Diagnosis and Initial Workup

Let us just go through the diagnosis and initial workup. Typically, diagnosis is made with flow cytometry. Basic labs would include, obviously, CBC, CMP, a FISH panel is typically done, and for patients who need therapy, you would want to also know the mutational status, the IGVH mutational status, as well as the TP53 mutational status. Imaging is not always needed. You could consider doing it if you are feeling significant adenopathy or if the patient has significant splenomegaly. Just so that in the future you could assess the response with future imaging as well.

Obviously, if they have bulky adenopathy, that is also important to know if you are initiating therapy with venetoclax for TLS, prophylaxis. A PET scan is typically not needed in a patient with CLL unless you are suspecting there is Richter's transformation so that it could guide you to the site of a biopsy. Typically, a bone marrow is not needed at diagnosis, but it should be considered at the time of treatment.

Because sometimes these patients come in with cytopenias and most of the time they will be related to CLL but once in a while, you will see a patient who's coming in with Cytopenia who actually has another issue going on like MDS, or autoimmune cytopenias that might not have significant involvement in the bone marrow.

[00:18:58]

Prognostic Variables in CLL/SLL

These are tools that we have. The FISH studies we would focus on the 17P deletion, the karyotype to look at complex cytogenetics, NGS, and the most important, there is going to be TP53. Although there are other things that you could look out for as well, they may not be important initially at the time of initial management, but things like NOTCH1, for example, can sometimes be associated with higher risk of Richter's. You could sometimes pick up BTK mutations that patients could be refractory to BTK. Again, these are usually going to be patients who are already on therapy and they are progressing on it.

[00:19:41]

CLL: Dynamic Monitoring vs Treatment

When patients come in, a third of them will be an observation and they will never need treatment. Another third will start out with observation and then they will need therapy in the future. The third will present with CLL in the beginning needing therapy at the get go.

[00:19:59]

Indications for Treatment

Does everybody need therapy for CLL at the beginning? No, because as I said, about a third of patients will never need therapy. Typically, therapy is indicated. There is the iwCLL 2018 criteria but the bottom line is a patient is symptomatic. They have bulky, splenomegaly or bulky adenopathy. They have cytopenias, most commonly anemia. Hemoglobin less than 10 or 11. Platelets less than 100,000. B symptoms, although sometimes patients will come in with fatigue and those can be multifactorial so you have to put that in mind as well. If you have autoimmune cytopenias that are not responsive to steroids or rituximab, that can be another reason. A rapid doubling time, so a lymphocyte count that is rapidly doubling in less than 6 months can be considered an indication. The absolute lymphocyte count is not typically an indication for therapy. It is very rare to see leukocytosis in these situations.

[00:20:58]

Background: Firstline Chemotherapy Is Inferior to BTKis and Ven/Obi

We know now from multiple studies that novel therapies are superior to chemoimmunotherapy. For example, the ALLIANCE study looked at ibrutinib-rituximab vs BR. The ECOG study at the top right here looked at ibrutinib-rituximab vs FCR. Actually, the ECOG study did not only have PFS advantage but also overall survival benefit. The SEQUOIA study at the bottom right here looked at zanubrutinib vs BR with a very significant PFS as you see.

[00:21:28]

First-line Treatment: Guideline-Recommended Options

The use of chemoimmunotherapy now has significantly decreased so, bendamustine-rituximab or FCR are both inferior to novel therapies. When we are seeing these patients, we used to have a few options, but now we have a lot of options. Typically, the conversation that you want to have with your patient is, do you want to be on a continuous pill? It is relatively convenient and easy to start with not a lot of monitoring.

There you have the acalabrutinib, zanubrutinib, ibrutinib. Do you want to go on a time-limited therapy option? We have here the venetoclax-obinutuzumab, requires a little bit more monitoring in the beginning. There are infusions associated with it, but then at the same time, it is also time limited for a year. We now also have the option of venetoclax-acalabrutinib, all oral therapy that is fixed duration, as well as venetoclax-ibrutinib. Although most of us now are using second-generation BTKs.

