Optimizing BTK Inhibitor Therapy in CLL: Updates and Strategies for Oncology Pharmacists

[00:18:37]

BTK Inhibitor Approvals and Current Status in CLL/SLL

Okay, let us get started. We have a lot to cover today, so I will talk a little bit fast. But we do have several BTK inhibitors that are approved for treatment of both upfront and relapsed/refractory CLL.

On the left of the screen, you will see the first class of drugs we have. We call these irreversible covalent BTK inhibitors, in which we have 3 agents, the first-generation ibrutinib and second-generation acalabrutinib and zanubrutinib. All 3 are approved in both the upfront and relapsed/refractory setting.

On the right-hand of the screen, you will see the first-in-class approval of pirtobrutinib, which is a reversible non-covalent BTK inhibitor and currently holds FDA approval in the relapse setting for CLL.

[00:19:20]

Covalent vs Noncovalent BTK Inhibitors

Just to level set, so BTK, Bruton tyrosine kinase is an intracellular protein that plays a very important role in B-cell receptor signaling growth differentiation and survival. Shutting down BTK with small molecule inhibitors is a really effective way of killing malignant B cells, such as in CLL.

Ibrutinib, acalabrutinib, and zanubrutinib, which are our covalent BTK inhibitors, bind to the C481 residue of the BTK and block the ATP binding site. That is how they shut down BTK.

Our non-covalent BTK inhibitors, so the FDA approved one, again, pirtobrutinib as well as other that are being studied in the pipeline, they bind to BTK but not in that C481 residue. So potentially carry benefit in patients who develop mutations in that C481 residue when treated with these first and second-generation covalent BTK inhibitors.

The other major difference within non-covalent BTK inhibitors is they have much longer half-lives than the covalent BTK inhibitors, which allows them to retain some efficacy.

[00:20:30]

Kinase Selectivity of Irreversible Covalent BTK Inhibitors

When we look at binding and efficacy of the covalent BTK inhibitors, you could say, well, why do we need so many on the market? The reason why is because first-generation ibrutinib was really potent at binding to BTK, but had a lot of off target effects and potent binding to off-target kinases, which led to less than desirable side effects. These were mainly cardiac and bleeding.

Acalabrutinib and zanubrutinib were designed not necessarily to improve upon efficacy of ibrutinib, but to really improve upon the toxicity profiles. You can see they are also quite potent against BTK, but have a lot less off-target binding.

[00:21:11]

Selectivity of Noncovalent BTK Inhibitors

Pirtorutinib, again, the first non-covalent BTK inhibitor is very similar to the second-generation BTK inhibitors in how potent it binds to BTK, as well as having less of that off-target inhibition. Again, potentially an improvement in the side effect profile.

[00:21:28]

cBTKi Monotherapy for the Management of CLL

First-Generation cBTKi: First line for CLL

Looking at the use of these covalent BTK inhibitors for first-line or even relapse treatment of CLL, ibrutinib really paved the way for the BTK inhibitors. There were 3 very large prospective randomized trials in which ibrutinib was studied in younger and older patients compared against our standard at the time, which was traditional chemotherapy, essentially demonstrating that ibrutinib significantly prolonged progression-free survival compared to chemotherapy, as well as overall survival in one of these trials.

This really paved the way for covalent BTK inhibitors to be used as monotherapy for first-line treatment of CLL. Again, ibrutinib was less than desirable because of its side effect profile, mainly atrial fibrillation, bleeding, bruising and hypertension, which led to a lot of toxicity and patients having to stop therapy.

[00:22:23]

Next-Generation cBTK Inhibitors: Fewer AEs and Superior to CIT

That leads us into looking at our second-generation BTK inhibitors, acalabrutinib and zanubrutinib, which both, again not surprisingly demonstrated significant improvements in progression-free survival in the front-line setting when compared to traditional chemotherapy.

When we cross trial compared these studies to the trials of ibrutinib, we thought we saw a decrease in those toxicities that we did not like with ibrutinib such as AFib and hypertension. But we did not really have any head-to-head comparison of the BTK inhibitors.

[00:22:56]

ELEVATE-RR: Phase III Trial of Acalabrutinib vs Ibrutinib in R/R CLL

In the relapsed CLL setting, we finally though got that head-to-head comparison. This was the ELEVATE-RR trial. It was a phase III trial in which patients with relapsed CLL who had not seen a BTK inhibitor prior were randomized to either acalabrutinib or ibrutinib. Not surprisingly, acalabrutinib was seen to be non-inferior to ibrutinib in terms of efficacy, which is what we expected.

[00:23:20]

ELEVATE-RR: Tolerability of Ibrutinib vs Acalabrutinib

When we look at the toxicity profile, we do see a significant decrease in the incidence of atrial fibrillation. We see a decrease in the incidence of hypertension with acalabrutinib, and we see a numeric decrease in the risk of bleeding, although it is not statistically significant.

With acalabrutinib though, the 1 side effect that we do see an increase of is headache and we are not quite sure why this occurs with acalabrutinib compared to ibrutinib, but as we will talk about, these are usually low grade and very manageable. You also see a decrease in some other side effects that we have not discussed with ibrutinib, with acalabrutinib such as myalgias, arthralgias, rash and diarrhea.

Similarly, in the relapse setting, we had a head-to-head comparison of zanubrutinib with ibrutinib.

[00:24:08]

ALPINE: Phase III Trial of Zanubrutinib vs Ibrutinib in R/R CLL

Here, zanubrutinib did demonstrate a significant improvement in efficacy compared to ibrutinib. I do not think this was something that was expected by many because again, these second-generation covalent BTK inhibitors were not really designed to improve upon toxicity. Nonetheless, we see zanubrutinib did beat ibrutinib in terms of progression-free survival.

