Taylor M. Weis, PharmD, BCOP

To conclude, Dr Weis, I think our attendees or audience would appreciate maybe 1 or 2 points, in terms of advice that we have for clinicians in the community on how we can optimize success of treatment. Please, I want you to lead us with this, and I think either of us could potentially provide a couple of points of advice for our attendees.

 Of course, one of the biggest is involving the patient in all your decisions. Make sure they are an active participant. Make sure they are aware of the pros and cons of each treatment decision, so they can make a good decision with you as the expert on the data. The second important thing as a pharmacist is education, education, education. Inform the patients of what they can expect with these therapies. Often the [adverse] effects that they may see, for example, with BTK [Bruton tyrosine kinase] inhibitors, ibrutinib specifically, may include diarrhea within the first 2 weeks. Just by telling them that this will get better with time, and how to manage it home, could significantly decrease the rate of patients who are self-discontinuing at home due to toxicities. The other thing is with these novel agents, it’s very different than our chemoimmunotherapy-based approaches in terms of monitoring adherence. We’re not at home watching the patient, making sure they take their oral medication each day, and so be sure to check in on the patient. Ask them what’s bothering them. Ask them why they aren’t taking their medication. Ask them if they are refilling their medication. Just by asking those questions, you can get a lot of more information.

Excellent points. The only couple of things I would add to that, on top of education, ensuring that pharmacists play a role here in terms of evaluating drug-drug interactions. They are critical in this patient population whether, it’s CYP3A inhibition with your BTK inhibitors, CYP3A inhibition during their BCL2 ramp-up phase and while patients are on therapy. Try to evaluate that. We talked about the ease of somebody walking in and getting a PPI [proton pump inhibitor] and if they are on acalabrutinib, how that could be problematic. Ensure that patients understand what the expectations are. If you’re going the BCL2 anti-CD20 route, look at that risk assessment in terms of TLS [tumor lysis syndrome], especially during the ramp-up. Know who’s responsible for getting the laboratory tests done. Make sure patients understand the lab schedule, because sometimes within 1 day, the patients could be coming to the clinic, if it’s not inpatient, to get 1 or 2 labs drawn while they are getting ramped up. That’s going to be very important for your patients. Then lastly,stress the importance of adherence and compliance on therapy. Out of some of the trials we discussed today, such as RESONATE-2, there have been sub-analyses that looked at dose intensity, and those who were nonadherent or noncompliant to therapy, had a worse PFS [progression-free survival], and there was a trend toward decreased overall survival. Thus, it’s very important that there are strategies in place to ensure that patients are adherent and compliant with therapy and to intervene when you need to as a health care provider.

With that, I want to thank my colleague, Dr Weis. I think this discussion has been extremely informative. I know I personally have learned a lot. To our viewing audience, we hope you found this 

insights discussion to be rich and informative. Thank you so much for the opportunity and for listening to us today.

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Experts share final thoughts and advice for clinicians in the community to help optimize treatment success in CLL.

Advice for Optimizing Treatment Success in CLL

What does the pipeline of CLL [chronic lymphocytic leukemia] therapies look like? We’ve seen this significant shift over the past several years, and I think there are a couple of notable trials we should highlight, or a couple of notable concepts, that are up and coming. Certainly, MRD [minimal residual disease] negativity is becoming a new favorable end point in the majority of clinical trials we’re seeing. Some of these include the CAPTIVATE study, for example. This is a phase 2 study that’s looking at a fixed-duration frontline treatment with BTK [Bruton tyrosine kinase] inhibition as well as BCL2, so it’s looking at ibrutinib in combination with venetoclax, and they are looking at various strategies. Patients will get a couple of months of ibrutinib, they will then be on venetoclax for a couple of months. Depending on MRD negativity, they will either been on placebo or be on ibrutinib to evaluate all these various schemas and approaches. One notable thing with a fixed duration, CR [complete response] rates were about 55% in some early data we saw in this phase 2 trial. There were only 80-something patients or so who were evaluated in this,but this is something notable that is, again, up and coming. It’s taking out the CD20 [monoclonal antibody] and putting on the BTK inhibition because we know how effective that is.

