We are going to be talking about considerations affecting choice of frontline agents in CLL/SLL, and we are going to start by selecting initial therapy for patients based on some of the prognostic variables.

 

[00:17:49]

 

As is probably well known to the audience, there are 2 major biologic classes of CLL. Those that harbor a mutated IGHV gene and those that harbor 1 that is mutated or not undergone somatic hypermutation. Those CLLs tend to be derived from a B-cell clone, which is more immature and less highly proliferative than those CLL cases that are derived from a B-cell clone that has undergone somatic hypermutation. And as a result, those patients who have unmutated IGHV tend to have worse outcomes across the board, and this testing is available.

 

[00:18:38]

 

Going back over 20 years now, the other classification scheme that is used is cytogenetics, usually assessed by FISH testing, although there are other methods available. The most commonly identified high-risk cytogenetic change is deletion 17p. Other ones include 11q, which is considered to be high-risk, and then 13q deletion or a normal FISH panel, which is seen in about up to around 20-25% of cases, is intermediate-risk.

 

And this on the left is the survival of patients with CLL based on abnormalities in an era when patients were treated with chemoimmunotherapy. And then on the right is from the time of diagnosis to the time for first treatment. And as you can see, certain markers, including 17p, are generally associated with a more rapid disease progression and time for initial treatment.

 

[00:19:48]

 

If we pause and look at the updated NCCN guidelines, this is already looking forward to the 2026 version. That is available on the NCCN website.

 

You can see that the recommendations for treatment of CLL/SLL really rely still on predominantly clinical factors. So the symptoms that you are probably familiar with drenching night sweats, fatigue, unintentional weight loss, fever, threatened end-organ function. This is 1 of the more tricky ones, progressive lymphadenopathy. There are some size criteria, lymph nodes over 10 cm, or spleen more than 6 cm below costal margin are commonly used guidelines for initiation of treatment.

 

If you do not have these, of course, you go through the iterative process of active surveillance. And if you do develop an indication for treatment, as shown on the lower right, the recommendation is for prior initiation of treatment to obtain FISH panel and consider TP53 mutation testing as a standalone, because there are mutations in TP53 that will be revealed that are not, of course, picked up by FISH, which really just is a test to look for deletions or duplications of large pieces of chromosome material.

 

And then IGHV mutation testing. Imaging is not essential, but may be done in certain cases. And again, bone marrow biopsy is not essential, but may be done under certain circumstances.

 

[00:21:40]

 

So now that you have your patient with a need for treatment and you have done your molecular risk assessment, let us pause and look at a global view at the major mechanisms of action of CLL-directed therapy.

 

[00:21:55]

 

At the bottom, we have our good friends, chemotherapy. These are the DNA-damaging agents that are very active in CLL, but have largely fallen by the wayside due to the toxicities of agents like FCR or bendamustine.

 

At the top, in the middle, we have the B-cell receptor pathway inhibitors. The most notable and most widely used would be the covalent BTK inhibitors. And we are also going to talk about the noncovalent BTK inhibitor options.

 

PI3 kinase inhibitors are also part of this pathway, although less commonly used due to toxicity. And then on the right, we have really the only approved agent in class, venetoclax, which is a BCL-2 inhibitor, which triggers rapid apoptosis. And then on the upper left, our commonly known friends, rituximab and obinutuzumab, are options for inducing antibody-dependent cellular cytotoxicity.

 

[00:23:04]

 

And when we think about how to put these together, we know cross-oncology that there is always often synergistic activities with combination agents.

 

[00:23:16]

 

So let us look at some of the treatment options that are on the current NCCN guidelines. On the left, we have preferred regimens for patients with CLL/SLL.

 

This is specifically called out to be without 17P or TP53 mutation, and they are listed in alphabetical order, with Category 1s all on the left. So we have BCL-2-containing regimens, venetoclax-acalabrutinib combination, ± obinutuzumab as a fixed duration as 1 option. Another option is venetoclax-obinutuzumab, again, fixed duration, also Category 1.

 

BTK-inhibitor-based treatments, such as continuous therapy with acalabrutinib ± a 6-month duration exposure to obinutuzumab, and then continuous therapy with zanubrutinib as monotherapy. And then there are other recommended regimens on the right and others useful in certain circumstances, but rather than focusing on those, let us look at the data behind what led to these recommendations.

 

[00:24:30]

 

Some of the factors when considering choosing available covalent BTK inhibitors ± venetoclax ± obinutuzumab, of course, would be the patient's comorbidities.

 

So if they have cardiac disorders, arrhythmias, if they have anticoagulation or antiplatelet therapy requirements, kidney function insufficiency, or a propensity for bleeding, of course, these are all things to consider.

 

Toxicities of the drugs, of course, are known ahead of time, but you are not going to know what the toxicities your patient may have, but things to at least discuss. Cost, drug availability, in and outside of the U.S., I would say, are always a consideration due to insurance limitations at times. Convenience and comfort of administration. And then probably 1 of the bigger markers that we really focus on is the 17P and/or TP53 mutation status.

 

[00:25:40]

 

So let us start just with the standard first-line management of CLL with continuous BTK inhibitor.

 

[00:25:50]

 

This goes back over ten years now. One of the first frontline trials that compared a covalent BTK inhibitor, which, of course, the first approval was ibrutinib. And in the Alliance trial, A041202 study. It was a 3-arm trial, which randomized patients to receive the standard of care at the time for older patients, which was bendamustine-rituximab, and then compared it to ibrutinib monotherapy, and then asked the additional question of whether there was additional benefit of adding rituximab to ibrutinib.

 

And as you can see in this important study, ibrutinib outperformed bendamustine-rituximab. But interestingly, the addition of rituximab to ibrutinib did not lead to significant improvement in progression-free survival.

 

[00:26:57]

 

So as time went by, other BTK inhibitors were introduced, developed, and approved, and acalabrutinib was the next approval.

 

So the ELEVATE-TN trial was the study of 3 arms, again, because this is for older patients over 65, or those with impaired cranial clearance and/or high cumulative illness rating scales. This is a slightly older, frailer patient population, and at the time of the study, the accepted approach for that group of patients was obinutuzumab with chlorambucil, based on prior randomized studies.

 

So that is the control arm here, but we have 2 important comparators. One is in the middle, the blue rectangle shows the continuous acalabrutinib BID dosing, and this is compared to continuous acalabrutinib dosing with 6 months of obinutuzumab as a third arm.

 

[00:28:08]

 

And just focusing on the top 2 of interest, if you compare the doublet of AO, so acalabrutinib obinutuzumab, vs acalabrutinib, there does seem, and it has held up over long-term follow‑up, to be an improvement in progression-free survival from 78% to 62% at about 5-6 years of follow-up. So interestingly, the benefits of the obinutuzumab, which are really only given during those first 6 months, continues to hold up even years out into the future.

 

[00:28:56]

 

If you look at the toxicity of the various regimens in the ELEVATE-TN study, you can see, actually, that the rates of, for instance, Afib were low in the acalabrutinib arms, but slightly higher than in the chlorambucil-obinutuzumab arm. We know that bleeding is a known toxicity of most all BTK inhibitors to varying degrees, and you can see the major bleeding episodes are listed there as 4.5% or 6.7% in the 2 acalabrutinib arms. Other toxicities worth noting are infection, which is common in patients of this demographic, and cardiac events overall are listed.

 

[00:30:06]

 

The next BTK inhibitor that was introduced, developed, and approved was zanubrutinib, also, a covalent BTK inhibitor. This was compared to bendamustine Rituxan in, again, patients over the age of 65, or younger patients with comorbidities who are felt to be unfit for FCR chemotherapy as the standard. And you will see that the cohorts that we will be looking at first are those without 17P deletion, although we will also look at some of the single-arm cohorts of those patients who did have 17P deletion.

 

And so it is a pretty straightforward, randomized head-to-head trial with continuous therapy with zanubrutinib.

 

[00:30:56]

 

And as you can see, the zanubrutinib significantly outperformed bendamustine Rituxan with a 3-year PFS of 82%.

 

[00:31:10]

 

So this safety data of the 2 arms is shown here. Again, hypertension is an AE that we may be silent, but needs to be appreciated because it can be seen in patients on BTK inhibitors.

 

Again, the other nuisance side effects, such as rash, GI toxicities, are listed. And then the bleeding events at the bottom, as you can see, are slightly higher compared to the chemotherapy bleeding events.

 

[00:31:52]

 

So that data we just looked at was specifically for patients with an absence of 17P deletion. So what are the data of approaching patients who have this abnormality?

 

[00:32:04]

 

Again, there is a separate panel or a separate table in NCCN for patients with 17P deletion. And if you look on the left, the preferred regimens, again, listed in alphabetical order by category, should look actually quite similar to the previous slide.

 

So BCL2-containing regimens, including venetoclax-obinutuzumab as a fixed duration, venetoclax-acalabrutinib with obinutuzumab in an MRD-guided fashion, venetoclax-zanubrutinib in an MRD-guided fashion also are listed, and then BTK-based treatments where there is no BCL2 inhibitor. So continuous treatment with acalabrutinib ± obinutuzumab, and then zanubrutinib as continuous monotherapy.

 

[00:32:54]

 

If we go back to the data that has the longest follow-up for using a covalent BTK inhibitor as the initial and final destination therapy for patients with high-risk CLL, this is an NCI study of single-agent ibrutinib, which showed 6-year PFS of 61%, which, again, compared to some of the earlier slides I showed about the outcomes of chemotherapy, is clearly dramatically better than what we would have ever expected with chemotherapy with these high-risk patients.

 

[00:33:33]

 

If we look at the subsets in the ELEVATE-TN trial, again, this was the 3-arm study in which acalabrutinib alone was compared to acalabrutinib with obinutuzumab.

 

This is a little bit of a busy slide, but I would really just focus on the top 4 lines where we have 17p deletion patients in the solid lines, and the dashed lines are without 17p deletion. What I would just point out is that when we think about using obinutuzumab for patients who are receiving acalabrutinib, the question often comes up is which patients are most likely to benefit. It is a little counterintuitive, but actually what you would hope would be the case is that the higher-risk patients would benefit the most, but it turns out that the dashed line, the orange dashed line at the top, is actually the patients treated with the doublet who did not have 17p deletion.