[00:24:33]

ALPINE: Tolerability of Zanubrutinib vs Ibrutinib

Again, when we look at the toxicity improved profile, we do see a significant improvement in the incidence of atrial fibrillation with zanubrutinib compared to ibrutinib. Again, you still see bleeding with zanubrutinib but you are going to see a lower incidence. Hypertension though with zanubrutinib, at least in the ALPINE trial, looked to be quite similar to ibrutinib.

You do, again, see a decrease in the risk of myalgias, arthralgias, diarrhea. Zanubrutinib is actually the most potent BTK inhibitor against BTK. So you do see maybe a slightly increased risk of neutropenia or infection with zanubrutinib, but I do not know if this is clinically relevant.

Overall, what we have are 3 BTK inhibitors that are approved for first-line treatment of CLL. They are given as monotherapy indefinitely until disease progression or intolerance or death.

What we know is that zanubrutinib and acalabrutinib are at least as effective as ibrutinib, if not more effective but definitely do have an increased safety profile compared to ibrutinib. Acalabrutinib, zanubrutinib, I think have become the 2 favored covalent BTK inhibitors for front-line treatment of CLL.

[00:25:49]

Combination Therapy With cBTKis for the Management of CLL

CLL14: Phase III Trial of First-line Obinutuzumab + Venetoclax or Chlorambucil (Fixed Duration)

We also have some combination based approaches to discuss. The big 1 is venetoclax with obinutuzumab. This was the CLL14 trial. Venetoclax is an oral BCL2 inhibitor, and obinutuzumab is an IV CD20 monoclonal antibody.

These drugs were given for a fixed duration. Obinutuzumab is given for 6 cycles and venetoclax given orally for 1 year, and then all therapy is stopped and patients are observed. You can see based on these Kaplan-Meier curves, patients treated with this fixed duration based regimen have very prolonged progression-free survival. At 6 years of follow-up, we have over 50% of patients who have not progressed yet indicating with this treatment approach, patients can stop therapy and be off for quite a bit of time in comparison again to our BTK inhibitors, which are given every day indefinitely until progression.

[00:26:42]

Frontline cBTKi vs Venetoclax + Obinutuzumab: Factors to Consider

With both of these treatment options on the table, how do we decide for a patient? While the covalent BTK inhibitors, they are very convenient, patients can take them at home, the inconvenience is that they are taken indefinitely and this can be 8, 10 years, if not longer. They have a lot of phase III data compared to standard of care chemotherapy as well as head-to-head comparisons.

We do not have as much data for using covalent BTK inhibitors after patients relapse following venetoclax-based therapy. Retrospective studies have shown efficacy does not seem to decrease when that occurs.

With the venetoclax-obinutuzumab, it is nice because it is fixed duration, so it saves cost for patients. It limits adverse effects ongoing and is definitely an quality of life benefit. However, obinutuzumab is an infusion drug, has a high risk of infusion-related reactions, and venetoclax does require a lot of monitoring, at least initially for tumor lysis syndrome.

We weigh the risk and benefit for each patient and their situation, their comorbidities, their drug-drug interactions, and then we let the patient get involved too, in which kind of therapy they would prefer.

One group though that we are a little bit hesitant to recommend a fixed duration regimen in its patients with high risk cytogenetics, so deletion 17p or P53 mutations.

[00:28:08]

High-Risk Subgroups

To illustrate why, we know that these patients do really poorly with chemotherapy. When we look at how these patients did in the BTK inhibitor trials, we are seeing very prolonged progression-free survival in these patients. These are small numbers, but these progression-free survivals are rivaling what the general population without these high-risk cytogenetics are doing.

In patients with these high-risk cytogenetics that were treated with fixed duration, venetoclax-obinutuzumab, the median progression-free survival was still over 4 years but not as long as what we are seeing with BTK inhibitors. A lot of people are hesitant to recommend a fixed duration approach in a high-risk cytogenetic patient, but it is certainly an option. They will respond and they will get some time off therapy. It just would not be as long as a patient without a high-risk feature.

[00:29:00]

AMPLIFY: Acalabrutinib + Venetoclax ± Obinutuzumab vs CIT in Untreated CLL

Then lastly to discuss a trial that was recently approved and published in the New England Journal of Medicine this year is a new fixed duration based regimen, acalabrutinib, so a covalent BTK inhibitor with venetoclax, with or without obinutuzumab. This was the AMPLIFY trial. It was a phase III trial in which acalabrutinib and venetoclax were given for 14 cycles, and 1 of the arms had 6 months of obinutuzumab and compared against standard of care chemotherapy.

Notably, they did not enroll patients with the high-risk cytogenetics, so deletion 17p or P53 mutation because it would be unethical to really put them on a chemotherapy arm.

[00:29:39]

AMPLIFY: PFS per BIRC

Not surprisingly, we see that the novel approach to acalabrutinib with venetoclax, with or without obinutuzumab does significantly improve progression-free survival. That progression-free survival may be a little bit longer if you add the intravenous CD20 monoclonal antibody, obinutuzumab.

[00:29:58]

AMPLIFY: OS

Overall survival is a little bit immature, but there was a significant improvement in overall survival with the acalabrutinib and venetoclax compared to the chemotherapy arm as well, which is not surprising based on what we know for the drugs individually.

[00:30:13]

AMPLIFY: Safety Summary

In terms of side effects, combining acalabrutinib with venetoclax does increase the risk of neutropenia, infection, diarrhea. You still see the cardiac events with acalabrutinib, but adding venetoclax does not increase that risk. Then overall, the risk of tumor lysis syndrome was quite low with venetoclax.

With obinutuzumab, you do get the risk of infusion-related reaction, and adding the monoclonal does increase neutropenia risk as well as infection.

[00:30:41]

Utility of MRD-Directed Therapy in CLL

Before we talk about how do we include this AMPLIFY regimen into our treatment paradigm, one thing to quickly discuss is the role of measurable residual disease, or MRD, in CLL. An undetectable MRD is defined as not being able to identify or not identify 1 CLL cell when you examine 10,000 leukocytes.