They’re also looking at various triplet regimens. There is something called the AVO regimen, which is looking at acalabrutinib, venetoclax, and obinutuzumab. This is another phase 2 trial. There were some results presented at ASH [American Society of Hematology annual meeting] in 2020, and patients had about 78% bone marrow MRD negativity, which is very impressive. MRD negativity in the peripheral blood versus the bone marrow or in lymph nodes, there are some differences. Again, these are very early data, and it’s going to be exciting for what we see; you’re combining here 3 primary mechanisms of action that have been big drivers in this disease state in general. Dr Weis, you already mentioned this, but there are some novel drugs too. The 3 BTK inhibitors that we have on the market, whether for CLL or not CLL, are all irreversible inhibitors of BTK. One thing that’s in the pipeline, up and coming, is reversible BTK inhibition. Thus, could we potentially offer a reversible drug to not bind to BTK as tightly, as well as other off-target kinases and maybe offer a better safety profile in terms of those drugs? Other novel therapies too include an anti-CD20 monoclonal antibody called ublituximab. There’s umbralisib, which is a novel PI3K inhibitor. All of these therapies are looking at different combinations in treatment naive and in the relapsed/refractory CLL population. Very quickly, Dr. Weis, are there any other notable ongoing trials you guys have going on in New York, or anything that you care to mention in this space?

 Definitely. I’m really excited to see what comes of these new combinations up front. Also, it will be interesting to see what do the CD20 monoclonal antibodies add to the ibrutinib and plus venetoclax data that we saw presented at ASCO [American Society of Clinical Oncology] and EHA [European Hematology Association]. It will be exciting to learn, does this deeper remission correlate to longer, more durable remissions? That’s something that will be very important. You alluded to this as well, but we have several BTK inhibitors on the market. Two of them are FDA approved for CLL. One of them, zanubrutinib, is showing promising data compared to ibrutinib, with potentially even longer progression-free survival and improved tolerability. Thus, these are all exciting things too. What will happen if we can combine venetoclax with zanubrutinib and potentially more tolerable agents? Hence, these are all things that are exciting, and we look forward to the results. The reversible BTK inhibitor pirtobrutinib is having data presented in both the CLL population and in patients who have a very unfavorable progression of their CLL called Richter transform disease, for which there is no current standard of care. It’s looking like pirtobrutinib has activity in these patients, even patients who have already progressed on prior BTK inhibitors. What we know from our other data is that patients who progress on BTK inhibitors, say a patient on ibrutinib who developed resistance and progressed, there’s really no role for switching them to acalabrutinib. However, pirtobrutinib may be another line of therapy for these patients. For patients who have resistance mutations, including one of the most common resistance points, the cysteine 841 moiety, which often is a mechanism of resistance for covalent BTK inhibitors, if we can overcome this, we may be able to provide more lines of therapies for these patients.

 Excellent. It’s an exciting pipeline, and I just hope that [it doesn’t get more complex] when we have the new thing on the block, and we don’t have novel data from what we’re currently looking at, and we don’t know what to do. But it’s certainly an exciting time for patients.

Emerging combination therapies and novel agents being studied as initial therapy for CLL are discussed.

Emerging Therapies in CLL

Dr Weis, I would love to hear from you about when you’re picking therapy. We talked a little about the ambiguity of BTK [Bruton tyrosine kinase inhibitor] versus BTK plus anti-CD20 [monoclonal antibody]. Now, what about BTK versus BCL2? How are you treating MRD [minimal residual disease] negativity? What do you see in the literature and in your clinical practice in terms of picking one regimen over the other? I would love to see what you guys are doing up there in New York.

