Chronic Lymphocytic Leukemia and BTK Inhibitors

Amy Goodrich, RN, MSN, CRNP: Hello, and thank you for joining this OncLive®events program titled, “Strategies for Managing Toxicities and Special Patient Considerations.” I’m Amy Goodrich, and I’m a nurse practitioner at The Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. I’m joined by my colleague Kirollos Hanna, PharmD, oncology pharmacy manager at M Health Fairview, Maple Grove, Minnesota; assistant professor of Pharmacy, Mayo Clinic, College of Medicine; and associate editor of JADPRO [Journal of the Advanced Practitioner in Oncology]. The treatment of CLL [chronic lymphocytic leukemia] continues to evolve, and we will discuss how to incorporate new agents and improve our use of established therapies. We hope to discuss approaches for adverse event management in patients with CLL who are receiving BTK [Bruton tyrosine kinase] inhibitors, and promote medication adherence through the continuation of therapy in patients with CLL.

I’d like to start with the data. First the Elevate Relapsed Refractory trial, this was a head-to-head phase 3 trial, which randomized over 500 previously treated CLL patients from 15 countries. This was an international study and looked at the standard dose of ibrutinib [Imbruvica] or acalabrutinib [Calquence], so patients were randomized. To cover some key exclusion criteria, patients who were on anticoagulation with Warfarin or a similar agent were excluded, and this trial accrued in 2015 to 2017. Prior BTK inhibitor [BTKi], or BCL2 [B-cell lymphoma 2] inhibitor therapy, was also prohibited; as were proton-pump inhibitors [PPIs], which we’ll discuss as it’s an issue with acalabrutinib. The primary end point was noninferiority of acalabrutinib versus ibrutinib, and if you look at the median progression-free survival, it is quite equal. The conclusion is that it was a lower rate of significant side effects when we think about with BTK inhibitors—you can see a 9% in acalabrutinib versus 16% with ibrutinib. The hypertension was higher in the ibrutinib arm as well. Two great drugs, very effective, but acalabrutinib had a better side effect profile than ibrutinib. Kirollos, do you want to talk about the ALPINE trial?

Kirollos S. Hanna, PharmD, BCPS, BCOP: Before we delve into the ALPINE trial, it’s important for us to pause and take a step back, because the landscape of CLL has been exciting for many of our patients. Just as we saw reported out of ASH [American Society of Hematology Annual Meeting] several weeks ago, utilizing these novel BTK inhibitors, not only as monotherapy, but even in combination therapy. In clinical trials, like ALPINE, comparing different types of BTK inhibitors is the goal. It’s exciting that we’re able to treat CLL for such a long period of time now. Even when we talk about our oldest kid on the block, ibrutinib, out of the RESONATE study, we have 8-year data readouts and we know that patients do well for a long period of time. We can now treat these patients like the chronic disease that it is. Often, these patients succumb to older age and other comorbidities. It’s important when we talk about BTK inhibitors, that a lot of what we learned from ASH, like some of the readouts from ALPINE, is that people on BTK inhibitors experience adverse events, and often these adverse events have a lot to do with off target kinase activity of some of these BTK inhibitors. That has provided the rationale in terms of these head-to-head comparative trials.

The ALPINE trial looked at the relapsed/refractory CLL patient population, it was not frontline treatment. They randomized patients to either receive zanubrutinib [Brukinsa] or ibrutinib. Patients who received zanubrutinib had a slightly higher overall response rate, 78.3 versus 62.5, which was deemed statistically significant, and again, this was investigator assessed. The 12-month rate of progression-free survival, also favored zanubrutinib versus ibrutinib. When we talk about patients who experienced adverse events, often these adverse events lead to treatment discontinuation. If you look at some real-world data that’s been published about ibrutinib—hypertension, arthralgias, aches and pains, neutropenias, and atrial fibrillation [A-fib] often led to discontinuation in many of these patients. When we looked at the rates of cardiac arrhythmias, A-fib and A[atrial]-flutter in ALPINE, fewer patients experienced some type of cardiac arrhythmia in the groups that received zanubrutinib versus ibrutinib, and the 2-sided P value was statistically significant in the percentages, which were 2.5% versus 10.1%.