Measurable residual disease or MRD is just a really sensitive way to measure a patient's disease burden. We know that it is predictive of a patient's progression-free survival being able to obtain unmeasurable MRD, and it is prognostic for time to next treatment when you look at fixed duration regimens and chemotherapy.

However many patients who are just treated with a single-agent BTK inhibitor never obtain unmeasurable MRD and still do really well and can be on therapy for a decade or longer.

[00:31:39]

Outstanding Questions on Use of MRD in CLL

Really I think there is a question mark on what the role is of MRD in the treatment of CLL and should we be using it to guide treatment decisions and how should we be doing that?

Really it is not ready for prime time yet. We do not know when to test for it. We do not know what the goal should be. We do not know how to make treatment decisions based off of it. It can be used to tell you the depth of a patient's response to therapy.

[00:32:04]

AMPLIFY and CLL14: Rate of uMRD (<10^-4 )

That brings me to looking at the rates of unmeasurable MRD in both the AMPLIFY trial and CLL14, both of our fixed duration regimens. What we see is that with venetoclax and obinutuzumab, we see quite high rates of unmeasurable MRD with this fixed duration regimen, which may be the reason why patients can stop therapy at 1 year and stay off therapy for quite a bit of time.

The rates are not as high with acalabrutinib and venetoclax, at least that is what has been published. We only have about 3 years of follow-up in that treatment arm right now. We do not know how long patients are going to be off therapy in the acalabrutinib-venetoclax arm. You do see higher rates of unmeasurable MRD when you add the obinutuzumab to the acalabrutinib and venetoclax.

[00:32:47]

Time-Limited Therapies for First-line CLL: How to Choose?

Looking at these 2 fixed-duration combination regimens together, acalabrutinib and venetoclax is an FDA-approved option. It is an all oral time-limited therapy. Venetoclax-obinutuzumab is time limited, but it is not all oral. Patients still have to come in for those 6 months of obinutuzumab infusions. We do know unmeasurable MRD rates are lower with acalabrutinib and venetoclax compared to venetoclax and obinutuzumab. We know patients on venetoclax and obinutuzumab at 6 years, over half of those patients are without progression and many of them are still off treatment.

We do not know how long patients with acalabrutinib and venetoclax are going to be able to be off of therapy. We do not have that long-term follow-up yet, and we do not know if the lower rates of unmeasurable MRD will impact that. It is a definitely an option for a patient. I just think there is a little bit of question remaining and how it does compare to our other fixed duration regimen.

Unfortunately, we do not have any data right now for acalabrutinib with venetoclax in high-risk cytogenetics, but we know that PFS is inferior with combination-based approach. Again, many are hesitant to recommend these fixed duration regimens in these high-risk patients.

[00:34:02]

Treatment Algorithm for Newly Diagnosed CLL/SLL

Here is a current NCCN guideline recommendations for how we treat. Essentially, all 3 covalent BTK inhibitors are approved as monotherapy in the front-line setting. Acalabrutinib and zanubrutinib are preferred because of the improved toxicity profile, but you can also give venetoclax with obinutuzumab or venetoclax with acalabrutinib with or without the obinutuzumab as fixed duration if the patient desires or that is better for your patient.

Again, high-risk cytogenetic patients. Covalent BTK inhibitors given indefinitely is the preference, but you can still use fixed duration if the situation requires that.

[00:34:41]

Let's Revisit Our Patient Case

68-Yr-Old Man With Newly Diagnosed CLL

Back to our patient. This is a 68-year-old male with CLL who does not have high-risk cytogenetics. Has a history of hypertension and diabetes but is needing to initiate therapy for the CLL. He requires something fixed duration and he really does want an all oral regimen because it is hard for him to come back to the infusion area for treatment because of his career as a truck driver.

[00:35:05]

Posttest 2

Based on what we have discussed in the case, in your clinical practice, which of the following would you recommend as best first-line therapy for this patient?

1. Acalabrutinib with obinutuzumab;
2. Acalabrutinib with venetoclax;
3. Venetoclax with obinutuzumab; or
4. Pirtobrutinib.

[00:35:40]

Posttest 2: Rationale

The correct answer we would say here would be B, acalabrutinib and venetoclax because this is now in NCCN based on the results of the AMPLIFY trial. Acalabrutinib with obinutuzumab or venetoclax or obinutuzumab are certainly options. Venetoclax with obinutuzumab would be another fixed duration, but it would be probably hard for this patient to get the obinutuzumab because of his career. Then pirtobrutinib as we will discuss is only approved in the relapse setting currently.

[00:36:14]

Managing CLL With Noncovalent BTK Inhibitors

With that, I will pass it on to James to discuss our non-covalent BTK inhibitors.

Dr James Davis (MUSC College of Pharmacy): Thank you so much, Victoria. Very well done. Victoria has done a really nice job about talking about our first and second-generation covalent BTKs. But what she has left to me is to talk about our novel non-covalent BTK inhibitor.

[00:36:38]

Now, Another Patient Case

We will start with another case.

[00:36:42]

Patient With PD After Venetoclax + Obinutuzumab and Acalabrutinib

This is a 76-year-old gentleman with CLL who has relapsed following venetoclax and obinutuzumab, notably only 8 months after completing the fixed duration therapy. Currently, he is receiving a BTK inhibitor, acalabrutinib. He has tolerated acalabrutinib well but 3 years in, he has a slowly progressive symptomatic disease.

His counts are not really notable here. His white count is 36,000, which is not typically notable. I have seen white counts of 150,000, 200,000 in these patients. He has slight cytopenias, a little bit low hemoglobin, and platelet count is 80.

