Transforming CLL Management: Pharmacists' Impact on Treatment Strategies, Adherence, and Quality of Life

Pharmacy Times® interviewed Anthony Perissinotti, PharmD, BCOP, a clinical pharmacist specialist, inpatient hematology at University of Michigan Health System, on key unmet needs and trends in managing chronic lymphocytic leukemia (CLL), emphasizing the pivotal role of pharmacists. For example, despite the shift away from chemotherapy towards better-tolerated targeted therapies, tolerability challenges persist, particularly for patients with multiple comorbidities who find it difficult to manage Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (Bcl-2) inhibitors. High-risk patients with specific mutations, such as P53, still experience poorer outcomes compared to other patients. The use of minimal residual disease (MRD) as a possible end point or marker for guiding therapy is also under active investigation. Additionally, despite advancements, CLL remains incurable, often requiring lifelong therapy.

Anthony Perissinotti, PharmD, BCOP, is a clinical pharmacist specialist, inpatient hematology at University of Michigan Health System in Ann Arbor.

Currently, favored second-generation BTK inhibitors for CLL treatment include acalabrutinib (Calquence; AstraZeneca) and zanubrutinib (Brukinsa; BeiGene) due to their improved tolerability and efficacy. In addition to prolonging patient survival, there is also a strong focus on quality of life, with emerging strategies aimed at providing treatment breaks to reduce long-term adverse effects (AEs). Combinations like venetoclax (Venclexta; AbbVie) with obinutuzumab (Gazyva; Genetech) are becoming standard, while fixed-duration therapies are being explored.

Pharmacists play a critical role in CLL care, moving beyond traditional patient education to serve as advisors to other health care professionals on treatment guidelines and the latest data. Their role includes supporting AE management, coordinating financial resources, and ensuring medication access.

It is also now best practice for pharmacists to support shared decision-making with patients regarding treatment, which can lead to improved medication adherence. To further support adherence, pharmacists can address with patients some of the common reasons they may stop medications prematurely, including toxicity, financial burdens, and a misconception that feeling well equates to being disease-free. By providing individualized support and fostering collaborative care, pharmacists are pivotal to advancing the quality and effectiveness of CLL management.

Pharmacy Times: What are some unmet needs in the management of patients with CLL?

Anthony Perissinotti, PharmD, BCOP: During our clinical forum, it was really refreshing to hear that all pharmacists within their lifetime, within their career time, they've been able to see the metamorphosis away from chemotherapy towards some of our targeted therapies. But we all still admitted that there were some unmet needs. So, the first unmet need was the tolerability. Even though these therapies are better tolerated than chemotherapy, in real-world patients with several comorbidities, with the logistical challenges, patients that are on several medications, it can be pretty challenging to manage these patients, even with our very well-tolerated BTK inhibitors and Bcl-2 inhibitor, venetoclax. We have seen that this has improved with our second generation BTK inhibitors, acalabrutinib and zanubrutinib, but there's still some room for improvement. Another unmet need are patients with high-risk molecular or cytogenetic abnormality. So a patient with a P53 mutation, although these patients now do tremendously much better compared to chemotherapy, they still don't do as well as patients that don't have a P53 mutation. Another unmet need is trying to learn how to use measurable residual disease. Should we use that as an end point? Should we use that as a way to stop therapy? Should we use it as a way to compare therapies? These are things that we're still learning how to apply in the medical community. Another unmet need, patients that relapse after our BTK inhibitors and Bcl-2 inhibitors can be particularly challenging. And then lastly, I think another unmet need is we still can't cure CLL. Despite all of the advancements, despite the metamorphosis of the treatments of CLL, we still have a chronic lymphocytic leukemia, a chronic disease that requires lifelong therapy for many of our patients.

Pharmacy Times: What are some recent trends of note in CLL management?