 Yes, clearly, there are no randomized controlled trials in this area. The comparator arm in all these BTK inhibitor, randomized clinical trials, the venetoclax and obinutuzumab- based trials, the control arm is often a chemoimmunotherapy approach, with often chlorambucil. We don’t know exactly head-to-head which regimen is better than the other in terms of efficacy. What we can do is look at patients’ specific factors, [adverse] effect profile, the data we have, and try a cross-trial comparison, however flawed that might be, to the best of our abilities. We go through pros and cons of each approach. In terms of BTK inhibitor-based therapies, the biggest upside I think is convenience for a lot of patients. It’s often scary to get a cancer diagnosis, and a lot of times just the relief you hear when you tell a patient there’s an oral medication that they can take once or twice a day; it can be a lot for a patient. Lots of times we have patients who live very far away. It’s nice that they don’t have to come to the clinic for monitoring as frequently. They don’t have to get infusions and infusion monitoring, so convenience really is a pro there. We do have the longest follow-up with these BTK inhibitor studies, and while we are getting longer follow-up from venetoclax and obinutuzumab in the frontline setting, we still do see that after about a year, after the fixed duration of treatment has ended, we are seeing progression events. It does seem that potentially patients with high-risk features, like deletion 17p or 

 mutations, may be having progression events more so than the rest of the population. So this will be something that we’ll need to monitor with other longer follow-up studies.

We also have some information about when a patient progresses on a BTK inhibitor. We have some retrospective studies showing that venetoclax-based approaches can have induced response rates in these patients, so we know they can be salvaged with other novel agents. Also, you mentioned before that tumor lysis risk can be concerning for some patients, and although we follow the ramp-up, we do weekly ramp-ups for 5 dose levels. If a patient is high risk for tumor lysis, we admit them for monitoring with fluids and allopurinol. Thus, there are a lot of things we can do to mitigate this, but we sometimes have patients who have stage 3 CKD [chronic kidney disease] or severe renal dysfunction that could be very dangerous, the electrolyte shifts from this regimen. In that case, we often do BTK inhibitors. There are some cons though, cardiovascular [adverse] effects, bleeding [adverse] effects; these are older patients with a lot of comorbidities. That’s something we consider as well.

 In terms of BCL2 inhibitor-based regimens, I think for a lot of our younger patients, it’s very appealing. Some of them think of it as a light at the end of the tunnel. It’s not a medication that they’re going to have to take indefinitely, as long as it’s benefiting them. They have an end point, and a lot of times just knowing that in 12 months they could potentially be treatment free can be very motivating for these patients. Not to mention cost savings if they have a durable response and not having to stay on a very expensive oral medication indefinitely.

I think that as we continue to see data maturation and further end points, and hopefully as we reach this overall survival difference that these potentially have, this could change the lay of this entire landscape in terms of cost effectiveness, because it’s a finite duration, as well improving overall survival. That could be a great thing.

Experts discuss factors and approaches to consider if choosing between a BTKi-based and BCL2i-based regimen for frontline therapy in CLL.

BTKi-Based Vs BCL2i-Based Regimens in CLL 

With all these combinations, it seems like the data with BTK [Bruton tyrosine kinase] combining with an anti-CD20 are somewhat iffy right now, and that’s why it’s usually a plus or minus. Now, transitioning and going to the BCL2 [inhibitor] route and combining venetoclax, which is our only FDA-approved BCL2, with other anti-CD20 monoclonal antibodies. Thus, I think there are 2 notable trials here. There’s CLL14 and MURANO, and these are really exciting trials because one was looking at treatment-naive patients with CLL and one was looking at the relapsed/ refractory patient population. One combines venetoclax with obinutuzumab, and one combines venetoclax with rituximab. It’s really exciting because the approach to these studies is around this whole MRD [minimal residual disease] negativity concept, or undetectable minimal residual disease, and if we can get patients to that, or even if we don’t, could we treat them for a finite period, 1 year, 2 years, and then get them off a therapy? We know that with BTK inhibitors, these patients are on therapy indefinitely until progression, or unacceptable toxicity, or death. Ultimately, one notable thing we saw that was published from CLL14 and MURANO, as the years go on, we’re seeing more and more positive end points showing that those who reach MRD negativity, or even those in the entire intent-to-treat population, it still favored targeting BCL2 in combination with an anti-CD20, whether it was obinutuzumab or rituximab. I believe from CLL14 now, we have 4-year data, and the PFS [progression-free survival] rate there was 74% favoring the venetoclax, obinutuzumab arm, some call it Ven-G for the brand name [Gazyva], versus chlorambucil, obinutuzumab.