Now there is obviously the evolving strategy of using MRD guidance to determine the duration of therapy rather than use a fixed duration for everybody.

[00:22:37]

ELEVATE-TN 6-Yr Follow-up: PFS With Acalabrutinib ± Obinutuzumab vs Chlorambucil

We will go through the trials that led to continuous BTK inhibitors to elevate TN. This is the 6-year update. Looked at acalabrutinib-obinutuzumab vs acalabrutinib vs obinutuzumab-chlorambucil. Acalabrutinib-containing arms had a superior PFS, as you could see here. The Obinutuzumab addition did improve the PFS, but at the same time it is associated with more toxicity, particularly COVID-related deaths.

[00:23:07]

SEQUOIA 5-Yr Follow-up: PFS With Zanubrutinib vs BR

Zanubrutinib. This is the SEQUOIA study. You can see here on the left hand side, clearly a PFS benefit with zanubrutinib compared to BR. Even in the subset of patients with mutated IGHV, you could see on the right-hand side here that zanubrutinib still did better even in the group of people who had mutated IGHV.

[00:23:32]

SEQUOIA Arm C: PFS and OS in Patients With del(17p)

Recently the SEQUOIA Arm C was presented. This is for patients who had 17p deletion. You could see here superior PFS, 72.2% in these high-risk patients.

[00:23:47]

cBTKi Head-to-Head Comparisons

Covalent BTK. Which 1 to pick? We have head-to-head comparisons between ibrutinib-acalabrutinib as well as ibrutinib-zanubrutinib. The second generations have less toxicity, particularly cardiovascular toxicity. We do not have head-to-head comparisons looking at acalabrutinib vs zanubrutinib, for example, or pirtobrutinib. We know that in terms of efficacy, there are all fairly similar, although zanubrutinib in the ALPINE study had better PFS compared to ibrutinib.

[00:24:23]

Time-limited therapy With BCL2i combinations

Let us go through now next-time limited therapy options.

[00:24:27]

CLL14 6-Yr Follow-up: PFS With 1L Obinutuzumab + Venetoclax or Chlorambucil

We have here the CLL14 study that looked at venetoclax-obinutuzumab vs obinutuzumab-chlorambucil. We could see clearly that with the venetoclax-obinutuzumab clearly superior to obinutuzumab-chlorambucil. Importantly, patients who had TP53 mutation, yes, they did worse than the rest of the group. Again, you are talking about more than 4 years of median PFS with a fixed-duration therapy. That can be considered a good option for these patients.

[00:25:05]

AMPLIFY: Acalabrutinib + Venetoclax ± Obinutuzumab vs Chemotherapy in Previously Untreated CLL

The next approach here we have, this was presented at ASH, the AMPLIFY study. It introduced the acalabrutinib-venetoclax, which is an all-oral fixed duration therapy for 14 cycles compared to a triplet acalabrutinib-venetoclax-obinutuzumab, and the third arm unfortunately was not venetoclax-obinutuzumab. It was FCR.

[00:25:27]

AMPLIFY: PFS per IRC

Not surprisingly, we know that the acalabrutinib-containing arms did better than the FCR. We see that the triplet had a PFS that was better compared to the acalabrutinib-venetoclax. The MRD was actually much better with the triplet arm. 94.4% undetectable MRD with the triplet vs 38% with acalabrutinib-venetoclax.

[00:25:54]

AMPLIFY: OS

The issue that I am going to get to is you could see here on the overall survival, the curve was better for the acalabrutinib-venetoclax compared to the triplet.

[00:26:09]

AMPLIFY: Safety

That is because, the triplet even though it has better PFS, it comes with higher toxicities that led to deaths, particularly COVID pneumonias. Again, you are getting maybe a little bit better PFS, but you have to remember that is at the expense of more immune suppression, more cytopenias, and this trial was done during the COVID era. They saw more COVID-related deaths with the acalabrutinib-venetoclax-obinutuzumab vs the acalabrutinib-venetoclax.