Another notable study, which is not listed on these slides, but I think it’s important is the SEQUOIA trial, which looked at the role of zanubrutinib in the frontline CLL patient population. The comparator arm in the SEQUOIA trial had 3 cohorts, and in cohort 1, which was 1 of the main cohorts, it compared zanubrutnib versus bendamustine [Treanda]/Rituxan [rituximab]. It was chemoimmunotherapy, which again, all of us who treat patients with CLL know that chemoimmunotherapy has fallen out of favor with the advent of our BTK inhibitors. SEQUOIA was an interesting trial. In that frontline patient population where they compared BR [bendamustine, rituximab] versus zanubrutinib, in cohort 1, they excluded patients with high-risk cytogenetics, so they didn’t incorporate deletion 17p, for example. Cohort 2, incorporated those high-risk cytogenetic factors in CLL, but it wasn’t randomized, it put patients on zanubrutinib. They also had cohort 3, which looked at combination BTK with BCL2. There’s been many changes and there will continue to be changes coming in this landscape, not only around BTKs head-to-head, but various combinations. We’ll talk about what it means to have a finite treatment duration, treat patients for a certain period, and potentially be able to get them off.

Another important thing that we must highlight is the BRUIN study. When we looked at what was reported in ASH, it covered a novel BTK inhibitor. One thing that we currently know about our BTK inhibitors is how they bind to BTK. They can covalently bind to BTK and ultimately, by doing so, they are impacted by a mutation that some patients with this B-cell malignancy can have. When they have that specific mutation, many of these patients may be unable to tolerate BTK or be refractory to BTK, and that mutation is the C481 mutation. When looking at our 3 currently FDA [Food and Drug Administration] approved BTK inhibitors, all of them covalently bind to BTK, and would be impacted by C481. This novel BTK inhibitor, pirtobrutinib, is a noncovalent binder to BTK. It has the ability to noncovalently bind. There’s a lot of rationale for this approach, 1, to not be impacted by that primary mutation, that’s C481. If you have a patient with that mutation, they could be eligible to receive BTK inhibitors but this could potentially offer a BTK inhibitor that might be slightly better tolerated in patients with CLL. In this clinical trial, in that phase 1/2 BRUIN study, they looked at 300-plus patients with B-cell malignancies and BTK inhibitors used across the board, not just in CLL, and thus the rationale, and of those 323 patients, 170 of them were CLL or SLL [small lymphocytic lymphoma] patients. They looked at various dosing levels, and ultimately, they came up with the RP2D [recommended phase 2 dose] dose, which is 200 milligrams daily dosing. In those 170 patients with CLL or SLL, you can see some of the characteristics listed on the slide in the second bolded bullet point, a majority of them were older patients; the median prior lines of therapy was 3; 86% of these patients were already exposed to a BTK inhibitor, which will be a covalent binder; 90% were exposed to as an anti-CD20 monoclonal antibody, rituximab or Obinutuzumab [Gazyva]; and 82% were exposed to chemotherapy. You’ve already had patients that have had chemoimmunotherapy, a BTK inhibitor, about a third had BCL2 inhibitor, venetoclax [Venclexta], and about a fifth had a PI3K inhibitor, a heavily pretreated patient population. They also looked at high risk molecular features, [deletion] 17P, TP53 mutations, IGHV [immunoglobulin heavy chain gene] unmutated status, etc. What we saw in this clinical trial is that pirtobrutinib was extremely well tolerated. Fatigue occurred in about 1 out of 5 patients, GI [gastrointestinal] side effects in terms of diarrhea was about 70% of patients, and most common grade 3 or 4 adverse event [AE] was neutropenia. With BTK inhibitors, this is a normal AE, but with some of our covalent binders, the incidences of grade 3, 4 neutropenia, which can lead to discontinuations or dose reductions, are much higher than 10%. Hemorrhage and hypertension also had very low rates that were observed, 2% and 1% in that group of patients. In terms of the hemorrhage and hypertension, 1% of patients discontinued therapy due to some type of adverse event that’s a tolerated BTKi or a novel BTKi.