Now, again, this is going to go back to my argument with BTK and the RESONATE trial, for example. It was ibrutinib versus chlorambucil. Here we have venetoclax in combination with obinutuzumab versus chlorambucil and obinutuzumab, which at the time, could have been a treatment option, but chemoimmunotherapy is not really how we treat most of our patients now. What does this mean in terms of efficacy outcomes for our patients? It’s really exciting, and very important that as we continue to see these long-term outcomes, 4, 5, 6 years, that we see the sustained PFS or even OS [overall survival] benefit. It’s important to note that from CLL14, for example, we have not yet seen a statistically significant overall survival benefit, so in terms of the overall survival, there’s no difference. When comparing Ven-O [venetoclax, obinutuzumab] versus chlorambucil [and obinutuzumab], the 4-year overall survival is still about 85% versus 83%. Thus, there has not yet been enough death events to deem one group more significant than the other. But this will come with time. I love when you look at the Kaplan-Meier curve between these 2, and I encourage all of our participants to look at it, there is no crossing by any means between the 2 regimens in venetoclax-O [obinutuzumab] or venetoclax-R [rituximab] versus the comparator regimens. It’s very notable, especially these trials, in front line they only treated patients for 1 year then got them off of therapy. Treatment-free. The other trial looked at patients on 2 years of therapy, and then are seeing these benefits sustained throughout.

In terms of safety events, I think the biggest thing to note is going to be managing tumor lysis. With BCL2 inhibition, tumor lysis is always going to be a toxicity of interest, especially in the CLL population. Some patients, I think, at presentation could have bulky disease, so it’s really important for us to risk stratify these patients as low, moderate, or high risk, and based on the risk stratification, we have to provide antihyperuricemics, potentially with something like allopurinol, to ensure that we are keeping that uric acid level. Also, evaluating their CMPs [comprehensive metabolic panels], for those high-risk patients, you might need to hospitalize them, unless you have the infrastructure to monitor them very closely in the outpatient setting. Aggressive hydration, aggressive fluids. All these things are what we are going to stress to our patients, especially during the ramp-up of venetoclax.

One notable thing we have to talk about though in terms of safety, both in CLL14 and MURANO, if you follow the debulking algorithm that they have, one started venetoclax first and then the anti-CD20, and the other started the anti-CD20 first then put venetoclax on board. But in both, it was ultimately a 5-week ramp-up of venetoclax, and both of these clinical trials had 0% incidence of clinical TLS [tumor lysis syndrome]. Now, there was some laboratory-reported TLS, which is not an oncologic emergency. But if you follow the ramp-up, risk stratify your patient, do so accordingly, it is very uncommon that you’re going to end up having clinical TLS, which would require hospitalization, aggressive intervention, etc. Thus, it’s very exciting that now with CLL we are beginning to see these finite treatment durations or intervals or approaches. Again, we’re dealing with a completely different type of regimen, different [adverse] effect profiles. I think with both BTKs and BCL2s you’re going to deal with neutropenia across the board, and you’re going to have to evaluate your patient and support your patient accordingly. But these are all going to be important things we have to keep in mind.

In terms of MRD negativity, this is a new topic of interest that I think many of us don’t know what to do with yet. We certainly know that if we can reach MRD negativity—aka undetectable minimal residual disease, it’s abbreviated differently throughout the literature—it’s demonstrating that patients are doing better, but we don’t yet have a home run outcome in terms of MRD negativity. The way I think about it right now, it’s kind of like PD-L1 expression; PD-L1 expression is not always about PD-L1 positive, nor is it about having totally MRD negative. There are a lot of factors, but I think most of the clinical trials have shown that if you can reach MRD negativity, we can get patients off of therapy. But you can still get your patient off of therapy, even if they are MRD positive. There are all these different things, because you can still have a CR, a complete response, but be MRD positive, and vice versa. You can be MRD negative, but not have a CR.