 

Really, it seems to be the lower-risk patients that have the most benefit from that combination.

 

[00:34:54]

 

Then with zanubrutinib as a single agent, cohort 2 of the SEQUOIA trial, it was a large number of patients followed with a median follow-up of over 4 years, now with 79% PFS at 42 months, so very favorable long-term single agent activity.

 

[00:35:18]

 

If we move to what are the options for time-limited venetoclax-based treatment –

 

[00:35:27]

 

I think probably the most important study to address this question is from the German CLL13 study.

 

Like many German studies, this is a wonderfully conceived and executed clinical trial that simultaneously addressed multiple questions at the same time. It is a little complicated, but it was a 4-arm randomized trial of patients who were fit for chemotherapy. At the bottom in gray, they either got FCR or BR as standard of care, depending on their aging comorbidities.

 

Then the investigators asked the question, what is better than chemotherapy, venetoclax plus rituximab or venetoclax plus obinutuzumab? That is the purple box and the blue box in the middle. It is really then asking the question in a head-to-head fashion, which monoclonal antibody is a better partner for venetoclax?

 

Then, not to be outdone, the investigators also asked the question, what is the added benefit of adding the BTK inhibitor to venetoclax and obinutuzumab?

 

[00:36:34]

 

As you can see, if you look at the undetectable MRD rates in the purple blood at 15 months with chemoimmunotherapy, it was about 52%. With venetoclax-rituximab in purple, a little higher, 57%, but not statistically significantly better.

 

Where you really see the jump is changing the monoclonal antibody from rituximab to obinutuzumab. Then the MRD rate goes to 86%. If you look at the addition of ibrutinib, now you are going from VO to IVO or triplet, there is really minimal movement in the MRD rates.

 

[00:37:14]

 

This all plays out very beautifully in the 3-year progression-free survival curve, which in gray shows the chemoimmunotherapy arm at the bottom doing worse, the venetoclax-rituximab doing not much better in purple. But then if you look at the blue line at the top next to the orange line, you can see that the VO arm does extremely well. The addition of ibrutinib to VO really does not accomplish very much, other than perhaps causing more toxicity.

 

Again, this is looking specifically at the 3-year PFS of 90% for the triplet vs 87.7% for the doublet of VO.

 

[00:38:00]

 

Then again, small numbers, but if you look at the subgroups, I would focus on this is actually a separate trial. Sorry to move quickly from a different site. This is an older patient. We did not have 17p deletion patients in the prior study because of the chemotherapy arm, but there were some 17p deletion patients in this study, which was the CLL14 study. The point here really is to focus on the orange lines, which gives us a little insight into how the VO regimen performs in patients ± 17p deletion.

 

As you can see, those in the solid orange line have inferior PFS than those in the dashed orange line with VO. Similarly, the IGHV mutation status tends to show that patients treated with a time-limited VO regimen have better outcomes with mutated IGHV compared to those with unmutated.

 

[00:39:08]

 

If we think about obinutuzumab compared to rituximab, we know that obinutuzumab improves PFS and actually overall survival in prior studies when compared with chlorambucil. Venetoclax-obinutuzumab beats aggressive chemotherapy in patients with higher rates of undetectable MRD. We know that obinutuzumab infusion reactions can be more severe than rituximab.

 

So some pearls for using obinutuzumab on the right, I think really setting patient expectations is important regarding infusion reactions, particularly on the first dose, and with an understanding that it is likely that they will have at least some reaction.

 

We have liberal use of steroid premedications. We often can give steroids even for a few days before the first dose. We tend to use very slow infusion rates and have a low threshold for interrupting at the first sign of a reaction rather than trying to charge through and then giving patients a break and giving them the day off and coming back for the next dose. With those measures, we find that most patients can tolerate this regimen.

 

[00:40:30]

I want to move quickly to talk a little bit more about the study that describes using venetoclax in combination with a BTK inhibitor, acalabrutinib.

 

[00:40:46]

 

This is the AMPLIFY study that was recently published in the New England Journal of Medicine.

 

This really was intended to seek out the potential for an all-oral regimen or a triplet. We have patients with CLL needing therapy who are randomized to receive chemotherapy, acalabrutinib-venetoclax on a time-limited basis, so basically a little bit more than a year of therapy. Then at the top, we have the triplet of AV with 6 months of obinutuzumab. The obinutuzumab, in this case, is launched in cycle 2 after some debulking.

 

[00:41:28]

 

Here are the long-term outcomes of patients treated. The stop sign shows the stopping point for the AV and the ABO arms. Technically, the chemotherapy arms would have stopped at 6 months. But what you can see is that the outcomes are, again, excellent with 83% or 76% PFS at 36 months for ABO and AB, respectively.

 

[00:41:58]

 

If we look at the rates of undetectable MRD with a sensitivity of 10^-4 as some of the other pre‑specified endpoints, at the end of treatment with AV, it is about 30%, and with ABO, it goes up to 65%, so, clearly showing the added benefit of adding obinutuzumab to the doublet to achieve higher rates of undetectable MRD.

 

[00:42:26]

 

Then, interestingly, survival is a little complicated, primarily because the AMPLIFY study was operationalized during the peak of the COVID waves that led to many deaths, unfortunately, in patients internationally, many of whom did not have access to COVID vaccines. The overall survival, actually, on the left, you can see that the AV arm, actually, despite having maybe less CLL-directed activity, had fewer deaths than the AV arm, probably because the obinutuzumab led to B-cell depletion that was associated with increased risk of mortality from COVID. If you censor as best you can to account for this, on the right, you can see that, really, it washes out.

 

Whether this is still applicable in the modern era with better antiviral therapies and better vaccines, I think we have seen much less morbidity or mortality from COVID in the current era, so that is something to consider.

 

[00:43:36]

 

Then, this, of course, brings up the question, what is the best frontline treatment approach for CLL, and the debate rages on.

 

[00:43:44]

 

This is a summary of the slides.

 

I think all these cross-trial comparisons are tricky, but I would just point out that some of the higher 3-year PFS rates, for instance, in AMPLIFY was 83% at 3 years, and some of the ELEVATE-TN studies also show longer follow-up, and still holding up at 6 years with very high PFS rates.

 

[00:44:12]

 

With that, I want to just mention that there are, of course, other things in the pipeline, including a new BCL-2 inhibitor. There is an investigational BCL-2 inhibitor, sonrotoclax, which the chemical structure of which is shown on the right, and as you can see it is very, very similar to venetoclax.

 

It has a high in vitro preclinical activity against BCL-2 kinases, and this is in late-stage clinical development, so we are all excited to see those data mature.

 

[00:44:58]

 

I will conclude just by saying, in summary, that chemoimmunotherapy really has come by the wayside. It has a limited role in the management of patients with CLL/SLL.

 

Novel therapeutics have significantly improved PFS with both continuous BTK inhibitor and time-limited options available, and now we have BTK inhibitor plus venetoclax combinations for time-limited treatment.

 

[00:45:21]

 

I will revisit the case and then hand it over to Dr Parikh for the next module.

 

[00:45:30]

 

Again, we have the 63-year-old who has hypertension and diabetes. He needs treatment. He does not have 17p deletion. He does not have IGHV high-risk features. He is mutated. He, like many patients, lives a life outside of your clinic. He drives a truck. He does not want to come in all the time, sit in the chair and get infusions.

 

[00:45:55]

 

Question 1: In your current practice, what would you do for this 63-yr-old patient with CLL and progressive symptoms?

 

What do you want to recommend for this patient? Here is your posttest. In your current practice, would you do:

 

1. Acala-Ven;
2. Acala-Obin;
3. Obin-Ven;
4. Pirtobrutinib; or
5. Zanubrutinib.

 

Let us see.

 

We have the majority of responders saying Acala-venetoclax, and Obin-venetoclax is the next most frequently responded question.

 

[00:46:48]

 

The rationale of Ven-Acala is that it is an NCCN-recommended all-oral fixed-duration regimen for first-line management in CLL based on the results of AMPLIFY. This is now an option for our patients.

 

With that, I will conclude and hand it over to Sameer.

 

Dr Sameer Parikh (Mayo Clinic Alix School of Medicine and Science): Thank you very much, Dr Hill. Good morning, everyone. I am so happy you are all able to join this morning.

 

I am tasked to talk about how would you treat a patient with relapsed/refractory CLL. We will get right into it with a case.

 

[00:47:28]

 

This is a 58-year-old male who was diagnosed with CLL about 4 years ago. At the time of diagnosis, the patient had bulky lymphadenopathy, had splenomegaly with a Rai stage II disease, and genomics revealed unmuted at IGHV genes with trisomy 12 on CLL FISH profile and no TP53 mutation. The patient was initially started on single-agent treatment with ibrutinib at the standard dose of 420 mg daily. Then up until about a couple of years ago, the patient was doing well. Unfortunately, there was evidence of disease progression with worsening lymphadenopathy.

 

[00:48:04]

 

The question when the patient comes to the clinic is, do you have any symptoms? The patient denies any constitutional symptoms. On physical exam has lymphadenopathy and splenomegaly. The white count now shows that it has increased up to 22. Hemoglobin was down to 10, and the platelet count was 90. LDH was normal, and the analysis of a peripheral blood NGS profile demonstrated 1 of the most commonly acquired mutations, the cysteine-481S mutation in the BTK gene in patients who are on continuous ibrutinib-based therapy.

 

[00:48:37]

 

And so the question is that for this patient, a 58-year-old male who was diagnosed with CLL 4 years ago is currently on ibrutinib and is experiencing disease progression, which 1 of the following would not be an appropriate treatment option? So if you have not had your cup of coffee, I just remind you this is a trick question. Which 1 of the following is not a correct treatment option?

 

1. Venetoclax/rituximab;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax/obinutuzumab.

 

So please go ahead and vote.

 

Okay, so I see a very even spread between venetoclax/rituximab, zanubrutinib, and pirtobrutinib. And so we will come back and revisit this question as we go on.

 

[00:49:40]

 

And then let us talk about maybe another patient here.

 

This is case number 2, a 64-year-old male now, who was diagnosed with Rai stage IV CLL in 2016. And at that time, apart from hypertension, had no other significant past medical history. Molecular features had unmuted IGHV genes, deletion 11q by FISH, and no TP53 mutation by NGS testing.