Perissinotti: The major trend that I've seen in CLL is the complete shift away from chemotherapy. I'll admit, I have not used chemotherapy in almost a decade now, and when you speak to pharmacists across the country, that's also true in their practice, whether it's been a decade or 5 years. The bottom line is: none of us are using chemotherapy at all anymore. We're now using our targeted therapies, and our targeted therapies are either our BTK inhibitors or a venetoclax-based regimen with obinutuzumab or rituximab (Rituxan; Genetech). And we've also started to move away from even using our first-generation BTK inhibitor ibrutinib (Imbruvica; AbbVie, Janssen Biotech), in favor for our second generation BTK inhibitors like zanubrutinib and acalabrutinib. I've also seen a lot more trends towards us emphasizing quality of life. Patients with CLL can now live as long as the general population, but we also want them to live as good as the general population as well. We've been really focusing on, how can we not only reduce disease symptoms, but how can we help patients live a life where they're not having symptoms from their therapy as well. Other trends are, how are we going to stop therapy? Because it is a lifelong disease, is there a way for us to give our patients a treatment break? So, there have been some emerging combinations with venetoclax. Obinutuzumab with venetoclax is the mainstay, but there's also venetoclax with ibrutinib; that got approved in Europe, it did not get approved in the United States. I think there are some issues with tolerability because of ibrutinib. We also would like to see some longer follow up to make sure it's as durable as venetoclax with obinutuzumab. But I think in the future, what we're probably going to see is our second generations added to venetoclax, and hopefully we can see as durable, if not more durable, remissions for those patients.

Pharmacy Times: What are key takeaways when looking at real-world patient cases discussed during the clinical forum relating to recent guideline updates and new clinical trial data on bruton kinase inhibitors (BTKi)?

Perissinotti: The major takeaways from the clinical forum, and I'm going to sound like a broken record, is, none of us are using chemotherapy at all for CLL. And I think that, something that might be surprising to some listeners, are none of us are using Ibrutinib as our first line treatment anymore as well. And again, it's because of the favorable toxicity profile of our second generation BTK inhibitors, whether that's acalabrutinib, and that's based off of the ELEVATE relapse/refractory study, or zanubrutinib, which was based off of the ALPINE study. Interestingly, with ALPINE, it may show superiority not only in the toxicity profile, but also potentially in the efficacy. Many of our cases that we discussed was, we're now going to be picking between either a second generation BTK inhibitor, or a fixed duration treatment with Bcl-2 inhibitor, venetoclax with obinutuzumab. Now, the other thing that I noticed during our real-world discussions was that many of us really would prefer fixed duration therapy with venetoclax and obinutuzmab, but in the real-world setting, that's not always possible. There are a lot of logistics that impede this. Many patients also don't have the preference of wanting to have frequent lab draws, have to come into the hospital. For that reason, many of our patients that many of us would think, “Oh, we should put them on fixed duration therapy,” they end up on BTK inhibitors. But ultimately, I think we all agreed that we have excellent options in the front-line setting. In the second line, we had some cases that we discussed, “Well, how do you treat a patient that progressed after BTK inhibitor?” And we all agreed that we would use venetoclax with either obinituzumab or rituximab. And then if a patient started with venetoclax with obinutuzumab, we discussed 2 potential options. One is yes, we could switch to a BTK inhibitor. But we also discussed that, if a patient had a prolonged remission, we're talking years of remission after stopping venetoclax and obinutuzumab, that we would consider retreating them. Ultimately, we would sit down with the patient and talk about the pros and the cons. Lastly, we discussed some cases that were relapse or refractory after all of those therapies that I discussed, and what options do our patients have now? Some emerging options are pirtobrutinib (Jaypirca; Eli Lilly), which is a reversible BTK inhibitor. It's much more selective for BTK, and then also chimeric antigen receptor therapy (CAR-T).

Pharmacy Times: What is the role of pharmacists in the care of patients with CLL on BTKi?