Kirollos S. Hanna, PharmD, BCPS, BCOP, discusses data on a BCL2 inhibitor in combination with anti-CD20 monoclonal antibodies in the treatment of CLL.

BCL2 Inhibitor in Combination With Anti-CD20 mAb for CLL

When you’re picking BTK [Bruton tyrosine kinase] therapies, what has your experience been in terms of picking BTK monotherapy or combining it with an anti-CD20 [monoclonal antibody]? We know there are some trials looking at this, such as the Alliance trial, E1912, Elevate TN trial, whether they’re looking at ibrutinib or acalabrutinib, plus or minus various anti-CD20s, such as rituximab or obinutuzumab. What have we been seeing from there, and is there a certain approach we need to take when we’re selecting treatment, monotherapy or combination?

 Great question, and as I mentioned before, the NCCN [National Comprehensive Cancer Network] guidelines interestingly stick with ibrutinib monotherapy as a recommended frontline therapy, or acalabrutinib plus or minus obinutuzumab, and this can be confusing for some providers and patients. Why do we need a CD20 antibody with acalabrutinib and not with ibrutinib? The reason it is this way in the guidelines is based upon randomized controlled trials undertaken that have compared ibrutinib monotherapy to ibrutinib plus rituximab. One of them was a phase 3 study by Jennifer Woyach, [MD,] and colleagues that was published in the 

 in 2018. They compared ibrutinib alone, ibrutinib and plus rituximab versus bendamustine and rituximab as first-line treatment in an older patient population, and they didn’t show that the combination of ibrutinib with rituximab had any benefit in terms of response rate, progression-free survival, or overall survival versus ibrutinib monotherapy.

Unfortunately, we don’t have any randomized controlled trials comparing ibrutinib alone versus ibrutinib plus obinutuzumab, which is a more potent second-generation CD20 antibody. Thus, at this time, we really don’t have any data to show that CD20 antibodies may have any benefit, with the exception of a recent study. The phase 3 GENUINE study that was published compared ibrutinib monotherapy to ibrutinib plus ublituximab. This is an investigational next-generation CD20 monoclonal antibody, and this was in a relapsed/refractory patient population with high-risk features, where they did report preliminary results with increased overall response rates. However, for this population overall response rate is not really a good surrogate end point. Unfortunately, due to slow accrual they weren’t able to look at progression-free survival as a primary end point, and that’s why we don’t have this FDA-approved combination at this time.

However, for acalabrutinib in the phase 3 ELEVATE-TN study, we did see in a 4-year follow-up that the combination of acalabrutinib plus obinutuzumab had a small but significant increase in progression-free survival with the combination. We saw 87% 4-year progression-free survival with the combination versus 78% alone, suggesting that it may provide a deeper remission for some patients. This comes up as a question in the clinic, when we’re starting a patient on acalabrutinib, do we need to add obinutuzumab? Sometimes we favor this in a younger patient with high-risk features for whom we want to have a deep long remission, although with the follow-up data at this time, we don’t know if this correlates with any long-term benefits.

Taylor M. Weis, PharmD, BCOP, discusses data on a BTK inhibitor in combination with anti-CD20 monoclonal antibodies in the treatment of CLL. 

BTK Inhibitor in Combination With Anti-CD20 mAb for CLL

One thing I really like about this specific space in terms of patients is that this is not like immunotherapy, where we have indications across the board for every immunotherapy and we don’t have any head-to-head trials. It’s really exciting to see that we’re beginning to see acalabrutinib versus ibrutinib trials, and zanubrutinib versus the others, to show us if there is one superior BTK [Bruton tyrosine kinase] over another. But it’s also showing us that these BTK inhibitors, in terms of efficacy, share a very similar efficacy profile. What we saw out of ASCO [American Society of Clinical Oncology annual meeting] as well, were final results from a head-to-head acalabrutinib versus ibrutinib trial in previously treated patients with CLL [chronic lymphocytic leukemia]. They looked at patients with deletion 17p. They randomized patients based off of numerous things, and in terms of clinical efficacy, this was a noninferiority trial, and acalabrutinib was deemed noninferior to ibrutinib, with both having a median PFS [progression-free survival] of about 38 months.