His FISH panel shows no deletion 17p or TP53 mutation. He is not high risk in that regard, but he does have a BTK C481 mutation.

[00:37:41]

Pretest 3

Pretest question number 3. In your current practice, what would you consider to be the optimal therapy for this patient? Would you:

1. Continue acalabrutinib;
2. Retreat with a venetoclax-based therapy;
3. Switch to zanubrutinib;
4. Switch to pirtobrutinib; or
5. Switch to a PI3K inhibitor and an anti-CD20 antibody-based therapy.

[00:38:15]

Summary of Pivotal Studies in R/R CLL

We will come back to that question. To summarize, Victoria has done a really nice job in summarizing the evidence for naive patients to BTK, but we have a number of trials, and we do not have time today to go into depth of all these trials.

We have a number of trials looking at these BTK inhibitors in patients with relapse or refractory CLL. These patients live for decades and decades, and most patients with CLL live a normal lifespan compared to patients with non-CLL. We know these patients are at some point likely to receive a BTK inhibitor and a BCL2 inhibitor like venetoclax.

[00:38:56]

The BTKi Era

Victoria also did a nice job in laying out the history of these things, but I always like to see these kind of slides. In the 50s, we had chemotherapy. In the late 90s, we added rituximab, so we really gave something like FCR or fludarabine, cyclophosphamide and rituximab. Then in 2014, ibrutinib came along and really changed the game. From that point on, we have really been using these all oral regimens. Then venetoclax and obinutuzumab is also an option.

I am here to talk specifically about pirtobrutinib, which was approved in 2024. Let us talk a little bit about that.

[00:39:34]

How Do We Sequence at First Relapse?

How do we sequence patients that are relapsing at the first relapse? They have either previously had a covalent BTK or venetoclax-based regimen, and we really divide the treatment into 2 buckets. On the left here, you have a patient that is had a progression on a venetoclax-based regimen like venetoclax/obinutuzumab. We really look at whether they have progressed soon after stopping or if they had a durable response.

It makes sense to, in my mind, if a patient has relapsed after 8 months, like our case patient, you probably do not want to use the same thing because they did not get a durable response. In a patient like that, you can switch to a covalent BTK, and our NCCN preferred options are the second-generation BTK inhibitors due to the favorable adverse effect profiles. Those are acalabrutinib and zanubrutinib here in the green box.

If a patient got a durable response from a venetoclax-based regimen in the front-line, and we really look at that 2 years or so is what many experts say is durable. There is evidence that you can re-treat those patients with a limited duration venetoclax-based regimen. That can be venetoclax-rituximab, or more recently we have data with venetoclax and obinutuzumab.

If the patients do not want retreatment, let us say they are a truck driver or do not want to come in for infusions, you can also opt for a second-generation BTK inhibitor like acalabrutinib, zanubrutinib.

The right bucket. In the orange, we have got patients that have progressed after 1 of these second-generation or ibrutinib, our first-generation covalent BTK inhibitor. In that case, you can offer a venetoclax-based regimen or our newer drug, pirtobrutinib, if they have intolerance or are resistant to the BTK inhibitor. Let us move forward.

[00:41:35]

Treatments After Progression on cBTK Inhibitors and Venetoclax

Treatments after the first relapse really get a little bit more complicated. We know these patients live a long time and at some point they are likely to receive a venetoclax-based regimen and a BTK inhibitor regimen. Second relapse or third relapse, you really do not have great options like we do earlier. These options do not give 7, 8, 10 years of progression-free survival like we have.

We are looking at things like pirtobrutinib, which we will talk about. CAR T-cell therapy is now approved for patients. Allogeneic stem cell transplant, when you get your stem cells from a donor. Then we have some older options like traditional chemoimmunotherapy, lenalidomide-based regimens, and PI3K-based regimens.

[00:42:24]

BTK C481 Mutations

Our patient in our case had a BTK C481 mutation. Victoria talked a little bit about that. But essentially this mutation is a mutation that confers resistance to our traditional covalent BTK inhibitors. We have data which I will present next with pirtobrutinib and why it is important in those patients with these mutations.

[00:42:44]

BRUIN: ncBTKi Pirtobrutinib for Previously Treated CLL/SLL

The BRUIN trial is the trial that led to the approval of pirtobrutinib for previously treated patients with CLL. It was an international open-label, phase I/II study that included 317 patients. These patients were either intolerant or had previously progressed on a BTK inhibitor or 2 or prior lines of standard of care treatment.

The phase I was the dose-finding stage, and the phase II looked more at efficacy outcomes and safety.

[00:43:14]

BRUIN (CLL/SLL): PFS

We will start at the top left here. These are our progression-free survival curves for the BRUIN trial. You can see that all patients on the top left, this is all patients, including patients with C481 mutations and patients with prior covalent BTK inhibitors. The median progression-free survival of these patients was about 19 months, 19.4 months.

If you look on the right curve, you can see patients that had venetoclax-based therapy in the past, and the progression-free survival here was 15.9 months. Still pretty good, but a little bit less than all comers.

I did want to point out in the bottom box here with the blue, these are our overall response rates, and Victoria alluded to how these BTK inhibitors really put patients in a shallow response. You can see the differences here in complete response or CR vs partial response, the PR. There are not a lot of patients that attained a CR with pirtobrutinib here. Most of the responses were shallow responses, and that is why, in general, we continue patients on BTK with indefinite therapy.

[00:44:22]

BRUIN (CLL/SLL): AEs of Special Interest

Adverse events of special interest for patients that received pirtobrutinib in the BRUIN trial. Infections were probably the most common and significant thing here. Most of these infections were respiratory infections such as pneumonia or bronchitis. We do also see bruising, which is typically on the arms and hands of these patients. Most of these patients, again, are older and are frail or have thinner skin than younger patients. Bruising is very commonly seen.