 

The patient was initially started with ibrutinib and rituximab in a clinical trial from July 2016 through January 2020, at which time there was evidence of disease progression. And the patient switched to venetoclax and rituximab at that time and achieved an excellent response and continued with single-agent venetoclax up until now.

 

[00:50:24]

 

When the patient returns for follow-up and is now complaining of mild fatigue and has been having progressively worsening lymphadenopathy with anemia and thrombocytopenia and a white count that has gone up to 38. And the patient now remains TP53 mutation-negative.

 

[00:50:44]

 

The question is, in this patient who has previously received therapy with a BTK inhibitor such as ibrutinib and then subsequently with venetoclax and is currently receiving continuous venetoclax-based therapy, what would you recommend as the next line of therapy according to the 2026 NCCN guidelines? Your choices include:

 

1. Acalabrutinib;
2. Duvelisib;
3. Glofitamab;
4. Pirtobrutinib; or
5. Zanubrutinib.

 

Okay, so roughly one half of you chose pirtobrutinib. Excellent. So, we will again talk about this patient, and how would you treat this patient.

 

[00:51:48]

 

Diving right into the treatment options for patients with relapsed CLL. So, this is again, as Dr Hill pointed out, the 2026 NCCN guidelines. And this page is for patients who have experienced disease progression and are in need for second or subsequent line of therapy.

 

And so, as you can see on your top over here, the preferred treatment regimens in second-line really include either a BCL2-containing regimen such as venetoclax and obinutuzumab or covalent BTK inhibitors including acalabrutinib and zanubrutinib or a noncovalent BTK inhibitor called pirtobrutinib. And we will go over some of the data as to why these regimens are listed in the way they are.

 

One thing I will mention here is that the BCL2-containing regimen with venetoclax, the preferred CD20 antibody is listed here as obinutuzumab. The data are sparse in that setting. The most data are with venetoclax and rituximab. However, we have extrapolated a lot of the information from the frontline setting into the relapsed/refractory setting. And generally, that is what is used even in the relapsed setting.

 

And as you can see on the bottom are options for patients who have had relapsed disease on both a frontline covalent BTK inhibitor and venetoclax or a BCL2 inhibitor-based treatment. And these are dual refractory patients.

 

And these are some of the options listed, including the use of lisocabtagene maraleucel, which is a CAR T-directed therapy, or pirtobrutinib, which is a noncovalent BTK inhibitor-based treatment.

 

So now let us just go over some of the data that have led to the inclusion of these regimens here.

 

[00:53:32]

 

And so this is my framework. I should say our framework at Mayo Clinic of how we approach patients with relapsed disease. And this is complicated, but we will break it down according to each of these categories. But the way I think about this, the way we approach this is patients who have never received any targeted treatments are on the far left. And these patients, you can either use the covalent BTK inhibitors or venetoclax or obinutuzumab. In the second from the left are patients who have received covalent BTK inhibitors. And then further right to that are patients who have received prior BCL2 inhibitors. And on the far right are patients who have disease progression on both the BTK inhibitors, the covalent and venetoclax, the so-called double refractory patients.

 

[00:54:16]

 

And so if we begin our discussion with those patients who have never received any prior targeted therapy, there are 3 covalent BTK inhibitors that are currently available. And we heard some of this from Dr Hill's talk. These include ibrutinib, acalabrutinib, and zanubrutinib. And these are the pivotal trials that actually show the benefit of each of these agents against the different comparators.

 

So the RESONATE trial is the original trial comparing ibrutinib to ofatumumab with an excellent progression-free survival. On the top right is the ASCEND trial looking at acalabrutinib that is compared to either the investigator's choice of bendamustine or rituximab or idelalisib and rituximab. And then on the bottom right, you will see the ALPINE trial comparing zanubrutinib to ibrutinib. Each of these showing that a BTK inhibitor, a covalent BTK inhibitor, was better compared to a comparator arm. And the ALPINE study, actually, zanubrutinib was shown to be superior from a PFS perspective compared to ibrutinib.

 

And so clearly, these are very effective treatment options. They need to be given in a continuous fashion. And as you can see, the median progression-free survival ranges anywhere from 5-6 years for the majority of these patients.

 

[00:55:30]

 

Another very effective treatment option is fixed-duration therapy with a venetoclax-based treatment option, which includes venetoclax and rituximab. On the left is the MURANO study. This was a study that compared venetoclax and rituximab where venetoclax was given for 2 years against bendamustine and rituximab.

 

And you can see that the median progression-free survival of patients who received venetoclax and rituximab was close to 54 months compared to about 17 months with bendamustine and rituximab, clearly showing the superiority of a novel agent in the management of CLL. And again, the vast majority of these patients had received chemoimmunotherapy as their initial frontline treatment. And a very, very small number of patients have received a novel agent like ibrutinib before they went on this study.

 

On the right is a combination of an all-oral regimen of ibrutinib and venetoclax. This is the CLARITY study, which was conducted in the UK. Again, median number of prior lines of therapy was 1. And again, you can see the excellent progression-free survival that was shown with the use of this combination, suggesting that if a patient has received only chemoimmunotherapy, and these patients are not as many in the clinic these days because we have started to use these agents in the frontline setting.

 

[00:56:52]

 

But these do suggest that you have the option to use either of the 2 approved options, which includes either continuous BTK inhibitor-based therapy, such as acalabrutinib or zanubrutinib in my practice. Typically, it is 1 of these 2 compared to ibrutinib, given the superiority of zanubrutinib compared to ibrutinib.

 

And also given the improved toxicity profile with the second-generation BTK inhibitors, so-called second-generation with acalabrutinib and zanubrutinib compared to ibrutinib. And of course, like I mentioned, the other option is venetoclax and rituximab, given for a fixed duration of time.

 

[00:57:28]

 

So what about a patient that has received a covalent BTK inhibitor or may or may not have received chemoimmunotherapy in the past?

 

I think 1 of the first questions to understand is, you know, what was the reason for stopping the BTK inhibitor? Was it toxicity or progression? Because many of the things that you would do would depend on what you start with.

 

[00:57:47]

 

So in my practice, when I see patients who are on a continuous covalent BTK inhibitor like ibrutinib or acalabrutinib or zanubrutinib, and patients are experiencing toxicity, 1 of the first things I will do is I will try to obviously modify the dose according to the prescribing guidelines. And if that does not ameliorate the toxicity, I would think about switching to another covalent BTK inhibitor or venetoclax or even pirtobrutinib, because that is now on the NCCN guidelines. However, the 1 thing I would like to caution everyone, and I try to keep this in the back of my mind is, does this patient really need to be on any treatment? Because frequently you will see patients who are on a BTK inhibitor, and they have been on it for a year or 2. They have achieved a very good partial remission, and their lymph nodes are all gone. Their white count is better. They do not have any more symptoms. And then the question is, does this patient really need to continue any therapy at all? Or can I just observe and see what happens?

 

And indeed, in the ECOG frontline trial, the E1912 trial, where patients stopped ibrutinib because of a toxicity reason, the median time to, you know, initiation of the next line of treatment based on progression of disease that met criteria for therapy was roughly 2 years. And this obviously means that not everyone who is experiencing toxicity on a covalent BTK inhibitor immediately needs to go to a next line of treatment. If they have achieved a good remission and are otherwise doing well and do not meet indications, you are perfectly fine in just clinically observing them and waiting until they actually have disease progression before you switch to any of these treatment options.

 

[00:59:22]

 

Now, if a patient really needs to switch treatments, there are a lot of data that suggests that switching from ibrutinib to either acalabrutinib or ibrutinib to zanubrutinib is very effective, and it does not lead to recurrence of the original toxicity in roughly 75-80% of patients. And as you can see on the left, are data from zanubrutinib-treated patients who were originally on ibrutinib. And you will see that in orange is a very small number of patients where there was a recurrent toxicity noted at the same grade. The vast majority of it did not recur at all.

 

And on the right, you will see data of a similar study looking at the efficacy of acalabrutinib, where roughly three-quarters of patients did not have recurrent toxicity when they switched after having been on ibrutinib and experienced toxicity. So most of the time, this is very important information if you are going to make a switch to a different BTK inhibitor.

 

[01:00:20]

 

So this is about toxicity-related reasons. What about patients who have had disease progression on a BTK inhibitor, a covalent BTK inhibitor? Now, unfortunately, this is a high-risk group of patients, and the only prospective study evaluating the efficacy of venetoclax is on your left by Jeff Jones, et al.

 

This is a study that was conducted early on when venetoclax was becoming available. And you will see that in patients who had progression of disease on covalent BTK inhibitor, and the vast majority of these were ibrutinib, the median progression-free survival is about 2 years. So it is not a very effective long-term solution.

 

And so, in a more recent multicenter retrospective study, again, patients who had progression of disease on a covalent BTK inhibitor, and this included other covalent BTK inhibitors besides ibrutinib alone, the time to next therapy was about 30 months, which is approximately the same as a PFS of about 2 years, suggesting that once patients have disease progression on ibrutinib or any other covalent BTK inhibitor, this is a high-risk situation because patients, unfortunately, even with venetoclax-based treatment strategies, do not have a long-term progression-free survival.

 

[01:01:34]

 

So that constitutes 1 treatment option for patients who have had progression of covalent BTK inhibitor. There are recent data now suggesting that pirtobrutinib can be used in this group of patients.

 

So this is the BRUIN-321 study where all patients had relapsed CLL on a prior covalent BTK inhibitor-based treatment and were randomized to either pirtobrutinib alone or the combination of investigator's choice of either idelalisib and rituximab or bendamustine and rituximab with a crossover allowed at the time of progression of disease to pirtobrutinib. And as you can see on the right, that 119 patients were randomly assigned to 1 of the 2 treatment arms with a median number of prior lines of therapy in both treatment arms of 3, again, suggesting that this is a high-risk group of patients. And by design, all patients needed to have received a prior covalent BTK inhibitor-based treatment.

 

The primary endpoint was progression-free survival.

 

[01:02:30]

 

Which pirtobrutinib actually was superior compared to investigators choice of either BR or idelalisib-rituximab with a median progression-free survival of 14 months. And there was no difference in overall survival on the right. And this is obviously because there was crossover allowed.