[00:26:38]

?MRD guided duration of therapy

What about the last approach here? This is an evolving approach with MRD-guided stopping rules. The previous trials that I showed, it was fixed duration, whether you are doing 12 cycles or you are doing 14 cycles, and then you are stopping whether MRD is positive or negative. These are just some of the evolving approaches here.

[00:26:59]

SEQUOIA: Zanubrutinib vs BR or Zanubrutinib + Venetoclax in Previously Untreated CLL/SLL

The SEQUOIA study, it had the Arm D. This was updated last ASCO. Here zanubrutinib-venetoclax fixed duration, all oral therapy, but the duration was determined by MRD negativity. Patients stopped when they had 2 consecutive undetectable MRD tests that were at least 12 weeks apart. The trial initially started off with patients with 17p deletion or TP53 mutation, but then it was expanded to patients with wild-type TP53..

[00:27:39]

SEQUOIA: Best Peripheral Blood uMRD and PFS

With that approach, whether the patients had 17p or TP53 or not, the undetectable MRD levels were up to 60% with really high overall responses here. You could look at the PFS. Again, you have the 2 curves here, patients with or without TP53 mutation or 17p deletion, they both did very well with this approach. Undetectable MRD was similar regardless of the mutational status.

[00:28:16]

FLAIR: FCR vs Ibrutinib or Ibrutinib + Venetoclax or Ibrutinib + Rituximab in Previously Untreated CLL

The second trial that I wanted to go over as well is the FLAIR study. Now, this is a UK study. It looked at ibrutinib-venetoclax all oral vs ibrutinib vs ibrutinib-Rituxan vs FCR. For the top 3 arms here, there were MRD guided stopping rules. The stopping rules were a little bit complicated, but it pretty much depended on how long the patient was with undetectable MRD and that determined how long the duration of therapy is.

[00:28:51]

Superiority of MRD-Guided Ibrutinib + Venetoclax to Ibrutinib and FCR

You could clearly see here the PFS with this approach with ibrutinib-venetoclax was superior to the other approaches, including ibrutinib and FCR, with even some overall survival benefit when compared to the FCR. Again, very intriguing approach of when to stop the therapy rather than use a fixed duration for all comers.

[00:29:19]

Ongoing Studies: Venetoclax + Obinutuzumab vs All-Oral Fixed Duration Therapy

One issue, of course, is that we are using more and more second-generation BTK inhibitors rather than ibrutinib at this time. The most important question that we are having right now is, what is a better approach? Use an all-oral fixed duration therapy or venetoclax-obinutuzumab fixed duration therapy, which obviously comes with infusions, which carries a little bit more inconvenience and maybe more cytopenias.

These are some of the important studies that will help to answer that question. CLL17 is looking at venetoclax-ibrutinib. It has venetoclax-obinutuzumab arm. The MAJIC study has acalabrutinib-venetoclax vs venetoclax-obinutuzumab. The stopping rules here are MRD-guided. The CELESTIAL study is zanubrutinib-sonrotoclax. Sonrotoclax is a new novel BCL2 inhibitor. Again, it is a fixed-duration BCL2 inhibitor, zanubrutinib both oral therapies compared to venetoclax-obinutuzumab. These trials, when they come out, they will answer that question.

[00:30:35]

Factors Guiding Therapy

How do we pick a treatment from all these options that I just mentioned? These are the factors that I am considering. When you are seeing the patient, what is their preference? They prefer time-limited therapy option. Not mine, but then the time limited therapy option comes with some TLs monitoring, comes with frequent visits to the infusion center, or do they want to start on an oral therapy that is easier to start and more convenient, but then they just have to stay on it? Do they want to avoid an infusion? Then you could use a BTK inhibitor or a venetoclax BTK inhibitor.