Rash and arthralgias can also be seen in patients, but I have patients taking this drug and it seems anecdotally that my patients tolerate this drug better than some of the other BTK inhibitors, especially ibrutinib, the first generation.

You can also see hypertension and AFib, like we do with the earlier BTKs, but here it is a lot less common and a lot less severe.

[00:45:15]

Treatments After Progression on BCL2 Inhibitors, cBTKi, ncBTKi, and Venetoclax-Based Regimens

Where do we go from pirtobrutinib? We have had a patient that is relapsed with venetoclax-based therapy or prior BTK. Pirtobrutinib is a really good option. It is an oral pill, oral tablets that you take once a day. Typically, we can go to that.

After pirtobrutinib, it is really a question of patient fitness. We have got 2 buckets here we alluded to earlier, either CAR T-cell therapy or allogeneic stem cell transplant or some of these non-preferred older type regimens.

It is really patient-dependent and physician-dependent on where we go from here. CAR T-cell therapy is an option for patients with some of these aggressive lymphomas. But for CLL, the response rates are not quite what we hoped for and can be about 30% response rates with the currently approved CAR T-cell therapy.

The good news is the patients that do respond to the CAR T-cells have really durable responses of years and years, but overall it may not be the best thing at this point.

Allogeneic stem cell transplant here is an option, but it is very logistically challenging and you have to have donor matched cells and there is a risk for mortality with GVHD and things like that. It really comes down to patient triage. We look at patient ages, comorbidities, frailties, patient preference, whether they want to do something logistically challenging like CAR T-cells or a transplant or whether they would want to have something more traditional like a chemoimmunotherapy-based regimen and then also donor availability.

[00:46:53]

Emerging Therapy Considerations in CLL/SLL

Let us talk about what is coming down the pipeline.

[00:46:54]

MRD-Guided Time-Limited Treatment

Victoria mentioned MRD and she did a nice job about what MRD, the definition of MRD is and how sensitive it is. We have a lot of ongoing studies looking into MRD-guided time-limited treatment.

Here is some studies on this table. The MAJIC trials, particularly interesting, acalabrutinib plus venetoclax vs our more standard of care what we use now, venetoclax plus obinutuzumab. All of these trials here are using fixed duration of MRD-guided time-limited treatment. If a patient is MRD negative at a certain time point, they stop therapy and they check MRD negativity longitudinally and they can leave patients off treatment for longer if they remain in MRD negative state.

MRD is definitely coming down the pipeline and I agree that we are not quite prime time using it. I have used it in a handful of patients in clinic but it is not something that we are doing routinely.

[00:47:54]

Novel Agents Being Investigated in CLL/SLL

More pipeline agents. We not only have talked about BTK inhibitors, BCL2 inhibitors, anti-CD20 monoclonal antibodies, but we also have some novel agents coming down. We have got sonrotoclax, which is a BCL2 inhibitor that is being combined with zanubrutinib. There is actually a phase III study, the CELESTIAL study that is looking at these 2 vs venetoclax and obinutuzumab.

BELLWAVE; nemtabrutinib is another non-covalent BTK inhibitor. We have got BTK degraders which is a novel type therapy that we do not have anything approved for. Then we have got these bispecific antibodies like epcoritamab. We are likely to see even more options in the next 3 to 5 to 7 years for these patients.

[00:48:40]

Let's Revisit Our Questions

Let us revisit some of our previous questions.

[00:48:44]

Posttest 1

This was one of Victoria’s questions. Which of the following pairings is correct?

1. Is ibrutinib a non-covalent BTK inhibitor with reduced cardiac toxicity;
2. Is pirtobrutinib a non-covalent BTK inhibitor with reduced cardiac toxicity;
3. Is zanubrutinib a covalent BTK inhibitor with increased cardiac toxicity; or
4. Is nemtabrutinib a covalent BTK inhibitor with increased cardiac toxicity.

I am not sure if the audience can see, but it looks like 73% of the audience chose pirtobrutinib. Let us go to the next slide and we can talk about why.

[00:49:39]

Posttest 1: Rationale

Pirtobrutinib or B is the correct rationale because we saw that is the only currently available non-covalent BTK inhibitor and like a third-generation BTK inhibitor almost, even though it is in a class of its own. We have seen that the second and third-generation BTK inhibitors have the reduced toxicity.

Ibrutinib here is incorrect because it is a covalent BTK and it actually has more cardiotoxicity than the other BTKs. Zanubrutinib here does not have increased cardiac toxicity. Nemtabrutinib is a non-covalent BTK and would likely, even though we do not have a lot of data on it, probably have reduced cardiac toxicity compared to prior BTKs.

[00:50:28]

Patient With PD After Venetoclax + Obinutuzumab and Acalabrutinib

Back to our patient. We have got a 76-year-old gentleman with CLL who has relapsed after venetoclax/obinutuzumab 8 months and is now on acalabrutinib. He is progressing after 3 years on acalabrutinib and he has got the BTK C481 mutation.

[00:50:46]

Posttest 3

In your current practice, what would you consider to be optimal treatment for this gentleman? Would you:

1. Continue acalabrutinib;
2. Retreat with a venetoclax-based therapy;
3. Switch to zanubrutinib;
4. Switch to pirtobrutinib; or
5. Switch to a PI3K inhibitor and antibody combination.

Again, 60% of the audience answered correctly. Well done here. Let us move to our rationale.

[00:51:30]

Posttest 3: Rationale

The rationale here, the correct answer is D, switch to pirtobrutinib. For a patient that has relapsed CLL and has received both a venetoclax base and a covalent BTK-based treatment in the past, we can really either re-treat with venetoclax or move on to something else. Re-treatment with venetoclax in this situation is probably not ideal because he only got 8 months and we would really only do that if they got a more durable response 2 years or longer.