 

Now, based on these data, just recently, as of a couple of days ago, the FDA granted full approval to pirtobrutinib for relapsed/refractory CLL after previous treatment with a covalent BTK inhibitor. And so I think, you know, this allows us to now use pirtobrutinib earlier during the lines of therapy. And so after progression of disease on a covalent BTK inhibitor, there is the approval for venetoclax and now pirtobrutinib as well.

 

[01:03:18]

 

And so, you know, this will then lead us to the next topic, which is, you know, what about a patient that has had progression of disease or has toxicity after venetoclax-based treatment options?

 

[01:03:30]

 

And so this is now a growing number of patients that are coming together with this particular scenario, given the approval of venetoclax and obinutuzumab in the frontline setting. And so here I show some data talking about covalent BTK inhibitor efficacy after venetoclax-based treatment in the frontline setting.

 

And you will see on the right that, again, much like the efficacy of venetoclax after covalent BTK inhibitor-based treatment, here the reverse sequence where you use a covalent BTK inhibitor after venetoclax-based treatment strategy yields pretty comparable PFS of about 30 months or so. This is a small study from Australia, but there are larger data sets that are now going to be presented at ASH this year. And I would encourage you to listen to the oral abstract session Monday next week, where they talk about the efficacy of second-line therapy after venetoclax-based treatment in the frontline setting with CLL13.

 

[01:04:34]

 

And this is if a patient has had progression of disease. But as you all heard Dr Hill talk about fixed-duration frontline strategy. And even in the relapse setting, you can do venetoclax and rituximab for 2 years and then stop treatment. So what about re-treatment with venetoclax both in the relapse setting as well as once you have received it in the frontline setting?

 

So data again here from the left show retreatment strategy with MURANO. So you receive venetoclax for 2 years, you stop, and then you have received rituximab for 6 months in the initial time period, and then you re-treat again. And you will note that in this patient population of 25 patients, when they were retreated with venetoclax and rituximab, the median progression-free survival was roughly 2 years.

 

Again, suggesting that it is feasible to re-treat with venetoclax in these group of patients. And that is certainly an effective treatment option. And on the right, you will see data from an ongoing prospective study called ReVenG, where patients get re-treatment with venetoclax and obinutuzumab after they have previously received venetoclax and obinutuzumab in the frontline setting.

 

And again, you will see here that there are a lot of interesting observations with great responses seen in the initial cohort of 15 patients, suggesting that this is an effective treatment strategy.

 

[01:05:58]

 

And so then, what about mechanisms of disease resistance? And this is becoming increasingly important because a lot of our patients, unfortunately, continue to experience disease progression. And it is important to be a little bit strategic about how would you pick an appropriate treatment option.

 

And so these are data from ibrutinib, initial data looking at what mutations you would see. And the most common mutations that are found are in the BTK and the PLC gamma 2 genes. And this is a large study of close to 400 patients where you will note that these mutations were mostly found in patients who had relapsed disease. So roughly 50% of patients that had progression of disease had a BTK mutation. In contrast, in the frontline setting, the number of patients with these mutations were rather small. Only about a quarter of these patients had the mutation.

 

Also, it is important to note that these mutations can occur early on, even before clinical progression occurs. And simply the presence of these mutations alone should not mandate a switch of therapy to something else, because you can have these mutations, and patients may actually be able to continue on the same drug for an extended period of time.

 

It is also important to note that these data now then suggest that the vast majority of the progression etiology or the reason for progression and the mechanisms of disease resistance is really outside of the BTK and PLC gamma 2 genes. And a lot of work is going on to try and elucidate that.

 

[01:07:34]

 

And I would draw your attention to this paper by Blombery, et al. in Leukemia that was recently published. But they actually very beautifully illustrate the different types of mutations that are occurring in patients who are on covalent BTK inhibitors. And so on your left, you will see that there are mutations that enhanced the BTK kinase function.

 

And these are the gatekeeper mutations, the T474I mutation or the cysteine 481S in the middle, which is a kinase-preserved BTK mutation. And then there are these increasingly identified kinase-impaired BTK mutations, including the L528W mutation. And so at the current time, we do not really pick the next line of treatment based on what these mutations are.

 

But there is a lot of work going on in the field to try and better individualize with precision medicine as to what the next treatment option should be for these patients. And then, of course, we also heard about PLC gamma 2 mutations that occur with all the covalent BTK inhibitors. And then on the right, you will note that there are also mechanisms of disease resistance being described in patients who receive venetoclax-based treatment.

 

[01:08:46]

 

And unlike BTK resistance mutations that occur on covalent BTK inhibitors, venetoclax or BCL‑2-directed therapy resistance is really a lot more than just simply mutations in the BCL-2 gene, because there are other reasons why there may be BCL-XL overexpression, MCL-1 amplification, etc., that really can drive a lot of these resistance mechanisms. And so it is more than just BCL-2 mutations alone that can explain resistance in patients who have been on a BCL-2 inhibitor.

 

[01:09:26]

 

And so finally, in the last part of my talk, I will focus on the far right, which is the double refractory group of patients who have received both a prior covalent BTK inhibitor and venetoclax, and how do you approach these patients.

 

[01:09:40]

 

And so unfortunately, this is a growing population because, as I mentioned, and you have heard that a number of our patients have received both a frontline covalent BTK inhibitor and venetoclax. And these patients, unfortunately, continue to experience disease progression, and the outcomes are quite poor.

 

[01:09:58]

 

There were 2 large series that were recently published, 1 from the European Research Consortium in CLL and the other from the Dana-Farber Cancer Center, where they evaluated the outcomes of these patients. And you can see that the median overall survival varied between 12-24 months, suggesting that this is a very high-risk group of patients that need to be included in a lot of our clinical trials that are ongoing. And we need to do a lot more to improve the outcomes of these patients.

 

[01:10:28]

 

And so what are some of the current treatment options, and what are things that are going on in clinical trials? So 1 of the treatment options, of course, is pirtobrutinib. And you heard about the use of pirtobrutinib prior to venetoclax in the 321 study. But here is the use of pirtobrutinib in the BRUIN study, where patients had received both a BTK inhibitor and may or may not have received a BCL-2 inhibitor. And this is a large study that included a variety of histologies. But we are going to focus here on patients who received pirtobrutinib for an indication of relapsed CLL.

 

And so a total of 282 patients were treated here. The median number of prior lines of therapy was 4, again, suggesting that this is a very high-risk patient population.

[01:11:12]

 

And again, you will notice that roughly 50% of patients had a TP53 disruption, either by del(17P) on FISH or a TP53 mutation. Roughly 85% of patients had unmutated IGHV genes. And roughly 40% of patients had a complex karyotype. Again, suggesting that this is a very high-risk group of patients.

 

[01:11:34]

 

And you will note that, you know, pirtobrutinib here really led to an impressive progression-free survival of 19 months.

 

And so, although this may not sound like a lot, it actually, in this group of patients, where the historic overall survival was about 12-24 months, a progression-free survival of 19 months is actually pretty good. And this drug is obviously approved in this setting. The progression-free survival was different according to whether the patients were BCL2 inhibitor-naive or they had previously received BCL2 inhibitors at 23 months and 16 months, respectively. And again, overall survival at 18 months was about 80%, suggesting that this is, you know, a very effective drug.

 

[01:12:19]

 

You can also see here in the forest plot that, irrespective of the prior lines of therapy, the reasons for discontinuation of prior BTK inhibitor-based treatment or the type of mutation in the BTK gene, pirtobrutinib was very effective.

 

[01:12:36]

 

Additionally, you will also note here in this table that the adverse effects of pirtobrutinib were pretty manageable. As you have heard, some of the more common complications of BTK inhibitors include atrial fibrillation or atrial flutter, bleeding, etc. And the risk of this complication was rather low at the grade 3 level in particular, thankfully, which, again, speaks of the excellent tolerability of this agent in patients with CLL.

 

[01:13:06]

 

A similar strategy is being employed for the use of this drug called nemtabrutinib, which is also a noncovalent BTK inhibitor. And this is being currently developed in patients with double refractory CLL.

 

[01:13:24]

 

And these are initial data from the Bellwave-001 study, where you will see it is a broad population of patients that are being treated, including a variety of different lymphomas. But we are going to focus here on the 57 patients who received this drug for CLL/SLL.

 

[01:13:44]

 

And you will note that there were 2 cohorts that were studied, cohort A and cohort B. Cohort A patients had a cysteine-481S mutation, and cohort B did not have this mutation. And although the number of patients are small at the current time, you will see that there are impressive responses, again, being seen with a median progression-free survival of roughly 15 months.

 

Of course, more numbers of patients with longer follow-up is necessary. But again, just to illustrate that similar to pirtobrutinib, another noncovalent BTK inhibitor called nemtabrutinib is currently under investigation.

 

[01:14:20]

 

So in addition to pirtobrutinib which is approved in the double refractory CLL setting, the other approach is the use of lisocabtagene maraleucel in CLL.

 

And this is CAR T-cell therapy, and I am sure all of you are familiar with how this works. And this is a standard protocol where 118 patients were enrolled. They went through liso-cel manufacturing, bridging therapy was allowed.

 

All got FLU lymphodepletion therapy and then were given liso-cel. And the standard DL2 dose was 100 million cells. And you can see that, you know, the median age of these patients was 65, with, again, a standard high-risk features as we have come to expect for all of these patients.

 

The overall response rate with the use of this treatment was about 48%, with a complete response rate of 19%.

 

[01:15:13]

 

And I think with longer-term follow-up, what has become apparent is that the overall median progression-free survival is about 12 months. And on your left, that is the curve here in purple. But it also depends on what response patients achieved after CAR T-cell therapy was administered.

 

And so if the patients had a complete remission, then they are way up on the top where the median progression-free survival is not reached. In contrast, in patients who unfortunately did not have a response, the follow-up after 20.8 months, the median response was only in about 3.7 months. And so, again, suggesting that if a patient does experience a response, then the responses really predict how long the progression-free survival lasts. And on the right, you will notice, again, that there are similar data with MRD status with patients who have achieved undetectable MRD experiencing a longer progression-free survival.

