside from TLS, TLS, TLS, there are potential for other toxicities. Typically, neutropenia is what I'm seeing in my practice. There are other nonhematologic toxicities patients can develop, but typically venetoclax is well tolerated and is mainly about neutropenia once you get that TLS risk over with.

So, you would interrupt at first occurrence, but start at the same dose. And then dose reduced if you have to hold a second time. For supportive care you can use G-CSF as indicated and then consider antibiotic prophylaxis during periods of neutropenia. So really managing as clinically indicated.

And, Kirollos, you had talked about this. You alluded to this. But I love this graphic here about the lead-in and ramp-up strategies. And they are different depending on what regimen you're using. But the bottom line is the same. The goal is to debulk and not give both of these agents at the same time because of risk of TLS.

With acalabrutinib and obinutuzumab we don't really think of acalabrutinib with TLS, but obinutuzumab causes TLS. So, we don't pair those up. We start lead in with the acalabrutinib and then move on to adding to the obinutuzumab.

And you had already talked about venetoclax and obinutuzumab first line. That's a 1-year therapy. You lead in with obinutuzumab and then start your venetoclax ramp-up.

And then with rituximab in the relapsed / refractory setting, you start with the venetoclax ramp-up and then add the rituximab. But again, this is all about not throwing 2 things at the patient at the same time.

For our anti-CD20s, certainly infusion reactions are an issue. Using acetaminophen, diphenhydramine to prevent, you may use steroids depending on which agent you're using and what the patient characteristics are, the bulk of their disease. And then also H2 antagonists -- things like famotidine, cimetidine -- that family of drugs can help prevent those infusion reactions.

Then, managing infusion reactions. I feel like we're really good at this now in oncology. You stop, you give fluids, you assess, you do the right thing. You're looking at the premeds that they have received. Do they have a history of allergies? And then treating. Again, maybe H1 blockers, maybe steroids, maybe H2 blockers. Hopefully folks are not needing oxygen or albuterol often or epinephrine. And then those folks who have reactions need to be watching for fevers or signs or symptoms of that infusion reaction at home as well. And then you may start them again at a lower rate. Again, we're really good at this at this point.

Then, optimizing oral drug adherence. Again, we've talked about shared decision making. We've talked about patient and caregiver education, and I really find that if we educate patients well, we watch them closely, we get on side effects quickly, we make sure that their questions, their issues, their little glitches are taken care of, patients are typically very successful on these therapies. There are assistance programs. We've got refill reminders, calendars, all sorts of things to help optimize adherence to these oral drugs.

And then if we look at our long-term data on ibrutinib from the RESONATE trial, patients who missed 8 consecutive days or more had a shorter median progression-free survival (PFS). And those who stayed on therapy and had higher dose intensity, it's really looking to appear that their PFS, overall response rates and trends toward improved overall survival are emerging. So, it really is important for these folks to stay on their drugs, adherent and taking them as prescribed.

So now, Kirollos, do you have any other management strategies to keep patients on therapy and keep them compliant? I have pharmacists in my clinic and I really appreciate the pairing of the nurse practitioner (PA), and the pharmacist because the things that I focus on are different from what the pharmacist focuses on. And I feel like, together, they get the whole picture. So, tell me what have I missed. -

Dr Hanna: I totally agree with you. I really think for these CLL patients now with everything we've talked about, that first 4- to 6-month window, you get the patient through it and majority of your patients will kind of go on autopilot, right?

Ms Goodrich: Yes.

Dr Hanna: You know, for the most part, exactly what you said. Just having a good program in place that can really support the patient through that initiation. Looking at their blood pressures, asking the questions, evaluating drug interactions, being that support system that they need particularly too with adherence because what we don't want is the patient under reporting and not telling us and not taking their medication or taking their medication incorrectly.

It's like you highlighted from RESONATE, Amy. The disease will become refractory to BTK. You're no longer going to be able to entertain that signaling cascade. And you said something really good too. Just because you use option 1 it doesn't mean option 2 is off the table, or however you sequence it. Right?

Whether you went BCL2 or whether you went BTK first, they're both still very good options, regardless of which one came first, right?

Ms Goodrich: Yes.

Dr Hanna: So, I think you've highlighted tons of excellent things and I just definitely want to thank you for this exceptional discussion that we've had.

Ms Goodrich: Yes. Well, thank you. Thanks to the audience. Thanks to Kirollos for joining us today and I hope you have a great rest of your day.

Dr Hanna: Thank you.

This transcript has not been copyedited.

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