Do they have any underlying comorbid conditions, bleeding issues, cardiac issues, then maybe avoid covalent BTK inhibitors, if needed. Do they have significant renal impairment? It is going to be difficult to do the TLS monitoring. Then a BTK would make more sense than a venetoclax-obinutuzumab. If they have a 17p deletion or TP53 mutation, yes, they could have many years off therapy with a fixed duration therapy. Generally, a lot of us would prefer a covalent BTK inhibitor for better disease control in the long run.

[00:31:48]

Patient Case 1: 63-Yr-Old Man With Newly Diagnosed CLL

Let us take a look at this patient again. This is the patient that had good risk CLL with IGHV mutation. Hypertension, diabetes, needs therapy. Prefers an oral regimen that is fixed duration.

[00:32:06]

Posttest 1

Let us just ask the same question again. What would you do now? All right. Let us take a look at the results. Most of you are selecting now venetoclax-acalabrutinib, which is a fixed duration all-oral duration therapy.

[00:32:38]

Posttest 1: Rationale

That would be the right answer. Pirtobrutinib is not approved in the first-line. The other options have obinutuzumab, and the patient is trying to avoid that. Zanubrutinib is not a fixed duration therapy.

[00:32:51]

BTK Inhibitors After Initial Therapy for CLL/SLL

I will hand this over now to Dr Jain, and he will be discussing the patients who are relapsed/refractory.

Dr Nitin Jain (University of Texas MD Anderson Cancer Center): Good afternoon, everyone. Myself, Nitin Jain from MD Anderson in Houston, and I am going to talk about relapsed CLL.

[00:33:12]

Patient Case: An 86-Yr-Old Man With Relapsed CLL

Let us start with a case. You have a 86-year-old gentleman in your practice. Patient was diagnosed with CLL back in 2013. You can see the genomics listed as unmutated B gene as well as trisomy 12. Patient received bendamustine-rituximab in 2014. That was a standard at that time. Then progressed a couple of years later. Got venetoclax plus rituximab based on the MURANO study. In 2018, he finished venetoclax for 2 years, but then within a year, in 2019, he progressed and he required acalabrutinib.

He has stayed on acalabrutinib since that time, but now he is progressing while on acalabrutinib with worsening notes. You do a next-generation sequencing assay. It shows that he has acquired a cysteine 481S mutation, and patient is coming to your clinic for the next line of treatment. As I said, his age is now 86 years old. Let us see. Go to the next slide.

[00:34:14]

Pretest 2

Your test question number 2 here. What would you recommend for this patient in your practice?

A. Duvelisib;

B. Lisocabtagene maraleucel, which is basically CD19 CAR-T cell therapy, also called liso-cel.

C. Pirtobrutinib;

D. You will retreat with venetoclax plus rituximab; or

E. You would consider using zanubrutinib;

Please vote. All right. Maybe let us see the answers now. We have half of the participants voted for pirtobrutinib. Some voted for zanubrutinib and venetoclax-rituximab as well. A couple of folks voted for duvelisib appropriately. An 86-year-old, probably not very people keen on doing a CAR T-cell therapy at this time. Let us go to the next slide.

[00:35:19]

Pretest 3

We have a pretest 3 question. How confident are your response? Which you just answered. The choices are listed there. Please vote. We can see the results. All right. Most of them are modest to good confident. We will move to the next slide now.

[00:35:54]

Choosing Between Treatment Options

Before we start more discussion about the relapsed/refractory CLL, I wanted to talk about the disease and patient-specific factors which come into play when you are thinking about treatment. I think these measures apply not just for relapsed/refractory but also to frontline in a way. You have to think about the patient age certainly and comorbidities. In this case, he is an older gentleman with 86 years of age. You have to also think about if a patient has a P53 mutation, which this patient does not, or a deletion 17p, which he does not. Patients who have bulky disease, those are the patients maybe you would think more for a BTK inhibitor. Patients with renal issues. Creatinine is elevated. You may think more again for BTK inhibitor as opposed to venetoclax.

On the flip side, a p53 aberrant disease, you would think more for a continuous BTK inhibitor. If you have favorable risk genomics, then I think venetoclax-based therapy is very, very appropriate. Also, we will talk about some continuous vs fixed duration therapy, which again, as was the discussion in the front-line, we have regimens which are fixed duration as well as we have regimens now which are continuous long-term therapies.