 

[01:16:18]

 

So in addition to the after-therapy response-predicting outcomes, there were also interesting data looking at the tumor burden in predicting response to CAR T-cell therapy.

 

Of course, this is prior to the administration of CAR T therapy. And you will note that patients who have less bulky disease, both in terms of lymphadenopathy burden, as well as a low serum LDH, actually had a better response, suggesting that it is best to give some treatment that can bring the disease under control before taking patients to CAR T therapy.

 

[01:16:54]

 

The side effects with standard CAR T therapy were pretty similar to what we have come to expect.

 

There were about 9% patients who experienced a grade 3 cytokine release syndrome and about 18% patients who had ICANS. Fortunately, there were no grade 4/5 cytokine release syndrome or grade 5 neurological events.

 

[01:17:20]

 

Now, you know, these data were impressive, but we also all know about the beneficial effects of BTK inhibitors in trying to improve T-cell function.

 

And that was exactly what was done in this subsequent study where ibrutinib was given in combination with liso-cel, where ibrutinib was continued and was given up to 90 days or even beyond for investigators' discretion. And this was a subsequent study after the original study that was completed.

 

[01:17:50]

 

And remarkably here, and although this is by investigator assessment, you will notice that in contrast to the efficacy from single-agent liso-cel, you will see that the complete response here has now gone up to 45%, and the median PFS has increased to 31 months compared to the 19% complete response and approximately 12-month PFS at a median with single-agent liso‑cel.

 

Of course, these are different groups of patients. The investigator efficacy might be differently assessed compared to a central review, etc. But these are very encouraging data suggesting that the combination might be the more appropriate route to go.

 

Thankfully, again, the CRS and neurological event toxicity was also lower. And then you can see that there were ibrutinib related grade 3 events were not significantly onerous for our patients to be able to have to deal with.

 

[01:18:44]

 

And this is, again, a similar table demonstrating the efficacy of liso-cel plus ibrutinib and relapsed CLL.

 

[01:18:54]

 

So in the last couple of minutes, I am going to review a few promising approaches, including BTK degraders.

 

[01:19:00]

 

So these are novel agents that are currently being used in the clinic that have shown a lot of hope and promise for patients with CLL.

 

[01:19:10]

 

The first 1 I will review is the NX5948. This has now got a name called bexobrutideg. And this is a BTK degrader that is being developed. About 60 patients have been treated so far in this study. Again, a high-risk group of patients with patients who have received either a BTK inhibitor or both a BTK inhibitor and BCL2 inhibitor. And roughly 80% patients with about 40% having a TP53 mutation.

 

[01:19:38]

 

And you will see that for the vast majority of these patients, there was a tolerable safety profile, with the most common grade 3 side effect being neutropenia.

 

[01:19:50]

 

With respect to efficacy, you will see that on the left, BTK degradation in vitro with these particular different types of BTK mutations was excellent with this compound. And that actually translated in the clinic, where you will see that in the waterfall plot, there was actually an impressive response for the vast majority of these patients. And this response was actually seen irrespective of the type of mutation that was present.

 

Again, suggesting that this is an effective drug that is currently being tested. And I believe we will hear updated data from this particular compound later on during this meeting at 1 of the ASH oral presentations.

 

[01:20:34]

 

A second compound that is also currently being tested, also a BTK degrader, is called BGB‑16673. Here, 66 patients were treated. Again, a high-risk patient population, 4 prior lines of therapy. All patients that received either a BTK inhibitor or the majority had received a combination of BTK inhibitor and BCL2 inhibitor previously. Again, a high-risk group of patients, roughly 65% had either del(17P) or a TP53 mutation.

 

[01:21:04]

 

And similar to the other compound here, the safety data were very reasonable. Again, the vast majority, grade 3 cytopenias were seen in the neutropenia setting.

 

[01:21:18]

 

But for the most part, the drug was well tolerated with an impressive overall response of close to 90%. And a median follow-up of 15 months, a PFS rate at 12 months was about 77%. And again, these data will be updated this year at the ASH meeting. And I think we will hear how these compounds are doing. And they are all now also being tested in combinatorial settings to try and improve the outcomes based on what we have seen as far as single-agent therapy is concerned.

 

[01:21:50]

 

And then finally, just talking about bispecific antibodies, we know that there are several in development. These are all CD20-directed targets. The 1 that has the most data in CLL is epcoritamab.

 

Here, patients were treated in 2 separate cohorts. The first 1 is the so-called expansion cohort, where patients received step-up dosing of epcoritamab starting at cycle 1, day 1, and then went up to cycle 1, day 8 at 0.8 mg. And then they had the first full dose by cycle 1, day 15. Because there was an increased risk of toxicity with this particular step-up dosing, there was a subsequent cohort of cycle 1, optimization cohort was enrolled, where instead of getting to the first full dose by cycle 1, day 15, this was achieved on cycle 1, day 22. And an additional dose was added in cycle 1, day 15.

 

[01:22:48]

 

And there were different numbers of patients treated, so 23 in the expansion cohort and 17 in the optimization cohort. Again, a high-risk group of patients, 4 prior lines of therapy with a variety of patients who have received a variety of different types of novel agents before getting on this trial.

 

[01:23:05]

 

And again, you will see that this led to an impressive 40% complete response rate in the expansion cohort with a progression-free survival at 12 months of about 52% and an overall survival of about 70%. Again, these are early data. We need to see longer-term follow-up with more patients. But this is also a very promising treatment strategy for our patients with relapsed/refractory CLL.

 

[01:23:29]

 

And as I mentioned, the adverse effect profile, particularly with the expansion cohort, was about 19% patients experiencing a grade 3 CRS event, which was almost zero at the optimization cohort, but all of that was not seen.

 

[01:23:49]

 

And so now, you know, let us return to the cases.

 

[01:23:53]

 

So this is the patient that we talked about, 58-year-old male, diagnosed with CLL 4 years ago, started an ibrutinib therapy, did well up until recently, and started experiencing progression of disease.

 

[01:24:06]

 

Physical exam, had lymphadenopathy and also had worsening cytopenias. And there is the presence of a cysteine-481 SBTK mutation.

 

[01:24:17]

 

So the question is, which of the following will not be a treatment option? So remember, this patient is having disease progression of a covalent BTK inhibitor, ibrutinib. And so which one would you not choose if you have to pick a treatment option?

 

1. Venetoclax/rituximab;
2. Zanubrutinib;
3. Pirtobrutinib; or
4. Venetoclax/obinutuzumab.

 

Okay, so I think after ibrutinib stops working, I think 1 of the questions is, you know, you should not consider the use of a covalent BTK inhibitor again, because it is unlikely to work. And so I think zanubrutinib would be the wrong treatment option for that patient who is experiencing disease progression on a BTK inhibitor.

 

[01:25:30]

 

So case number 2. A 64-year-old male was diagnosed with Rai stage CLL in 2016, received ibrutinib and rituximab, and then had progression of disease, and then got venetoclax and rituximab, and is now on single-agent venetoclax and is experiencing disease progression.

 

[01:25:46]

 

Question 3: In your current practice, which of the following would you recommend as a treatment option for this patient with progressive CLL, according to the 2026 NCCN Guidelines for CLL/SLL?

 

And the question is, which 1 of these would you now choose as a treatment option?

 

1. Acalabrutinib;
2. Duvelisib;
3. Glofitamab;
4. Pirtobrutinib; or
5. Zanubrutinib.

 

Perfect. So I think pirtobrutinib would really be the correct treatment option in this patient who has experienced progression of disease on 2 agents, including a covalent BTK inhibitor and a BCL2 inhibitor.

 

And so with that, I am going to hand it over to Dr Cortese, who is going to talk about managing adverse events. Thank you.

 

[01:26:43]

 

Dr Matthew Cortese (Roswell Park Comprehensive Cancer Center): Thank you so much, Dr Parikh and Dr Hill. It is my pleasure to be here, and thank you to Sarah for hosting us this morning. It is a sunny day here in Orlando.

 

And with that, I would like to begin managing some of the adverse events for our patients, actually with some of our agents we just talked about in the prior sessions.[01:27:02]

 

So in our current practice, how confident are you in your ability to devise supportive care strategies for targeted therapy-associated adverse events, which we use to improve clinical outcomes for patients with CLL?Not confident at all;

1. Low confidence;
2. Moderate confidence;
3. Confident; or
4. Very confident.

 

After this, you will be very confident. If you are not now, that is okay.

 

Great. So I see a mix of almost a perfect bell curve centered on modest confidence. I do not know if you can see that or not, but I can.

 

All right. So with that, I would like to begin our third case.

 

[01:27:52]

 

This is a patient requiring frontline treatment for CLL. This is a summative session where we are going to talk about some of the things that were already touched on by Drs. Hill and Parikh so expertly.

 

So we are going to start with a 66-year-old male with hypertension, hyperlipidemia, and obstructive sleep apnea. He is noted by his primary care physician to have a high weight count, over 50,000, weight loss, early satiety, night sweats. Labs, of course, confirm that.

 

Most of them are lymphocytes, so his absolute lymphocyte count is over 48,000. Hemoglobin is below 10, 8.9 g/dL. He is normal acidic. There are no micronutrient deficiencies. I just want to mention it is important to look for other causes of anemia before contemplating treatment and presuming it is CLL. But in this case, we are going to go ahead and assume it is from the disease, have the globin included in that hemolytic workup. Platelet count is 89,000, so less than 100,000.

 

So he is referred to his hematologist of choice for a workup, peripheral smear, etc., diagnosed with CLL. Molecular studies are performed and shows, basically intermediate- to high-risk disease. So he is 17P and TP53 intact. I just want to mention it is important to get next-generation sequencing for your patients to basically look at which algorithm to follow for our guidelines, centered on TP53, but other mutations do matter. We did update our guidelines on that, and I am proud to share and talk about that later.

 

So his CLL-IPI score is 6, high-risk. He lives 25 minutes from a small infusion center. Let us say he is up in Central New York, where I am from. There is no known cardiac or severe infection histories, and he wants to start a fixed-duration treatment.

 

[01:29:40]

 

So in your current practice, which of the following treatments would you recommend for this particular patient?