A is incorrect, continue acalabrutinib because he is currently progressing. B is incorrect because he only got 8 months out of his venetoclax-based therapy originally. C is incorrect because zanubrutinib would also be resistant to the 481 S mutation. D, pirtobrutinib is the best answer. E is incorrect because PI3K inhibitor and antibody combinations are not preferred and outcomes are not as good as pirtobrutinib.

[00:52:34]

AE Management, Adherence, and Drug-Drug Interactions

I am going to turn it back over to Victoria and she is going to talk about management, adherence, and drug interactions.

[00:52:45]

Now, Another Patient Case

Dr Nachar: Thank you, James. Before we get in, we have a quick patient case to discuss.

[00:52:49]

Patient With Relapsed CLL Initiating Acalabrutinib

This is a 76-year-old male who has high-risk T53 mutated CLL relapsing on the venetoclax/obinutuzumab 8 months again after completing fixed duration therapy. He recently initiated acalabrutinib. This is James's patient but 3 years prior.

You can see his white blood cell count is 54, hemoglobin 10, and platelet count is normal at 180,000. He is tolerating the acalabrutinib well. But he has got some nagging grade 2 muscle pain that is limiting a little bit of his daily activities.

[00:53:23]

Pretest 4

In your practice, what would you consider to be the optimal management of this patient's myalgia?

1. Continue acalabrutinib at the current dose;
2. Give him some NSAIDs such as ibuprofen;
3. Dose reduce acalabrutinib;
4. Switch to pirtobrutinib; or
5. Switch to zanubrutinib.

[00:54:05]

Monitoring and Managing BTKi-Related AEs in Practice

Okay, let us discuss how we manage the side effects. We talked a lot about the biggest side effects of these agents being cardiac and bleeding concerns. Again, AFib is much more common with ibrutinib, which has fallen out of favor, but you can still see a small percentage of patients develop atrial fibrillation or have worsening of preexisting atrial fibrillation with second-generation BTK inhibitors as well as our non-covalent pirtobrutinib.

Of course, we want to monitor. Patients do not need to stop the BTK if they develop atrial fibrillation. We just want to manage that AFib appropriately and if we can control it, then we can continue their BTK inhibitor. There is the bleeding risk with the BTK inhibitors. But if a patient does need to start anticoagulation such as a DOAC for the atrial fibrillation, you can overlap the BTK and the DOAC just knowing that there is an increased risk of bleeding.

We want to monitor for any bleeding signs, and as James alluded to, we do see a lot of bruising, particularly on the arms and hands of our older patients. Bleeding and platelet inhibition does seem to be dose related, so dose reductions can be quite helpful if they do have significant bruising.

We want to make sure we are having patients hold their BTK for an appropriate time before or after surgery, depending on the type of surgery and the bleeding risk as well.

If you do see diarrhea, I see this mostly with zanubrutinib. We can use over-the-counter antidiarrhea agents such as loperamide, but typically you do not need to hold or reduce doses for diarrhea.

Headache is unique with acalabrutinib and, again, it is very mild, usually low grade and something that happens early on in treatment and gets better over time. That is 1 education piece that I think is important for patients. But for managing headaches, if patient's platelet count is normal, NSAIDs can be utilized as well as caffeine or Tylenol can also be quite effective.

[00:56:03]

Monitoring and Managing BTKi-Related AEs in Practice

For hypertension. Hypertension was actually something that was not noted in the initial BTK inhibitor trials, but was seen with ibrutinib and post-marketing in long term. This is a side effect that can occur early, but is also something that can sneak up on a patient over time. We want to make sure we are just monitoring when they come to see their provider, whether they get to every 3 month or every 6 months, every 6 month visit, if they are coming to the pharmacy, just making sure we are watching their blood pressure.

Like AFib, we do not have to stop the BTK inhibitor for hypertension, but only if we are not able to control the hypertension on antihypertensives or they have a significant cardiac event.

These drugs do not carry a super high risk of infection. We just monitor. There is no infection prophylaxis that is really recommended. Then like our patient musculoskeletal pain, again, not as common with the second or third-generation BTK inhibitors, but you can use NSAIDs if patients platelet count is normal, they are not at bleed risk. You can hold or try dose reduction. In very severe cases, we can do pulse doses of steroids.

[00:57:08]

Switch BTKi to Mitigate Adverse Events

You might ask, what about switching among the different BTK inhibitors? Well, ibrutinib, being the first-generation and having the most side effects, you can definitely attempt to switch to a second-generation BTK inhibitor. There is a little bit of data showing that if you switch from ibrutinib to a second-generation BTK inhibitor, either the side effect does not recur or if it does recur, it is a much lower grade.

Then what about switching among the different second-generation BTK inhibitors, something like zanubrutinib to acalabrutinib or vice versa? There is a little bit of data on that. Again, I think it is worthwhile if the side effect is not something that was like super severe or life-threatening, you could try to switch to see if it recurs or happens at a lower grade. But the second generations are very similar to one another.

We do not have any data about switching to pirtobrutinib, but we do see a very similar side effect profile to the second-generation inhibitors. Hopefully, we can discuss what our practice has been in this regard. But I do think it is worthwhile to try.

[00:58:07]

Drug and Comorbidity Interactions With BTK Inhibitors

In terms of drug interactions, it is mostly CYP3A4. The 1 thing I will note is that some of the drugs, mostly the non-dihydropyridine calcium channel blockers and other antiarrhythmics are 1 of the drug interactions that does sneak up on us a lot. If we are managing the AFib, making sure we are not using interacting medications if we can avoid them and if we cannot, making sure we dose reduce the BTK appropriately and then does not show up as a drug interaction, but overlapping toxicity profile, overlapping BTK inhibitors with anticoagulants and antiplatelets, just making sure we are monitoring for the increased bleed risk.

