Lori A. Leslie, MD

 We’ve talked a lot about how this landscape has evolved, with all the new treatment options we have. There’s a lot coming in the pipeline too. CLL [chronic lymphocytic leukemia] is still considered an incurable disease, meaning that even if patients get into remission—maybe they’re on time-limited treatment and aren’t on any therapy for a while, or they’re on watch-and-wait—they’re advised that they’ll need to follow up with us forever. That fear of the CLL rearing up again and needing treatment is always in the background for our patients.

The field is shifting toward, hopefully, finding a way to cure patients with CLL. We’re not there, but a lot of things in development might help us do that. Some things include therapies that are being developed across other B-cell cancers. In CLL we follow something called minimal residual disease, or MRD, and that can be checked in a variety of ways. At a deep level, it looks to see if every single cell is gone. That doesn’t usually happen on BTK [Bruton tyrosine kinase] inhibitors; that’s why they’re given long term. You usually have some small detectable disease, and it’s chronic. One of the ideas—and we’ve participated in clinical trials looking at this—is adding something to someone who’s in a deep remission to try to eradicate those few cells remaining and allow people to come off treatment and hopefully not need treatment again.

One thing that’s being explored in that setting is different immune treatments, so chimeric antigen receptor T-cell therapy is being developed in CLL. That’s where you retrain the immune system to recognize the cancer cells. Bispecific T-cell engagers are another group of drugs that people might hear about in blood cancer in general. It grabs the immune system and the cancer cell, brings them together, and helps the immune system destroy the cancer cell. It sounds like science fiction when I explain it, but it’s exciting that we can be a part of it at our center and many others and give patients hope. I’ll talk to you about treatment now, but we might not need treatment for a few years. If that’s the case, I probably don’t have what I will treat you with in 2 or 3 years. It’s changing quickly. There are a lot of reasons for our patients to be incredibly hopeful. It’s a dramatically different landscape from even a few years ago, and I expect that trend to keep going for the rest of our careers.

We’ve talked about a lot today. Hoshi, any parting words of wisdom that might be helpful for patients?

 As you’ve described, there are a lot of changes going on in the CLL world with treatment. We’re far from the chemotherapy regimen that we used to use. We’re getting in the realm of patients going home, taking pills, and managing their disease like diabetes or hypertension, which is very promising. It’s a very exciting time. When our patients are on watch-and-wait, they often say, “It’s always watch and worry.” I hope this discussion will give our patients more comfort and get them excited about their future.

 Exactly. There’s no reason to treat them if they don’t have symptoms. That doesn’t help the long-term outcome. The longer one can wait, the more likely they are to shift into a new era, where we might have even more effective and better-tolerated drugs. That’s some great wisdom. I like the mention of “watch and worry” because that comes up commonly.

Thank you once again, Hoshi Iida, for this insightful discussion. To our viewing audience, thank you for joining us. We hope you found this session to be useful and valuable in your treatment with chronic lymphocytic leukemia.

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Lori A. Leslie, MD, and Hoshiyuki Iida, APN, offer closing thoughts on the future treatment landscape of chronic lymphocytic leukemia.

Future Directions in CLL Treatment

 Speaking of stress in our patients, there are a lot of things—I don’t know if this comes up in the support group—that come into being on treatments. Some of that is financial. Is that something people talk about: the cost of health care and their medications?

 It’s a concern for our patients in the support group. When you’re starting out, the therapy cost is always an issue. Newer treatments are expensive, and then you’re talking about being on it for several years as a possibility. We tell our patients who are starting therapy that there’s always patient support, co-pay assistance. So speak to your provider, and make sure you’re getting any support benefits that comes with the medication.

 It can be complicated. Thankfully, we have a whole team that does only oral medications because it’s so common throughout oncology. We have a lot of patients come in. If you talk about a medicine, they’ll call us the next day and say, “I looked this up on the internet. It’s several thousand dollars a month. I can’t afford that.” We tell them it first it goes to your insurance. Then there’s co-pay assistance, thankfully, with several options. The benefit of having those options is that there’s some competition, so the patient-support options from the companies that make the medications are quite robust. It’s a rare situation to have a patient who needs a certain therapy and can’t get it due to cost. As you highlighted very nicely, particularly when starting a new treatment, that’s a common, stressful concern for patients. It’s not necessarily an adverse effect, but that worry as they’re starting a new therapy impacts their quality of life. It’s nice to direct them to all the resources we have.

Experts on chronic lymphocytic leukemia discuss how to approach cost considerations and available resources for CLL treatments.