In terms of the actual efficacy, keep in mind when we discuss the efficacy of this agent, that this is a very heavily pretreated population; prior BTK exposure, chemoimmunotherapy, and BCL2 inhibition. The response rates observed in this patient population, 139 valuable patients, 63% of those patients had a response and almost 70% of them were deemed to be PRs [partial remissions]. This is exciting information to see in the CLL population, but there will be a lot more coming from these noncovalent binding BTK inhibitors. It’s something that as clinicians we must note that even after prior BTK exposure, we could see BTKs come to light that could be used after a covalent binder or could even displace our current covalent binders, based on the maturation of data. Amy, can you discuss this new approaching concept? We’ve had, VenR [venetoclax, rituximab] and VenO [venetoclax, obinutuzumab], and we’ve been doing those finite treatment durations, but we’re now combining BCL2 and BTK. What do you know about that?

Amy Goodrich, RN, MSN, CRNP: VenO is in the first line and VenR is in second line. The reason this is so attractive is, A, they’re finite but you can get people into a minimal residual, you could have no detectable circulating tumor on minimal residual disease testing; getting people into a deep remission using these venetoclax-based regimens with anti-CD20 monoclonal antibodies. This study is, along that line, this is the GLOW trial and its initial therapy. We’ve been discussing relapse/refractory trials, but this 1 is initial therapy and the patients were older, or younger if they had a high SEER scores or renal insufficiency; not the cream of the crop young folks. Patients with deletion 17p or TP53 mutations were excluded, which makes it difficult to take into general practice. The primary end point was reducing the risk of disease progression or death by 78%. This progression-free survival, and then we’re looking at MRD [minimal residual disease] parameters as well looking at bone marrow and peripheral blood. A little over 200 patients were randomized to this trial, the age was 71, which is typical for this patient population, and a slight male predominance which is also representative. At a median follow-up of 27.7 months, progression-free survival was superior for the ibrutinib/venetoclax versus chlorambucil with obinutuzumab. The median progression-free survival has not yet been reached in our 2 small molecule inhibitor regimens versus chlorambucil with obinutuzumab. This is something that we will continue watching.

The MRD, was significantly higher in the ibrutinib plus venetoclax arm, and there was little difference between bone marrow and peripheral blood. This is an important factor because as we rely more on trying to get people into a MRD undetectable state, it is important for us to understand whether we need to do bone marrows or we can send peripheral blood off. Outside of clinical trials, we’ve gotten away from doing bone marrows in our CLL patients, which they love. With ibrutinib and venetoclax, 84% of patients maintained that MRD undetectable status from the end of treatment at 3 months, and going on a year. Looking at how long patients have undetectable MRD we are waiting for these data points to mature. The CR [complete response] rate was higher for venetoclax plus ibrutinib as well, patients stayed on treatment for 13 months versus 5 months. This regimen was 3 cycles of ibrutinib and the fourth cycle of venetoclax, the 2-drug combination was given for a year. This was an intended 15-month therapy, and the chlorambucil plus obinutuzumab was intended to be 6 months; the median patient completed most of their therapy. When you consider these 2 drugs, neutropenia is common for both of them, it was the most common serious adverse event. Almost 35% incidence of neutropenia. Diarrhea was relatively manageable at 10%, and hypertension at 7%. Depending on whether this gets approved, and whether we start using this in clinical practice, there will be challenges to managing those neutrophil counts. We’re dealing with that now with these agents. Do you have other safety considerations that you’re concerned about with this combination?

Kirollos S. Hanna, PharmD, BCPS, BCOP: Outside of the standard adverse events we know with BTK inhibitors, in the combination groups, when you look at venetoclax monotherapy and BTK monotherapy, neutropenia stands out as a sore thumb. When you combine them, it’ll be something to watch out for. When looking at these patients, initiate if you have infectious prophylaxis, antifungal prophylaxis, or anything that you may need, even growth factors support in certain patients. But those with neutropenia will be profound.