[00:37:09]

Sequencing of Novel Therapies in CLL

Now 1 thing to recognize in the context of relapsed/refractory CLL is that not all relapses are created equal, which is obviously true in a way, because it really depends on what therapies you have received previously in terms of your therapy options. If you have received a BCL2 inhibitor previously and it was a time-limited BCL2 inhibitor, for example, venetoclax, then there is a potential for retreatment. You can retweet it or you can go to a BTK inhibitor.

On the flip side, if you use a BTK inhibitor frontline, most likely it will be a continuous BTK inhibitor like acalabrutinib or zanubrutinib or ibrutinib. In that case, certainly if you relapse on that, the next line, of course, would be either a noncovalent BTK inhibitor or venetoclax-based therapy. Certainly we also have patients still who have received chemo immunotherapy some years ago. If they are coming to your clinic and have they have never received a targeted therapy, then suddenly both the options are available to you, whether to go for a 1 based approach or to go for a continuous BTK based approach.

[00:38:09]

Key Biomarker Testing to Inform R/R CLL/SLL Treatment

We will first talk about some of the strategies, which are really for patients like approval for BTK and venetoclax in the relapsed/refractory setting before we talk about some novel strategies. As is important in the first-line setting, in the second-line and beyond setting also, it is important to test the genomics of CLL. I should mention that it is very important, in my opinion, to retest at the time of relapse for deletion 17p and p53 mutation, because patients can acquire these over time.

Also, presence of BTK and PLC gamma 2, which are the resistance mutations to covalent BTK inhibitors, and also in some sense to noncovalent BTK inhibitors it is important and can help you in sometimes when you are trying to make some decisions with the patient is progressing on a BTK inhibitor or not. As is highlighted in the slide, the IGHV or an individual patient does not change over time. That is something you do not need to repeat again and again.

[00:39:13]

Summary of Pivotal Studies With Covalent BTK Inhibitors and Venetoclax in R/R CLL

Now if you talk about the therapies which we have already heard about in the front-line talk acalabrutinib, ibrutinib, zanubrutinib and venetoclax, all these therapies were also obviously initially developed in relapsed/refractory CLL, and then they moved to frontline. When they were developed in relapsed/refractory CLL, multiple randomized trials were done, including ELEVATE-RR, ASCEND for acalabrutinib, RESONATE for ibrutinib and ALPINE for zanubrutinib, as well as the MURANO study for venetoclax.

Now, these trials were done in an era where these patients were relapsed/refractory, but their frontline or whatever previous therapies were all really chemoimmunotherapy, so they had not received another targeted therapy. Yet these were really their first targeted therapies they were receiving. BTK inhibitors were continuous, and venetoclax based on the MURANO study was a time-limited approach.

[00:40:06]

E1912: Ibrutinib + Rituximab vs FCR for Previously Untreated CLL

Now another point which is more appropriate. Sometimes a common question which comes from the clinic is that if a patient is on a BTK inhibitor and if they were to stop the BTK inhibitor for some toxicities and whatnot, what would happen to the disease? At least we have some prospective data where if in the frontline trial where the BTK inhibitor was discontinued, at least the median PFS after discontinuation was at least 2 years. I think you can have some patients who discontinued ibrutinib can benefit in the off treatment phase without needing treatment.

[00:41:00]

E1912: PFS After Ibrutinib Discontinuation

This is actually shown here where the patients who discontinued ibrutinib, they can still derive some benefit and there are some discrimination based on the IGHV and the FISH classification for these patients. Overall, in the clinical practice, I have several patients who have discontinued the BTK inhibitor for toxicities and they continue to do well actually for some time down the line.

[00:41:27]

BTK Inhibitor-Based Treatment for Previously Treated CLL

How do patients do when you are using BTK inhibitor in relapsed/refractory sphere? As I mentioned before, there have been multiple randomized studies done in this regard. We had the ASCEND trial which came up originally, which compared acalabrutinib with the more chemo-based approach or rituximab showing acalabrutinib is superior to chemo of bendamustine-rituximab or idelalisib-based regimen.