Cost Considerations for CLL Therapies

 There is a lower incidence of mostly the cardiac adverse effects that you can see with BTK [Bruton tyrosine kinase] inhibitors when you’re looking at the next generation compared with the first generation. What are those adverse effects? I don’t think we’ve touched on that yet. Even though these targeted therapies are well tolerated, there are a few groups of adverse effects that can occur. Some are uncommon but potentially serious, and others are a little more common and typically mild and relatively easy to manage.

Talking just about the less common but potentially serious, the main groups are cardiac adverse effects, you can have an irregular heartbeat called atrial fibrillation or atrial flutter. This is less common with the next-generation BTK inhibitors compared with ibrutinib. If we have patients who have a lot of cardiac comorbidities or have atrial fibrillation at baseline, typically that’s something we use to say we should select next-generation acalabrutinib or zanubrutinib for this patient due to their underlying cardiac comorbidities. That’s reflected more strongly now in the guidelines and has become our standard practice. Even though someone has atrial fibrillation, they certainly are appropriate [patients] to use a BTK inhibitor. We just work with their cardiologist or cardio-oncologist to help know that this might happen and they should be monitored. Another thing that can happen on BTK inhibitors is bleeding. When we’re talking to patients, we like to describe it as like a baby aspirin, so that if they’re having a surgery or a procedure, then they call us. When you’re teaching a patient, what type of advice do you give them about procedures and their BTK inhibitor?

 For a patient who’s taking a BTK inhibitor prior to procedures, we usually tell them to hold the therapy 3 days prior to and 3 days after, or a week before and a week after, depending on the procedures.

 It empowers them to talk to their surgeon or provider and say, “I’m on this drug that can cause bleeding. Why don’t you call Hoshi and Lori and see if we should hold it before and after the procedure?” It helps explain it in layman’s terms so they know why it’s important to let us know about that procedure and how they can make sure the procedure is done safely. [As far as] other adverse effects we didn’t talk about yet that are less severe but relatively common, mostly when the patients are first starting their BTK inhibitor, some people can have GI disturbance, gastrointestinal disturbance, like a mildly upset stomach or changes in their bowel movements. We like to empower them and tell them, “This happens, give us a call, but you can take Imodium at home, or you can take this at home.”

Specifically with acalabrutinib, some patients can get a headache when they start, particularly if they’re prone to headaches at baseline. This behaves like a migraine, so caffeine can be helpful. Patients love when we tell them they can drink extra coffee to treat their headache, they are always a fan of that management advice. Again, if a headache happens, it helps them to not be scared and know they can continue their medication, call and let us know. These things are usually a little more transient, so they last the first few weeks to 2 months while on therapy, and then usually get better once the body gets used to the BTK inhibitor.

It’s helpful to let them know that these things might happen and that we’ve got a large panel of patients with CLL [chronic lymphocytic leukemia] that we treat together. In our experience and in the studies, typically these adverse effects are more of an annoyance but can be managed at home with our assistants, and typically are relatively transient, so they shouldn’t expect that this is their new normal. If we can get through those first few months, then patients typically feel much better and can go on with a normal life, just coming to see us every few months to make sure things are going well.

Hoshi, in our patients treated with BTK or otherwise, you run the support groups, you’re an expert here. What type of things do you hear them discussing? What concerns do they have about treatment, adverse effects, or even supportive care that they could pursue?

 Most of our patients in our support group have been on a BTK inhibitor for several years, and they are tolerated well. Often our discussions aren’t driven by the adverse effects, or rarely, complications. However, you mentioned a lot of different complications that may occur. We mention that to our patients, and we empower them to call us for any issues, any bleeding that may happen. But we always tell them don’t go reading into the adverse effect profile too much because they’ll list everything on Earth.

 I like normalizing it. I say, if you get worried, read it. We give you the education, if it worries you reading all these things, then read the package insert for Tylenol, acetaminophen, a common over-the-counter drug. It’s 20 pages long and mentions terrifying things. We tell you everything that could happen. Your support group is a wonderful resource to say, “This is what can happen and we watch out for of course, but the most common experience is….” You guys are chatting about other things that go along with being a patient with CLL and not so much that patients are having unacceptable adverse effects on their treatment that impact quality of life.

 The main thing that was driven in our support group during COVID-19 was the vaccinations. That is one of the most important things you could do as a preventive measure. For our patients with CLL, they are at a higher risk for COVID-19 and the complications from it. The vaccination and medications such as Paxlovid have been integral to treating patients with COVID-19. The suggestion I would give patients in our support group is, if you tested positive for COVID-19, make sure you alert your health care provider.

 That is something that the COVID-19 pandemic has helped highlight, this particular immunosuppression that patients with CLL have. With their B cells, which are the cancerous cells, the normal role is to make antibodies and protect you. Even in the 2018 CLL guidelines, which was before we even knew COVID-19 was coming, there’s a whole section that highlights the importance of your regular vaccine. An annual flu vaccine, pneumonia vaccine, and shingles vaccine—the Shingrix newer nonlive vaccine—are standard of care for all patients with CLL, even if you’re not at the age where you otherwise would be appropriate for those vaccines. Because of that immune vulnerability, the earlier you start getting those vaccinations in the CLL journey, the more likely that patient is to have longer term immunity that could protect them down the line.