[00:58:45]

Adherence Barriers Among Patients With CLL

We know that adherence in CLL is less than ideal, particularly with covalent BTK inhibitors that are given right indefinitely into progression every day could be a decade or longer. But we do not know a lot about why the reasons of non-adherence occur, whether it is side effects, whether it is cost, whether it is just the fact that they are taking these pills once or twice daily every day for a very long time.

[00:59:09]

Impact of Adherence on Clinical Efficacy and Survival

But what we do know is that patients that have less than ideal adherence to BTK inhibitors have worse outcomes in terms of progression-free survival and overall survival.

[00:59:20]

Pharmacist’s Role in Optimizing Therapy

I think that brings us, and we had one question in the Q&A box about how do we optimize side effect management and how do we improve adherence to these therapies? I think that is where we play a huge role.

In our practice, we have pharmacists check in within the first 2 weeks and then we try to check in at least the month because we know a lot of the side effects are going to happen early on. But making sure we are optimizing a side effect management, we are monitoring for hypertension, we are making sure things are controlled so that patients can stay on therapy. Then we are addressing if there are lapses in adherence, what the actual reason for that may be, whether it is financial or just patient forgetting to take it and how can we work with the patient to improve that adherence. I think this is a huge role for us as pharmacists.

[01:00:05]

Patient With Relapsed CLL Indicating Acalabrutinib

Back to that patient again. This was a patient who is doing well on acalabrutinib, but having some grade 2 muscle pain that is limiting his activity. What do we think would be the best way to manage this at this time?

1. Would it be continue acalabrutinib at the current dose;
2. Give him some NSAIDs, see how he does so such as ibuprofen;
3. Dose reduce acalabrutinib;
4. Switch to pirtobrutinib; or
5. Switch to zanubrutinib.

It looks like we have a somewhat even split about trying NSAIDs or dose reducing the acalabrutinib.

[01:00:52]

Posttest 4: Rationale

I think at this time, because it is grade 2 and we have not really done anything. We could try NSAIDs first and continue the acalabrutinib or hold it and see how the patient does. I do not know if we need to necessarily have a dose reduction yet because I think certainly if NSAIDs do not work, you could definitely attempt a dose reduction at that point.

I do not know if we need to switch the BTK inhibitor yet either without trying some intervention.

[01:01:21]

Healthcare Utilization Costs

Lastly, in the last minutes, I will pass it over to James to talk about some healthcare utilization and costs with our management of CLL.

[01:01:30]

Projections of Economic Burden of CLL

Dr Davis: Thank you. Unfortunately, we have got these novel therapies that fortunately they make people live longer. Unfortunately, patients living longer comes with cost and that is their cost associated with the medications, cost with just general livability. We have seen in the last 15 years or so, the number of patients with CLL is almost doubled. If you look at Medicare claims data, the out-of-pocket costs are increasing substantially from annual cost of roughly $9,000 to some cost above $57,000.

There is always a question, how can we treat these patients effectively with best therapies, but not drive up economic burdens?

[01:02:23]

Drivers of Economic Burden With BTK Inhibitors

Like I mentioned, there is a number of applicable factors here. Direct drug costs, adverse events, progression, etc. Let us talk through some of these and what we can do to address them.

[01:02:37]

First-line CLL Therapies: Cost of Care

Our first study looks at first-line CLL total cost of care. I really like the graph, especially the 2 bars on left side, the venetoclax plus obinutuzumab and the ibrutinib. This compared cost over 3 years to our fixed duration venetoclax-obinutuzumab compared to our ibrutinib continuous duration.

You can see that the cost of care for the venetoclax-obinutuzumab was higher in the first year, but after the first year because the patients are not getting infusions and they stopped venetoclax after 12 months with first-line, the cost of care really come down. Ibrutinib is cheaper for Year 1, but after that there is still cost associated with the drug long-term.

We are really finding these time-limited therapies. Maybe these MRD-based treatment algorithms are probably going to lead to lower cost in the future.

[01:03:35]

Adverse Events and Cost of Care

The second study looked at adverse events and cost of care. This is a no-brainer for most of us. Number of adverse events was associated with a higher cost of care. You can see in this chart here patients with 3 to 5 adverse events had slightly higher cost of care, but patients with 6 or more adverse events had a lot more cost of care.

[01:03:59]

PCP: Pharmacist-Led BTKi Monitoring and Outcomes

What can we do to kind of address this? This is a pharmacist-led monitoring and outcome study of patients that received BTK inhibitors. This study was actually from a Parisian group pharmacist in France. They looked at clinical pharmacists or specialty pharmacists following patients on BTKs every 3 months and then every 6 months after a number of consultations. They found with patient education, follow up, intensive, adherence monitoring, patient diaries, adjudicated prescription claims that not only was efficacy higher, adherence was higher and drug interactions were lower.

Also in the bar graph on the bottom that there were less high grade adverse events with patients taking these BTK inhibitors. This is 1 of the tools, and I love studies like this that show pharmacists are impacting cost efficacy and adverse reactions for these patients. We can really get involved whether it is our specialty pharmacy folks that are doing refill calls and going over every month or whether it is the pharmacist in the clinic that is talking to patients.

[01:05:06]

Summary: Factors Associated With Therapy Selection

In summary, factors associated with therapy selection. Victoria and I have really gone through a lot of different patient-specific factors, disease factors and financial factors, including comorbidities, adherence, coordination and lab monitoring. Victoria alluded to patients with certain high-risk genetics like deletion 17p do not do well with some of these older things. Tumor burden also plays a factor. Then I think we are going to see MRD-guided therapy cessation earlier, potentially benefit our financial toxicity in the future.

[01:05:40]

Conclusion

In conclusion, we have seen that these small molecule inhibitors, these novel BTK inhibitors are the cornerstone of CLL treatment and exert activity in patients with both high and low risk disease. That our treatment options are really individualized per patient. There is not necessarily 1 treatment option. A lot of times we give our patients choices when they come to clinic, would you rather get your treatment over within a year and be done or would you rather take a pill longer term and not have to come for these infusions?

