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

Pharmacy Times® interviewed Anthony Perissinotti, PharmD, BCOP, a clinical pharmacist specialist in hematology at Michigan Medicine, 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 toward 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 (BCL2) inhibitors. High-risk patients with specific mutations, such as TP53, still experience poorer outcomes than others. The use of minimal residual disease as a possible end point or marker for guiding therapy is also under investigation. Additionally, despite advancements, CLL remains incurable, often requiring lifelong therapy.

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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 a strong focus on quality of life, with emerging strategies aimed at providing treatment breaks to reduce long-term adverse effects (AEs). Combinations such as venetoclax (Venclexta; AbbVie) with obinutuzumab (Gazyva; Genentech) are becoming standard, and fixed-duration therapies are being explored.

Pharmacists play a critical role in CLL care, moving beyond traditional patient education to advise 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 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 free of disease. 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 treatment 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, [have] been able to see the metamorphosis away from chemotherapy toward 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 [who] are on several medications; it can be pretty challenging to treat these patients, even with our very well-tolerated BTK inhibitors and BCL2 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 [is] patients with high-risk molecular or cytogenetic abnormality. So, a patient with a [TP53] mutation, although these patients now do tremendously better compared with chemotherapy, they still don’t do as well as patients [who] don’t have a [TP53] 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 [is that] patients [who] relapse after our BTK inhibitors and BCL2 inhibitors can be particularly challenging. Lastly, another unmet need is we still can’t cure CLL. Despite all the advancements, despite the metamorphosis of the treatments of CLL, we still have 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 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, [which] are either our BTK inhibitors or a venetoclax-based regimen with obinutuzumab or rituximab [Rituxan; Genentech]. And we’ve also started to move away from even using our first-generation BTK inhibitor, ibrutinib [Imbruvica; Pharmacyclics, Janssen Biotech], in favor [of] our second-generation BTK inhibitors such as zanubrutinib and acalabrutinib. I’ve also seen more trends toward 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 [well] as the general population….We’ve been really focusing on how [we can] not only reduce disease symptoms but how [we can] help patients live a life where they’re not having symptoms from their therapy. Other trends [include] how [we are] 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. 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, [we will see] our second generations added to venetoclax. Hopefully, we can see as durable, if not more durable, remissions for those patients.

Pharmacy Times: What are key takeaways from real-world patient cases discussed during the Clinical Forum relating to recent guideline updates and new clinical trial data on BTK inhibitors?

Perissinotti: The major takeaway 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 [readers is that] none of us are also using ibrutinib as our first-line treatment. And again, it’s because of the favorable toxicity profile of our second-generation BTK inhibitors, whether that’s acalabrutinib, and that’s based on the [phase 3] ELEVATE-RR relapse/refractory study [NCT02477696], or zanubrutinib, which was based on the [phase 3] ALPINE study [NCT03734016]. Interestingly, ALPINE may show superiority not only in the toxicity profile but also potentially in the efficacy. Many of our cases that we discussed [involved that] we’re now going to be picking between either a second-generation BTK inhibitor or a fixed-duration treatment with BCL2 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 obinutuzumab, 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 [prefer] to have frequent lab draws, [having] to come into the hospital. For that reason, many of our patients [about whom] many of us would think, “Oh, we should put them on fixed-duration therapy,” they end up on BTK inhibitors. But, I think we all agreed that we have excellent options in the frontline setting. In the second line, we [discussed] some cases. “Well, how do you treat a patient [who] progressed after BTK inhibitor?” And we all agreed that we would use venetoclax with either obinutuzumab or rituximab. And then, if a patient started with venetoclax with obinutuzumab, we discussed 2 potential options. One is [that] 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—we would consider re-treating them. We would sit down with the patient and talk about the pros and cons. Lastly, we discussed some cases that were relapse or refractory after all those therapies that I discussed, and what options do our patients have now? Some emerging options are pirtobrutinib (Jaypirca; Lilly), a reversible BTK inhibitor. It’s much more selective for BTK, and then [we] also [discussed] chimeric antigen receptor therapy.

Pharmacy Times: What is the role of pharmacists in caring for patients with CLL on BTK inhibitors?

Perissinotti: The role of pharmacists in CLL is really advancing, and it’s quite diverse. As you all know, there are many different types of pharmacists, and [each] plays an equally important role. So, we have pharmacists [who] are embedded in clinics, [who] are helping with treatment decisions, helping with adverse effect management, and 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 [in] understanding the advancing role [of] 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 health care professionals, our physicians, educating them on the newest data that [have] 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 [they] are empowered to make some decisions when they are called, when patients have questions.

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

Perissinotti: I believe that shared decision-making is by far the most important best practice we can have in CLL. We have multiple great options. You could 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 close to a normal life. That 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? 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 in 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 part of their treatment decisions, to be a part of even adverse effect management decisions. When you have a patient [who] is incredibly involved, they’re going to be more adherent to their therapy because, ultimately, these are all their decisions, not just us dictating their care. Another best practice is early intervention. So, these therapies can still cause some toxicities, and we want to identify them early. There are a couple of ways to do this. One is, again, educating the patient so that they are empowered 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 got access to their therapy. But then we’re checking every 2 weeks, monthly, every 3 months thereafter, to ensure patients are still tolerating their medications. And if they have any additional questions, we’re there to support them.

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

Perissinotti: Adherence in CLL is important. Obviously, patients are not going to benefit from a therapy that they’re not taking, and [because] these therapies are highly effective, we’re going to notice when patients are not adherent. The 3 [top] reasons why my patients stop their therapies prematurely would be toxicity, financial, and 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 toxicity or if they have any questions. It’s also involving them in some of the medical management, 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 medically manage their [adverse] 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 lucky to have incredible financial counselors within our specialty pharmacy. Having them on the case helps with the financial aspects. It gets 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 a close eye on those patients to make sure that they don’t fall through the cracks. And lastly, on the issue of patients feeling 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.