 

1. Ibrutinib;
2. Acalabrutinib ± obinutuzumab;
3. Zanubrutinib;
4. Venetoclax and obinutuzumab;
5. Ibrutinib and venetoclax; or
6. Acalabrutinib and venetoclax.

 

All right, so I see a good, healthy mix. I see largely CLL14 is the current choice with acalabrutinib-based combinations and zanubrutinib. Very little ibrutinib or I plus V use in this session.

 

[01:30:38]

 

Moving on, so I am not going to belabor this point, but just to talk about some of the side effects of BCL2 inhibitors. Our current and only approved drug for the moment is venetoclax.

 

We are looking for upcoming approvals for sonrotoclax and lisaftoclax in ongoing late-stage clinical trials, so I am sure we will be talking about comparing these agents in years to come after they are hopefully approved. But these BCL2 inhibitors are incredibly effective. I like to tell patients it is like having a battle essentially with your CLL as opposed to just blocking their growth. But they can trigger rapid apoptosis and something called tumor lysis syndrome, which I am sure we are all aware of.

 

[01:31:20]

 

Some of the other side effects, we also have to look not in isolation for these BCL2 inhibitors, we also have to look at them with respect to combination therapies as far as their side effect profiles to get the best efficacy results. So we have to look at some of these newer regimens, comparing essentially BTK plus venetoclax-based combinations and their effects.

 

We have to look, of course, at the side effects in the combination studies, and I will allude to the fact and talk about the fact that the risk of tumor lysis syndrome after covalent BTK inhibitor exposure for at least a few months is dramatically reduced, and we can also risk stratify patients for these side effects.

 

[01:32:07]

 

It is also important to talk about some of the infusion reactions, as Dr Hill alluded to already. This is, I think, a nice summary of some of the slides and infusion-related reaction rates. They are very common, generally low grade, and generally manageable and predictable.

 

[01:32:24]

 

In our patient's case, we are going to talk and continue. So he is opting to receive venetoclax and obinutuzumab, as many of you all have selected as well, for the CLL14 trial.

 

He started on treatment with obinutuzumab, but unfortunately, at the center, premedications were not given, and he develops a significant infusion-related reaction, requires epinephrine and ICU admission, pulse steroids and antihistamines, etc. We are going to ask, could this have been predicted? To a degree, yes.

 

So his lymphocyte count was over 25,000. He had some bulkier disease. He did have some cardiovascular risk factors. Could this have been prevented? As Dr Hill expertly alluded to, generally yes. So premedication with liberal uses of steroids, antihistamines, largely Benadryl in the very beginning, even despite older adults, you know, it not being a preferred drug on our beers list for elderly patients, we still will give it for this first treatment at least, generally.

 

I tend to give things like famotidine and montelukast for full histamine blockade for the first 2 doses, certainly for patients with bulkier disease, or I opt to treat in a different way to spare patients some of these really dramatic infusion reactions. So specifically, I just want to mention if people have bulky disease and have cardiovascular risk factors or advanced age, there is a signal of mortality if you are not careful in optimizing at least your premedications prior to infusions. And again, BTK lead-in therapy or actually starting with venetoclax, for example, even with an inpatient, you know, 1-day observational tumor lysis syndrome observation period can dramatically lower your risk for infusion reactions in the future, basically.

 

So you can choose your agent carefully in the very beginning, especially important for bulky disease.

 

[01:34:23]

 

So despite recovering fully from his unfortunate grade 4, near 5 infusion reaction, our patient is now terrified, does not want any more additional infusion treatments. He wants only venetoclax as monotherapy.

 

His ALC remains elevated, but this is, again, just immediately after his initial first dose, but his white count has dropped to, I am going to say, 24,999. ALC is 18,000. That is going to be important in a moment. And then his hemoglobin has just changed a little bit, and platelet counts stay relatively stable. CT scans are performed during his decompensation, and his maximum lymph node size is 4.5 cm. Spleen is 15 cm craniocaudally, and his labs are otherwise normal.

 

So can he start venetoclax as an outpatient at this point, despite what he is already gone through? And the answer is yes.

 

[01:35:26]

 

So this is per the label for venetoclax. There is a guideline, an algorithm, basically, to risk-stratify tumor lysis syndrome risk for patients. It is really defined by maximum lymph node size and absolute lymphocyte counts. It is important to note that we should be prescribing allopurinol with your venetoclax starter kit. Usually, I prescribe with an anti-nausea medicine like Compazine and prochlorperazine or Zofran, for example. And it is important to encourage hydration as well. And there are starter kit education packets out there as well, just so you are aware. It comes with a free water bottle.

 

And it is important, basically, to follow these guidelines, I think, generally to the letter, although there is some room for leeway, which we can talk about in the Q&A if there is time.

 

So can he start venetoclax as an outpatient? The answer is absolutely yes. As I mentioned, we are going to follow the protocol. He has TLS labs checked at 6 and 24 hours post his initial treatment.

 

[01:36:24]

 

And fortunately, he is meeting the data showing that, generally speaking, the risk of tumor lysis syndrome, once you follow these parameters, is very, very low. So he is actually technically low risk. And sure enough, he is no exception to the 0% TLS risk and does well as he starts his treatment.

 

[01:36:46]

 

So this is just a little snapshot from 1 select study with AMPLIFY, which is acalabrutinib with venetoclax compared to the same combination with obinutuzumab as a triplet in AVO compared to chemotherapy. And essentially, the risk of tumor lysis syndrome was about 1%, so it was really low. And patients generally did extremely well.

 

So essentially, tumor lysis syndrome is manageable. It is something that should certainly be considered. I generally advise our community colleagues who are uncomfortable to refer to an academic medical center, where we can help basically ramp up patients who especially have extensive comorbidities or lots of disease risk and burden. And we are very happy to help essentially start the drug safely and then continue and catch and release back to your capable hands as well.

 

So 1 of the takeaways I just want to mention is that lead-in BTK inhibitor treatment can reduce your risk of tumor lysis syndrome to actually less than 1%, frankly, at least in the AMPLIFY protocol. It was 2 months of acalabrutinib lead-in.

 

[01:39:30]

 

Now we are going to continue our case.

 

So our patient's taking venetoclax. He has basically enjoyed an okay course. He does have some cytopenias after a few weeks of treatment, but he gets through it. His ALC is now 1,500. His ANC is a little bit low. His hemoglobin is 7 g/dL, platelet count of 50,000.

 

Is this expected, I guess, as well as some arthralgias, fatigue and intermittent loose stool. So to a degree, yes. So normal marrow cellularity, it is important to remember, is 100 minus age. So this gentleman has, on a good day, a third of his marrow would be functioning normally with hematopoietic stem cells. And he, of course, has baseline CLL involvement with marrow infiltration with cytopenias. He did not have prior infections in our case or probably much malnutrition. But it is also important to note that BCL2 inhibitors are myelosuppressive, but most patients, frankly, will adapt in the first 3 months.

 

My practice is actually to continue with treatment generally at full doses with aggressive supportive care, including growth factor support and transfusional support if needed with close lab monitoring.

 

[01:40:46]

 

And I know a lot of folks in the community are not comfortable necessarily treating like that, but that actually, I will show you in a moment, has some data to support the practice.

 

So how are we going to manage him now? So we are going to try to continue his doses at near maximal ranges, 300-400 mg daily where possible. We are trying to optimize the clearance of his CLL and basically trying to target a dose of around 70% over the course of his treatment.

 

So if you need to do a brief interruption due to intolerance and then resume treatment, say, pause for a week, that is completely reasonable. And I do that all the time as well. But it is important to try to get back on treatment, back on track to maximize our progression-free survival and time to next treatment, and eventually overall survival outcomes.

 

So what about 3-12 months or so into treatment? Let us say he is in the middle and then later on in his course. So after 3 months or so of treatment, I generally have a little bit more leniency for dose reductions.

 

Generally speaking, the CLL has been cleared, especially if you are getting it in combination with obinutuzumab or with a BTK inhibitor. But generally, I try to maintain a dose around 300 mg per day on average. And if we are MRD-negative, as Dr Thompson presented last year as an oral abstract from Lindsay Rucker's study, basically, if patients are MRD-negative using NGS-based assays at 6 and 9 months into treatment, it is actually limited to consider stopping treatment if there is intolerance. Generally, I will try to push patients through their complete treatment all the way through at least the 12 months or using an MRD-guided approach, as we are going to talk about as well on our guidelines. But it is important to note that there is some data to support that practice if needed.

 

[01:42:34]

 

So this patient continues venetoclax despite having these low cell counts and mild symptoms. He has twice-daily lab checks with possible transfusions on standby. He is given a multivitamin to cover our bases with support intake from some nausea, and reassurance that his counts should eventually recover. And sure enough, they do.

 

At about 3 months or so, his counts dramatically improve, just minimal fatigue and nausea. His GI side effects go away. He completes his 12 full months of treatment. He achieves the optimal MRD^-6, which is a negative complete remission, and it lasts for about 4-plus years essentially just with venetoclax monotherapy.

 

[01:43:16]

 

There is an excellent paper by our colleague, Dr Al-Sawaf, who is going to be presenting that same presentation on Monday, as Dr Parikh alluded to. I am sorry. He has published a CLL-14 regimen. Excuse me. Dr Niemann's presenting, I think, the plenary on Monday.

 

Basically, this shows that the dose matters essentially and that fitness matters. But for me, the main takeaway was that a dose reduction to no more than around 70% or so is what you can get away with, basically to achieve optimal PFS and time-to-next-treatment outcomes. But otherwise, it is a very safe and effective regimen, including for those with advanced age and some frailty.

 

[01:44:00]

 

So we are going to move to second-line therapy. Our patient enjoys a 4-year complete MRD-negative remission. He then has a 3-year course of some progressive lymphocytosis, low-tempo. We are going to keep watching and waiting him per our guidelines, looking for indications for retreatments, which mirror those of frontline treatment.

 

At the age of 73, he developed some worsening CLL-related cytopenias. He is got an enlarged spleen again, and he has got some unintentional weight loss with early satiety as well. So clearly, he is going to benefit from retreatment.

 

Now, unfortunately, he does have some significant hypertension. It is not really all that well controlled on 2 drugs. He has got some early-stage kidney disease, likely as a result of that.