In terms of safety, going back to that point, acalabrutinib was actually superior to ibrutinib in all-grade atrial fibrillation, although the [the rates] were very low. Afib [atrial fibrillation] is always a toxicity of interest, is it a contraindication, is it not, what do we do? It was only 9% for acalabrutinib versus about 16% for ibrutinib. Certainly, I think with our patients who might come into the clinic with cardiomyopathy, atrial fibrillation, maybe we should have cardiology [colleagues] on board. Have them do some baseline assessment, clear the patient, and then we can probably treat them safely while on therapy. Most AEs [adverse events] in terms of hypertension, arthralgias, diarrhea, these are I think what we tend to see more in clinic. From this noninferiority trial, they were much lower in the acalabrutinib group versus ibrutinib. Some examples, for hypertension, it was about 9% versus 23% favoring acalabrutinib. Also, arthralgias were about 16% versus 23%, and diarrhea was also lower, about 35% versus 46%. Again, it’s very exciting to see this. AEs that led to a discontinuation were about only 15% on acalabrutinib versus 21% on ibrutinib. It’s very exciting that we are seeing similar efficacy, but also seeing a trend toward maybe one possibly being a better option for your more frail patients with comorbidities, etc. Go ahead Dr Weis, do you have something?

 I wanted to add some of my experience with treating patients with cardiovascular disease as well. Afib, as you know, comes up a lot, and in a lot of these real-world studies, we’re seeing that of the cardiovascular toxicities, atrial fibrillation seemed to be the most troublesome and caused the most rates of discontinuation. As a result, especially if the patient has a prior history of atrial fibrillation, has a lot of risk factors for developing atrial fibrillation, we try to get cardiology on board and make sure we’re managing with rate and rhythm control strategies that can be optimized with BTK inhibitors. What we’re also seeing is that when a patient comes in, they may be on a rate control strategy, such as diltiazem or verapamil, which also interact with ibrutinib, and so we’re often switching them to preferred β-blockers so the patient can tolerate it up front. Then, obviously if a patient is on ibrutinib and develops atrial fibrillation, we try to use these strategies from the get-go.

Another big thing that comes up is that based on a patient’s risk factors for stroke with atrial fibrillation, if they have enough risk factors, they may be candidates for anticoagulation. Bleeding is one of the notorious BTK inhibitor [adverse] effects that can be very scary for patients and also for providers. What we saw in the initial studies with BTK inhibitors is that patients initially who were treated with BTK inhibitors and a vitamin K antagonist, like warfarin, had very high rates of major bleeding and some fatal subdural hematomas in the studies. For this reason, all the major BTK inhibitor randomized-controlled trials excluded these patients altogether. Thus, as a clinician I try to at all cost to keep the patient from being on a concomitant warfarin. If the patient comes in warfarin for a good indication, we try to touch base with their cardiologist to see if we can get them switched to an alternative agent that may be safer.

As oncologists and oncology pharmacists, we’re getting a lot more comfortable with using the DOACs [direct oral anticoagulants] in the cancer population, and we have seen that patients can tolerate these, apixaban or rivaroxaban, with BTK inhibitors without significantly increased risk of bleeding. The one thing to note is a lot of these patients may have minor bleeding. About 50% of patients will have some minor bleeding or bruising, and it doesn’t necessarily mean that they are at higher risk of major bleeding, the more severe, dangerous bleeding. It’s important to educate the patient on that as well.

Experts discuss the results of a head-to-head trial of ibrutinib versus acalabrutinib in CLL and the cardiovascular toxicity associated with BTK inhibitors.

Taylor M. Weis, PharmD, BCOP

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