That we have evidence here that we have presented that pharmacists play a really vital role in these patients with CLL by educating, ensuring patient adherence and managing some of these toxicities.

[01:06:25]

Poll 3

Based on our program today, do you plan to make any clinical changes based on what you learned today in today's program?

[01:06:55]

Poll 4

Then our next poll will be, please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

[01:07:11]

Audience Q&A

While you are all typing, we have a couple minutes left, but we do have a lot of questions from the audience. We will get started on that while you are thinking of your practice changes.

James, we had a lot of good questions. I think the first 1, and maybe a quick one to answer is, outside of an insurance formulary, do you think there is a reason to ever pick ibrutinib over a second-generation BTK inhibitor?

Dr Davis: Ibrutinib over a second-generation. For CLL in particular, I do not know of a reason that I would pick ibrutinib based on the ELEVATE-RR and the ALPINE data that you presented earlier showing the equal efficacy and maybe even more efficacious, say, ibrutinib and the lower risk of adverse reactions.

In mantle cell lymphoma, which is a totally different topic, we know that ibrutinib penetrates the CNS and we have a lot of data and that can be something that we think about. But that is a whole another discussion.

Dr Nachar: I agree. A little bit more of a challenging question, but one we are all asking, how would you relapse after acalabrutinib-venetoclax-obinutuzumab, the AMPLIFY trial?

I guess I would say, it depends on how or when they relapse. If they relapse late, and what does late mean? I do not know if we use the 2-year cutoff that we use for venetoclax-obinutuzumab. I think you could either repeat it or do single-agent covalent BTK inhibitor or venetoclax-obinutuzumab alone fixed duration. If they relapse early, I am not quite sure what the right answer is. I think you could definitely use pirtobrutinib. But then what do you do after that? I am not sure.

I think that brings me back to with the AMPLIFY trial. I am not sure where AV or AVO fits into the treatment paradigm right now. We do not have long follow up yet, and we do not know how long patients are going to be able to stay off therapy. James, do you have thoughts on how you would manage a patient if that was utilized first-line, depending upon time of relapse?

Dr Davis: Yeah, that is a good question. I mean, time of relapse, if they relapse early and they got all 3 agents, you probably would like to expose them to something different, perhaps pirtobrutinib or a combination. We really do not have data after this, so it is really hard to speculate. It is a great question though. It is a really good question in that we are moving towards these combinations, these fixed durations. What happens if someone relapses early after a fixed duration and they have used all 3 agents or multiple agents upfront. Great question though.

Dr Nachar: Then speaking of these like fixed duration regimens, we have these 2 different ones that are now recommended in NCCN or FDA approved. Did you see any cost comparison yet for these fixed duration regimens? Anything comparing venetoclax-obinutuzumab to acalabrutinib with venetoclax or acalabrutinib with venetoclax and obinutuzumab?

Dr Davis: I have not seen anything. I am sure that there will be some of these match adjusted indirect comparisons. The industry loves those. I am sure we will see some of this. At some point, you really have to be careful when you analyze some of these, the cost studies because they can be misconstrued. You have to have a really good statistician also to do some of these things. But it will be interesting to see.

I think in general we know that that limited duration is going to be cheaper than longer. That is just a no-brainer. But it will be interesting to see like an all oral limited duration is cheaper than something with infusion and you have to get labs more frequently with the infusion and you have the infusion costs, etc., etc. Great question though.

Dr Nachar: Yeah. I would say on the other side of that, while we might think infusion costs will be high, the infusion is only given for 6 months when you give the doublet oral fixed duration, both of those are given for 14 months. I am curious to see what the cost comparison would look like between the 2.

We have a couple questions too about the side effect profile. The first one was a question on the atrial fibrillation risk. Does this occur in patients without cardiovascular disease or is this mostly in patients with underlying cardiovascular disease?

I think the answer is both. We know that patients with underlying cardiovascular disease or who have a preexisting atrial fibrillation are at higher risk of developing a cardiovascular toxicity from a BTK inhibitor or having a major cardiovascular event. But it can occur in patients who do not have any history of cardiovascular disease as well.

In patients who are severely neutropenic, an ANC less than 0.5. Do you have a BTK inhibitor preference and/or any dose adjustment recommendations, if you are adding in something such as antifungal prophylaxis that has drug interactions?

I will say in our practice we have had patients that develop severe neutropenia, mostly from the CLL and just having a very packed compact bone marrow. We have had patients with very prolonged neutropenia. Well, while prolonged neutropenia is a risk factor for a fungal infection, I personally do not think patients with CLL are at super high risk of fungal infections unless they are receiving other therapies like high dose steroids or maybe if they are post CAR T.

In those patients, we actually have not personally done any fungal prophylaxis. We have just treated them with full dose BTK inhibitor knowing that that is probably the best to help them resolve the neutropenia. But if we have had instances where we have had to use antifungals, we follow your typical dose recommendations per the package insert, even though they are based on very limited PK data.

James, do you have any experience or recommendations in that scenario?

Dr Davis: Yeah, I agree. I mean, it is usually because the marrow is packed with disease and once you start therapy, once the marrow starts getting cleaned out, you see the neutropenia resolve slowly. I have had patients, so as far as like BTK choice, I mean one of the second generations, I do not have an opinion there.

We have had patients getting venetoclax-based therapy and it is a little bit trickier with that. With the obinutuzumab, you do the 3 weeks of lead-in before you start the then, so I have had patients that have had severe neutropenia with the obinutuzumab and not resolved, and sometimes we have delayed starting the venetoclax for another cycle or so to kind of help that.

We also have used weekly or twice weekly growth factors to help some of that neutropenia resolve more quickly than it would. But I agree, there is not one right answer here. It is just really based on the patient and the institution.