 

His venetoclax retreatment is trialed. This, again, will come up on Monday, and it has been published widely as well. So it is reasonable to try. But unfortunately, in his case, results in only a partial response and then progression, actually, within the span of 6 months. So he is the unfortunate 15% of patients who sub optimally responds, and becomes primary refractory while taking the drug. So he is now considered refractory, growing on treatment.

 

We do a next-generation sequencing test, and unfortunately, he is developed some NOTCH2 mutations, which can upregulate MCL1, as we showed, is not covered by our VCL2 inhibitors. And then TB53 mutations are detected as well. So he has now developed high-risk disease.

 

[01:45:26]

 

Poll 4: In your current practice, which of the following treatments would you recommend for this patient?

 

In our current practice, which of the following treatments would you recommend for this particular patient? Again, he is been treated with essentially Ven monotherapy with a dabble of obinutuzumab, never wants infusions again.

 

1. Ibrutinib;
2. Acalabrutinib ± obinutuzumab;
3. Zanubrutinib;
4. Pirtobrutinib; or
5. CAR T-cell therapy with lisocabtagene maraleucel.

 

All right, so I see a mix of acalabrutinib, zanubrutinib, and pirtobrutinib, so we will talk about that.

 

[01:46:23]

 

So this gentleman, of course, has not seen a BTK inhibitor, actually, despite gutting it out, so to speak, for years. He has enjoyed years of remission.

 

BTKis, of course, have shared toxicities, including atrial fibrillation. Aspirin-like antiplatelet effects, like bruising, are extremely common. Major bleeding, things like bleeding in the head or in the gut, are extremely uncommon, generally less than 1%. Patient selection is important here. B-cell suppression and infection risk can come with that as well. Generally, it is a little bit less than with the anti-CD20 monoclonal antibodies, because you are not clearing the cells quite as efficiently, frankly.

 

A little hypertension is generally of concern more with ibrutinib and zanubrutinib, but a little whiff with acalabrutinib as well, and a little even similar low-whiff signal in pirtobrutinib. Cytopenias and some gastrointestinal side effects can be expected for some as well. I think it is important to mention that patients who are treated with antiplatelet therapies, like aspirin or clopidogrel, with BTK inhibitors, basically have a higher bleeding risk, even than those treated with anticoagulations with, say, DOACs or, God forbid, things like Warfarin.

 

[01:47:42]

 

I think this was maybe shown briefly by Dr Parikh, but basically it is just important to know that there is a different kinome and spectrum of activity for these drugs. Ibrutinib, of course, was the first approval and still beat chemotherapy despite having the broadest kinome. Some of the favorable effects we are seeing now, repurposed pre-cel therapy, as was already mentioned expertly by Dr Parikh. Acalabrutinib and zanubrutinib have a similarly narrow spectrum of activity. Acalabrutinib is a little bit less than zanubrutinib, and we will talk about some of the implications for these in a moment.

 

[01:48:18]

 

But as far as a head-to-head comparison of acalabrutinib and ibrutinib, this was the ELEVATE‑RR study, so patients who were previously treated basically had been BTK-naive, so our patient would have been eligible, and basically now has high-risk disease.

 

[01:48:32]

 

So acalabrutinib essentially was safer and better tolerated than ibrutinib with similar progression-free survival rates and greater adherence rates with less cumulative incidences of atrial fibrillation or flutter, less risk of hypertension, less bleeding events, less diarrhea, and less arthralgias. So generally speaking, as we will talk about, these second-generation covalent BTK inhibitors are preferred over ibrutinib.

 

[01:48:58]

 

Zanubrutinib similarly was compared against ibrutinib, as was mentioned in the ALPINE trial. Again, also relapsed/refractory patients.

 

[01:49:08]

 

And again, was superior in terms of atrial fibrillation and flutter. Also, superior in terms of cardiovascular disease risks. It was actually superior in progression-free survival as well, which was already mentioned. But it was basically similar in hypertension rates.

 

If you look into the detailed data, you will see that the diastolic hypertension rates were similar, but the systolic hypertension rates were slightly less with zanubrutinib as well. So take that for what you will. But again, related to just how these drugs are made and which other kinases, generally off-BTK kinases, they target.

 

[01:49:46]

 

So as far as managing comorbidities for patients and adverse events for patients treated with BTK inhibitors, generally for anyone who is hypertensive, like our patient is in our scenario, you really want to avoid ibrutinib at all costs, unless that is the only drug you really have available in your back pocket outside the U.S., for example. Acalabrutinib is generally preferred over zanubrutinib for patients with uncontrolled hypertension. And you can consider also, again, not for our patient, but the BCL-2 inhibitor-based treatment as well.

 

For those with gastrointestinal issues, say they have comorbid Crohn's disease or GI intolerance with the drug, we generally will offer supportive care medications. We look for other causes of GI side effects and basically try to manage as best you can with dose interruptions and dose reductions, generally temporarily. And if they are essentially uncontrolled and persistent, we are comfortable, as Dr Parikh mentioned, switching between BTK inhibitors within their particular class, and you can try to see if it is a drug-specific side effect as opposed to a class effect.

 

For patients with headache, especially severe migraine histories, you might want to avoid acalabrutinib, which has that unique headache risk, although I find that to be readily manageable with, again, dose reductions, dose interruptions, and, generally speaking, just with Tylenol. Of course, it is really important to mention if someone has the worst headache of their life, like a thunderclap headache, or any neurological issues, they need to go to the ER immediately and stop the drug and have platelets ready, looking for intracranial hemorrhage as well as the devastating potential complication of any treatment since it thins the blood.

 

And then atrial fibrillation, this is a mixed bag of practice, but generally speaking, we want to avoid BTK inhibitor-based therapy if patients have uncontrolled AFib. I consider that more of an absolute contraindication if patients have other options that are workable, essentially.

 

In this case, this gentleman really would benefit from a BTK inhibitor. You could try infusion-based treatment, but he probably has lots of disease burden and would never want that again, so this is something you would probably want to talk to a cardiologist about to see if they can get the atrial fibrillation under control for you. In his case, maybe look at a sleep study and see if his sleep settings are working for his sleep apnea, for example.

 

You want to avoid ibrutinib for these patients as well. Again, there is a signal of increased risk for ventricular arrhythmias with ibrutinib, not just atrial arrhythmias. Basically, you can safely treat if needed, but again, proceed with caution with cardiology. It is generally speaking not fun to treat patients with AFib. Although patients with known AFib that is well-controlled, generally speaking, in consultation with cardiology, you can consider treatment, but just proceed with caution.

 

[01:42:34]

 

I think I already mentioned with anticoagulation, antiplatelet-based therapies have a higher bleeding risk than venous anticoagulants. For me, I want to hold any of those treatments and consider pausing the BTK inhibitor and restaging or looking for other causes of low platelet counts if it is under 50,000, generally speaking for me.

 

I already mentioned antiplatelet therapy, so I am going to talk about skin and fingernails. It is generally a common side effect with ibrutinib. EGFR is 1 of those off-target kinases that are blocked by the drug, so we switch to an alternative agent, as probably would have been mentioned in the very beginning if patients come in to see you on ibrutinib. It is important to at least mention the second-generation BTK inhibitors as reasonable options to take them off ibrutinib if needed.

 

Although I find if patients are on ibrutinib for a long period of time with no side effects, you can get away with dose reductions, say to 280 mg daily. Basically, you can even stop treatment as well, and patients, generally speaking, will be in remission for some time after you stop, more so with ibrutinib, actually, given its immunologic effects.

 

As far as new and worsening cytopenias, you always have to consider an acquired cause that is acute, things like infections or bleeding, but you also have to see things that are subacute or chronic, things like immune cytopenias or malnutrition or myelodysplasia. Of course, DIC is always a major concern if you see that. Of course, you can dose-interrupt and potentially change treatment accordingly.

 

[01:54:14]

 

There was an excellent study by Dr Huntington, et al. It was a retrospective study, basically looking at discontinuation rates and tolerability of treatments. There was some signal that BTK inhibitors are discontinued a little bit more than venetoclax-based treatments, but take it for what you will.

 

Essentially, you can start with what you would like and are confident in, in my opinion, as long as you are following our guidelines and really taking into account the patient's preferences and their comorbidities, which will all, I think, have common ground to find at the end.

 

[01:54:48]

 

Moving to second-line therapy for our patients. He is 74 years old now. He elects to proceed with treatment with acalabrutinib, given the concern for hypertension with zanubrutinib and especially ibrutinib.

 

He improves significantly despite a low-grade headache. He takes 100 mg daily for a couple of days and some Tylenol, but it does not go away for a couple of weeks. He does not panic. We have told him that he has an expected lymphocytosis with any BTKi-based treatment, again, because chemokine receptors are also impacted by BTK inhibition. These cells become loosened from his lymph nodes and from his spleen. They circulate into the blood, and they slowly die over months, if not years.

 

[01:55:30]

 

Then he enjoys a 6-year-long remission until, at age 80 now, he develops worsening bicytopenia with lymphocytosis. He has got bulky disease. He has got splenomegaly. Flow cytometry, of course, confirms the worst. We do NGS testing. He now has picked up not only his NOTCH2 and TP53 mutations, which have been persistent, but he also now has a C481S mutation with a high variant allele frequency.

 

He is sad. He is afraid he is going to need chemotherapy. He thinks he is going to die, but you offer hope in the form of a noncovalent BTK inhibitor.

 

[01:56:02]

 

Basically, just a key point, if patients have progressive disease on a covalent BTK inhibitor, I just want to emphasize what Dr Parikh had mentioned. You should not be going back to the same second-generation covalent BTK inhibitors, except in the rare cases where you are consulting with a specialist, but generally you want to go to the noncovalent or out of the class entirely or onto a clinical trial.

 

Basically, I think it is important to check a next-generation sequencing test if there is progressive disease with a BTK inhibitor, looking for specific mutations that may or may not be covered by certain agents, and then if you are going to be starting pirtobrutinib per the traditional accelerated approval label after patients have been double exposed, so to speak, I think it is important to refer, at least, to discuss eventual CAR T-cell therapy.