We’ve seen these 3 novel BTK inhibitors continue to expand their indications and their reach into various B-cell malignancies, but it’s important for us to discuss some differences in terms of the pharmacodynamics, pharmacokinetics, even these therapeutics, because there are variabilities there. When we look at CLL specifically, we have 2 FDA approved ones, acala [acalabrutinib] and ibrutinib. In other B-cell malignancies, this information would be relevant, like mantle cell lymphomas, for example. All 3 are FDA approved and when looking at the CLL/SLL NCCN [National Comprehensive Cancer Network] guidelines, they mention zanubrutinib. You could potentially use zanubrutinib based on everything that we’ve learned and the guidelines support that, although it doesn’t yet have an FDA approval. These therapies have some challenges there. There are some dosing differences and considerations. For example, ibrutinib, comes as a capsule and as a tablet. If we’re using the tablet formulation, it’s 1 pill once a day. I don’t think you can get more simple than that in terms of adherence, compliance, and monitoring your patients in terms of those interventions. It may become challenging if you must dose reduce a patient due to an adverse event. If they’re on the 420 milligrams, standard CLL dose, dose reducing a patient is challenging. I won’t tell them to take three-fourths of their pill. Now there are trade-in programs and these kinds of things, but it’s something we must be cognizant of for some of our patients.

The capsules are available too, but sometimes economically we may be unable to make that 420 mg dose. It may cost you more as a system to go the capsule route, but also at the same time, you must tell your patient to take 3 capsules instead of 1 tablet. There may be a challenge in terms of pill burden. These medications can be taken with or without food. Many people lack an understanding of how food can impact the absorption of these medications. High fat, high caloric meals, can increase the AUC [area under the curve] of ibrutinib, so it’s important to keep that in mind if you are seeing increased adverse events in your patient; have that conversation with them. Acalabrutinib is the opposite, high fat, high caloric meals, can reduce the absorption. For acalabrutinib, 1 big issue that we’ve been dealing with is if your patient is commonly taking an acid suppressant. That’s why high fat, high caloric meals, can to some extent, neutralize the acidity of the GI tract, and why there’s a decreased absorption of acala [acalabrutinib]. One thing that I struggle with in health care in general, is that it’s so easy for our patients to walk into any convenience store, even a gas station, and pick up a PPI. As health care providers we may not know that a patient is on a PPI, and you could have this contraindication technically with this asset suppressant, and then you don’t see the outcomes that you potentially want to see from the drug.

Acalabrutunib only comes as a single capsule size, and it’s dosed twice a day so it will be a consideration for adherence and compliance. Will my patient be able to adhere to taking their medication twice a day? Both medications, acala [acalbrutinib], ibrutinib, and zanubrutinib, are impacted by CYP3A4 metabolism. If you have inhibitors or inducers you must intervene for your patient. Especially for moderate or strong CYP3A4 inhibitors and inducers across the board. We want to avoid those. Zanubrutinib is not FDA approved, but since we’ve been talking about it and it’s being studied in CLL, it’s an 80-milligram capsule and has a flexible dosing schedule. You can give it once a day or twice a day, it’s either 160 or 320 milligram once a day, and it’s not impacted by GI acidity or any high fat, high caloric meals. Again, all three of these drugs can be taken without food. Zanubrutinib would also be impacted by the CYP3A and 3A4 pathways. One exciting thing about acalabrutinib is that it is getting reformulated. I think our pharma partners have heard enough about this potential interaction, so it will be reformulated. It’s a new maleate salt and this tablet will no longer require an acidic environment for proper absorption. Generally, that’s as big of a concern in patients with acalabrutinib moving forward. Many exciting things in this space. Amy, is there anything else to add in terms of these medications from a pharmacodynamic or kinetic standpoint before we delve further into the adverse event differences?

Amy Goodrich, RN, MSN, CRNP: Yes. I have spoken to more primary care providers and cardiologists than I ever have in my entire career when people are on CYP3A pathway drugs. They are more than happy to switch patients or wiggle things around and they’re very happy to collaborate with us. Patients who we would have chosen 1 of these BTK inhibitors versus another, or not at all for some of these folks, or with significant dose reductions, we’ve been able to successfully treat them by working with our other specialty colleagues to optimize those concomitant medications. I always tell patients that when we’re getting ready to start, to empty their medicine cabinet and bring me everything they take. It’s amazing all the nonprescription bottles that they bring. Maybe that’s over the top, but I catch things that people are taking that they never would have said that they were on.

Kirollos S. Hanna, PharmD, BCPS, BCOP: I couldn’t agree more. We’ve run into numerous issues and we don’t know about it until that patient comes in with an adverse event.

This transcript has been edited for clarity.