Perissinotti: The role of the pharmacists in CLL is really advancing, and it's quite diverse. As you all know, there are many different types of pharmacists, and every single pharmacist in every single setting plays an important and equally important role. So, we have pharmacists that are embedded in clinics, that are helping with treatment decisions, helping with adverse effect management, and we have pharmacists at the bedside of patients. We also have pharmacists in specialty pharmacies, and they're helping with their financial coordinators to ensure access for patients. We also have patients within oral chemotherapy programs, where they're doing a lot of virtual care for those patients, following up on patients at certain intervals to ensure that patients are tolerating their therapy, have access to their therapy, and if they have any further questions, they're there to answer those questions. I think what I was most impressed with understanding the advancing role the pharmacist within our clinical forum was they're moving away from the traditional role of educating just the patients, but now pharmacists are really educating others. Other healthcare professionals, our physicians, educating them on the newest data that has come out. Whether it's new, published data or abstracts that have been presented at new national or international conferences, and really getting into the nitty gritty details, critically appraising that literature and coming up with pathways of how to treat patients best. Also educating our nurses, so that our nurses are empowered to be able to make some decisions when they are called, when patients have questions as well.

Pharmacy Times: What are some takeaways around best practices to optimize patient selection, education, and monitoring?

Perissinotti: In my personal perspective, I believe that shared decision-making is by far the most important best practice that we can have in in CLL. We have multiple great options. You could literally put the options in a hat. You can put venetoclax, you can put acalabrutinib, you can put zanubrutinib. Pick one out and it would be a fantastic option, and that option would likely lead to a patient living a very close to a normal life. That being said, because the options are so good, we still need to pick the option. So, who is the best person to pick the option? It's the patient. What is the best option that fits our patient’s lifestyle the best? In order to do that, we need to sit down with our patients and educate them on the pros and cons of each therapy so that they now have the knowledge to choose their therapy. When you empower patients, they're going to feel like they've now gotten back into control, right? So, they were just given a devastating diagnosis. They now have cancer. So, you feel like you're out of control, but the second that you can get them feeling like they're back in control of their decisions—shared decision making—you can then get your patient to be a part of their journey, to be a be a part of their treatment decisions, to be a part of even adverse effect management decisions. When you have a patient that is that incredibly involved, they're going to be more adherent to their therapy, because ultimately, these are all their decisions, and not just us dictating their care. Another best practice is early intervention. So, as I said, these therapies can still cause some toxicities, and we want to identify them early. There's a couple of ways to do this. One is, again, educating the patient so that they are empowered to be able to call us. But also, we want to check in on these patients at certain intervals. So initially, many of us are checking in on our patient within a week to make sure that they actually got access to their therapy. But then we're checking, you know, every 2 weeks, monthly, every 3 months thereafter, to ensure patients are still tolerating their medications. And if they have any additional questions, that we're there to support them.

Pharmacy Times: What are some strategies to enhance medication access and adherence for patients with CLL on BTKi?

Perissinotti: Adherence in CLL is very important. Obviously, patients are not going to benefit from a therapy that they're not taking, and since these therapies are highly effective, we're going to notice when patients are not adherent. The 3 number one reasons why my patients stop their therapies prematurely would be one, toxicity, two, financial, and three, they feel great, right? They're thinking, “Well, why am I taking this medication when I have absolutely no disease symptoms, my disease is under control, or there's no detectable disease. Why am I still taking this?” So those are the 3 major reasons. So, from a toxicity perspective, it really comes back to empowering the patients with the knowledge of when they should reach out when they're having any sort of toxicity, or if they have any questions. It's also involving them in some of the medical management, right? Giving them the option. And many times, there are multiple options. We can do dose holds; we can do drug holidays. We can do dose reductions. Or we can keep the dose the same, and we can medically manage their side effect. And so ultimately, a lot of times, there is no right or wrong answer, but having the patient help you decide and help them decide as a team can really help with some adherence.

From a financial perspective, I think we're all very lucky to have incredible financial counselors within our specialty pharmacy. Having them on the case definitely helps with the financial aspects. It gets a little tricky when the care gets sent out to third parties where we might lose the patient. So,I think in those cases, even though they're not within our system, we need to keep an extra close eye on those patients to make sure that they don't fall through the cracks. And lastly, on the issue of patients feel great, which is not an issue, it's a good thing. We want our patients to feel great. It's super important and a very traditional role of the pharmacist is to educate patients, not only on the good things about their medications, but also potentially some of the misunderstandings of their medication. So, letting patients know that just because you aren't feeling symptoms from your disease anymore does not mean that the disease is gone. We need them to understand that CLL is not curable, and the disease will eventually come back, and the best way to prevent it from coming back is to continue a medication that's still working.