 

[01:57:00]

 

This is just to highlight again that pirtobrutinib, in particular studied in the BRUIN CLL-321 study, was extremely well-tolerated with very, very low rates of atrial fibrillation or flutter or bleeding or hypertension, some low-grade but certainly not much grade 3+, so it is a very, very safe and well-tolerated and effective drug.

 

[01:57:20]

 

And then CAR T-cell therapy, as was mentioned, is a living drug. Basically, patients' T-cells are modified and manufactured and put back in the body. We know about toxicities like cytokine release syndrome and ICANS. Dr Parikh mentioned these briefly, but there are also these cytopenias you can get that can be complex and they can come in waves in different stages with different pathophysiologic bases, essentially. You have to look for acquired hypogammaglobulinemia, especially for these patients who have been treated, and then some rare hematologic or secondary cancer risks as well. Although the risk of secondary T-cell lymphomas is incredibly low, I want to mention. It has been a concern in the past. Multiple publications have showed that it is incredibly rare, fortunately.

 

[01:58:05]

 

So in conclusion for our case, he gladly accepts and starts his pirtobrutinib. He enjoys a good partial response for a couple of years because we have referred him to a CAR T-cell center.

 

While he is still responding to the drug, he basically is able to complete leukapheresis. He begins to experience, however, some indolent progression while the cells are being manufactured. He is then treated with a BTK degrader, as was mentioned, on the clinical trial, and he has debulked optimally, so he has got a good outlook on life here.

 

He then proceeds forward with CAR T-cell therapy with liso-cel. He experiences some grade 2 CRS, so he has got a little fever, maybe some low blood pressure that is easily manageable given Toci for a dose. He has a little bit of a bumpy ride, but then he has this MRD-negative complete remission and a chance for durable remission of treatment.

 

[01:59:00]

 

With that, I just want to highlight our NCCN guidelines for patients with CLL and SLL. I am honored to be here on behalf of our committee.

 

And thank you for your time and attention. I will go back to Dr Parikh to help us moderate and answer some questions.

 

Mandi Murph: Thank you, Dr Cortese, for that presentation. It was excellent. Before we go into our Q&A session, we just want to revisit some questions for the audience.

 

[01:59:28]

 

We have a couple of polling questions. So first, if you can see the poll audience, please respond. How many people or patients with CLL/SLL do you provide care for in a typical month?

 

1. 1-4;
2. 5-7;
3. 11-15;
4. 16-20;
5. More than 20; or
6. Not applicable.

 

Okay, let us go ahead and close this out and bring up our next polling question.

 

Which best describes your practice setting?

 

1. Academic
2. Community; or
3. Not applicable.

 

Please go ahead, audience, and poll in.Okay, and we will go to our next question.[02:00:34]

 

And in this question, in your current practice, how confident are you in your ability to devise supportive care strategies for targeted therapy-associated adverse events to improve clinical outcomes for patients with CLL?

 

1. Not confident;
2. Low confidence;
3. Moderate confidence;
4. Confident; or
5. Very confident?

 

Please go ahead. Okay, let us go ahead and close out that poll and move to our next question.

 

[02:01:14]

 

Poll 5: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No; or
3. Uncertain.

 

[02:01:34]

 

Poll 6: Please take a moment to text 1 key change that you plan to make in your clinical practice on this education.

 

And then our final polling question for today. If you would please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

 

And as you are doing that, I want to go ahead and transition to our Q&A session and hand it back to Dr Parikh and the faculty for some questions and answers.

 

Dr Parikh: Thank you, Mandi. Dr Hill, Dr Cortese, thank you very much for your excellent presentations. I think we have about 8 minutes or so for some Q&A.

 

So there are a couple of questions that I see in the chat box, and maybe I will start with you, Dr Cortese. This first question that asks about the role of a concomitant BTK inhibitor to improve the efficacy and toxicity profile of CAR T therapy. You know, there are some preclinical data suggesting that ibrutinib is perhaps the best combination.

 

What is your experience, and how do you think about this? You know, there are also some data suggesting that maybe pirtobrutinib might also be an effective treatment strategy. So how do you approach this in your practice?

 

Dr Cortese: I think it is a great question. I think really it does depend on the overall premise to not kill your patients, right? So always be mindful of safety first.

 

So if patients, again, have uncontrolled hypertension or ventricular arrhythmias, I would not start ibrutinib, even though it does look appealing as a pretreatment strategy pre-cel therapy. That said, though, if it is a time-limited course, you really want to maximize your CAR T-cell therapy outcomes as much as possible. It is a potentially curative strategy for some patients, and you want to try to give patients their optimal outcome.

 

So I think for many, though, it is a good strategy, actually, with ibrutinib. And in my opinion, it is related to the ITK blockade, inducible T-cell kinase, IL-2 T-cell kinase effects. And basically, though, it does seem appealing, and I think it will work.

 

Dr Parikh: Yes, yes. Sorry. No, go ahead. Finish up.

 

Dr Cortese: I just want to say achieving disease control and being optimally debulked is going to be the most important strategy in not killing your patients, keeping them on track. But if you do have the ability to give some ibrutinib pre-leukapheresis at least, say, for a couple weeks, I do think that is a really reasonable strategy.

 

Dr Parikh: Right, right. And I think, you know, originally it was thought that maybe it is the ibrutinib as a more promiscuous BTK inhibitor. Maybe you need that, but I think there is an abstract looking at pirtobrutinib right before CAR T therapy, and it shows that even that has a beneficial effect that is being presented by Dr Shadman, I believe, and colleagues. It is a multicenter experience. Of course, it is a retrospective study. So I think some BTK inhibition in addition to CAR T therapy appears to be beneficial. Of course, these are small numbers of patients. We have to see the poster and the full paper, etc., but it certainly appears to be a promising strategy.

 

Dr Hill, if I can maybe ask you about how would this new pirtobrutinib approval, how is that going to, you know, change your treatment sequencing? And I think really the question is, after a covalent BTK inhibitor failure, would you reach for pirtobrutinib or would you reach for a venetoclax-based treatment strategy?

 

Dr Hill: Great question. Historically, the approval of pirtobrutinib, the first approval was in the double refractory, so, exposed to covalent BTK inhibitor as well as BCL2 inhibitor, and now we can use it in earlier lines of therapy. I think for many patients who are relapsing after a covalent BTK inhibitor, we do not really know what the best answer is.

 

I think a lot of it does depend on their mutation. If they have a C481S, for instance, those are probably going to respond really well to pirtobrutinib, whereas if they have other mutations or unknown mechanisms of resistance, then venetoclax may be better. But I think this is an area where we need more data going forward.

 

Dr Parikh: Yes, I agree. Dr Cortese, anything else that you want to add?

 

Dr Cortese: I fully agree. I really like the FDA approval currently as it stands. You have to treat with a covalent BTK inhibitor first before you go to a pirtobrutinib.

 

I think that is reasonable, as the drug was designed for that, and we need definitely more long-term follow-up. I am really excited to see if the response times and the median time to progression or next treatment is longer in the second-line plus setting with pirtobrutinib compared to its traditional accelerated approval label before. So we will see with more follow-up.

 

Dr Parikh: Yes, I know that sounds great. Dr Cortese, you mentioned the use of acalabrutinib over zanubrutinib for patients who have hypertension. This is a question that comes up all the time in the clinic. Which 1 do you choose? Do you use acalabrutinib or zanubrutinib? Maybe you can provide some context of how you approach this question in the clinic.

 

Dr Cortese: Absolutely. First, they are both amazing drugs. I think that 1 of the key take-home points is to really avoid ibrutinib as a new start for the vast majority of patients, just given the fact that both of these drugs were compared against ibrutinib, and certainly all of them are better than chemoimmunotherapy.

 

That said, though, acalabrutinib is dosed twice per day. Zanubrutinib can be twice a day or once a day. Patients who have a hard time with adherence, it is very important, of course, to take the drug if you are going to expect a response from the drug. I think that is 1 discriminating factor between them. If someone has issues with, say, pill fatigue, I might go with zanubrutinib daily.

 

Similarly, for dose reductions, if you want to get away with once a day, maybe half-dosing, the half-life of zanubrutinib is a little bit longer than acalabrutinib and has higher BTK occupancy, whether that is clinically impactful or not. I think we need a little bit more follow-up data, and I would love, of course, a head-to-head trial, which we are never going to get, unless we do an Alliance study, for example.

 

But basically, they are both amazing drugs. Generally speaking, if someone has hypertension, they are on, say, at least 1 drug or they have effusions, they have more cardiovascular risk factors. I generally lean more toward acalabrutinib. I just find it to be a little bit cleaner and safer for my patients, but it is reasonable with close monitoring and input with primary care and cardiology to consider either drug. They are both really, really good.

 

Dr Parikh: Awesome. Thank you. I think in the last couple of minutes, maybe we can just talk about just a general question.

 

Obviously, we are doing this at the ASH annual meeting. Dr Hill, maybe you could tell us your favorite abstract that you are really looking forward to at the upcoming meeting.

 

Dr Hill: Yes, sure. At this year's ASH, we are going to be seeing at the plenary session on Sunday the results of the CLL17 study from Germany, which is, again, a 3-arm study comparing continuous ibrutinib vs time-limited ibrutinib with venetoclax, and then a third arm would be the time-limited venetoclax-obinutuzumab The abstract is available.

 

The conclusion is that they are not inferior to each other. Essentially, with the follow-up we have, have similar outcomes. I will be interested in seeing the upcoming peer-reviewed publication in some of the more detail.

 

Dr Parikh: Yes, that is great. Dr Cortese, any other abstracts that have caught your attention that you are looking forward to?

 

Dr Cortese: I think all the data at this ASH looks really fantastic. I am actually most interested in some of the novel agents and seeing some of their data emerge, especially the BTK degraders, their durability, their ability to overcome certain resistance mutations. I will be looking really into that high-need space for select patients.

 

+85% of our patients, at least for now, are well covered with our current armamentarium, but I am really excited to see new potential strategies to help the highest-risk patients.

 

Dr Parikh: Yes, wonderful. Thank you. I agree.

 

I think some of the data regarding the use of novel agents, particularly in Richter's transformation and understanding of the genomic aspects of the causes of Richter's transformation, which is, of course, the occurrence of large-cell lymphoma in our patients with CLL, have caught my attention. Because that is, again, much like double-refractory CLL, an area of unmet need.