I like to explain it as, please start the vaccines now, and it will help your future self, whether or not you’re on treatment and regardless of what the age is. COVID-19 has been an extension of that. Unfortunately, our patients with CLL, particularly in the beginning of the pandemic were, as you mentioned, at the highest risk of these poor outcomes, admission to the hospital, or having fatal events from COVID-19. It was a terrifying time for our patients.

As we’ve gotten these tools, vaccination, when we have a monoclonal antibody available either for treatment or prevention, things like Paxlovid—antiviral medication you can take—has transformed things for our patients in a way that they can be more comfortable in trying to get a bit more back to normal life. I know you’ve shared in the support group, COVID-19 has been so isolating, and that stress is terrible for our patients’ immune system. Having these tools to empower them has helped us get through the later phase of the pandemic and also helped us highlight this recommendation and importance of vaccines for all patients with CLL, whether or not they’re on treatment. That was present but not well vocalized before we had so much focus on COVID-19.

Insights on supportive care and approaches to managing adverse effects of BTK inhibitors in the treatment of chronic lymphocytic leukemia.

CLL: Supportive Care and Managing Adverse Effects With BTK Inhibitors

 We now have 3 covalent BTK [Bruton tyrosine kinase] inhibitors approved in CLL [chronic lymphocytic leukemia]. We talked a bit about the frontline setting, and the relapsed/refractory setting is different. In the front line, we talked about BTK inhibitor vs chemotherapy mostly, and in relapsed/refractory, we have head-to-head data looking at that first-generation BTK ibrutinib vs the next-generation BTK inhibitors, acalabrutinib or zanubrutinib.

I want to mention 2 studies, the first is ELEVATE-RR. That is a randomized study, so flip a coin, patients either get ibrutinib, which is the first generation, or acalabrutinib, which is the second generation. This specifically was focusing on slightly higher-risk patients who had certain molecular abnormalities, particularly 11q deletion or 17p deletion. This was a noninferiority study, which means it was done to prove that acalabrutinib, the newer BTK inhibitor, had the same efficacy as ibrutinib on an end point called progression-free survival [PFS]. That was found to be noninferior, the PFS was the same, but some secondary end points that emerged were the differences in safety. In particular, the cardiovascular toxicity profile of acalabrutinib was favorable compared with that of ibrutinib. This was one of the studies that helped us look at the medications head-to-head, not only from an activity perspective, but importantly, they have a similar mechanism of action, is one tolerated better than the other? The consensus from some of those secondary end points, particularly from a cardiovascular end point like atrial fibrillation, is that acalabrutinib is favored over ibrutinib.

There was a similar finding that came from the ALPINE study, which is also a randomized study in relapsed/refractory CLL, and is looking at patients who either could get ibrutinib or zanubrutinib, which is another next-generation BTK inhibitor. The end point of this study was a little different. This is a superiority study, meaning it was designed to potentially show that zanubrutinib is better or superior to ibrutinib. The primary end point was overall response, and that’s an important end point. That favored zanubrutinib over ibrutinib, showing that more patients had at least a partial remission or better. Something that was presented recently at our big blood cancer meeting, ASH [American Society of Hematology], at the end of last year surprised us, and that showed that zanubrutinib was superior to ibrutinib in terms of progression-free survival. People stayed in remission responding to therapy at the 2-year time point more commonly with zanubrutinib compared with ibrutinib.

This potential efficacy difference—it was a secondary end point—is really encouraging that not only are these newer agents better tolerated—that also panned out that zanubrutinib had a favorable cardiac toxicity profile compared to ibrutinib—but potentially we’re seeing an efficacy signal. Another thing that the development of zanubrutinib has done very nicely is they’ve teased out this higher-risk patient population that is 17p abnormal. This benefit over ibrutinib was not only in the whole population in terms of progression-free survival, but also was seen significantly in those with TP53 or 17p abnormal CLL. [These are] exciting results to show that not only are these new agents potentially better tolerated, but further follow-up will let us know if this difference in progression-free survival is durable and something we see with more time.

CLL expert Lori A. Leslie, MD, gives a comprehensive overview of the ALPINE and ELEVATE-RR head-to-head studies of BTK inhibitors in CLL.

Lori A. Leslie, MD

Future Directions in CLL Treatment

Cost Considerations for CLL Therapies

CLL: Supportive Care and Managing Adverse Effects With BTK Inhibitors

Head-to-Head Studies on BTK Inhibitors in CLL

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