Then more recently, we had the ELEVATE-RR trial, which compared head-to-head acalabrutinib vs ibrutinib, basically showing that acalabrutinib was noninferior to ibrutinib. In terms of the efficacy, though, acalabrutinib was superior to ibrutinib in terms of the safety, especially atrial fibrillation, hypertension.

[00:42:15]

BTK Inhibitor Head-to-Head Comparisons: Zanubrutinib vs Ibrutinb (ALPINE)

Zanubrutinib had a very similar trial, some study design changes, but pretty much the same concept where they compared head-to-head with ibrutinib alone vs zanubrutinib. In this trial, we saw that zanubrutinib was actually superior to ibrutinib in terms of efficacy, as is shown in the figure on the left. Also the point on the right side is that zanubrutinib also works for patients with deletion 17p quite well in relapsed/refractory setting, as is true in the frontline setting as well.

[00:42:49]

Venetoclax-Based Treatment for Previously Treated CLL

What about venetoclax-based therapy for previously treated CLL? One of the major trials which when originally came out, I think in 2016, was really a landmark trial in the field, was the MURANO study, which is on the left, which compared 2-year venetoclax-rituximab vs bendamustine-rituximab, which was a very standard relapsed regimen at that time for CLL.

As you can see clearly here that nonchemotherapy approach of venetoclax-rituximab really much better PFS and actually also oral survival was shown as well compared to bendamustine-rituximab making a strong point that we should not be using chemotherapy for patients with CLL.

Also on the right you see a slightly different approach where it is a combination venetoclax with ibrutinib. I should mention that this particular regimen of ibrutinib venetoclax is not approved in the United States, though it is used elsewhere, especially in the frontline setting. Again, that regimen of ibrutinib plus venetoclax is also quite potent as you can see here in this data from now, some years ago combining the 2. Certainly these drugs work in relapsed/refractory setting as we heard they work in frontline setting as well.

[00:44:05]

Venetoclax Retreatment in Patients Achieving Deep Response Following Venetoclax + Rituximab

Now 1 of the questions which I think some of you answered for the patient is that can you retreat with venetoclax? Because unlike the BTK inhibitors regimen, most of the venetoclax regimens are time-limited. In the relapsed/refractory setting, you give for 2 years in the frontline, you give for 1 year. An obvious question is if a patient progresses some years down the line, do they retain sensitivity to the venetoclax? Can we retreat it?

That has been reported now in some of the studies. This is a study reported from the MURANO study patients who got venetoclax-rituximab for 2 years and then they subsequently relapsed, they retreated those patients. As you can see, just a small number of patients, but still you can see that patients were regaining the response when they were retreatment with venetoclax again.

[00:44:58]

Outcomes With Venetoclax Retreatment

This was what the MURANO study was. Then also I should mention that there is a study called ReVenG study, which is listed on the slide deck here. This is a large prospective evaluation of retreatment with ven-g a nice name. ReVenG study, where they have reported a small number of patients, 25 patients. It is a much larger study which hopefully will hear updates in the next year or so, but basically making a point that it works. Retreatment works with venetoclax.

Certainly, retreatment with venetoclax should be considered as someone in the answer mentioned as well. I think there are some nuances about how long the first remission lasted with first venetoclax, and therefore you can then decide on if venetoclax would be appropriate or not.

[00:45:47]

ELEVATE-RR: Lower Cumulative Incidence of Any-Grade Atrial Fibrillation and Hypertension With Acalabrutinib

Now, I mentioned before this that the toxicity and we will talk about toxicity in the slide deck again as well, that acalabrutinib has better safety profile, especially for atrial fibrillation and hypertension compared to ibrutinib. Really because of this randomized trial, we are using the extrapolated from the same data in the front-line where we moved away from using ibrutinib for our patients.

[00:46:15]

ALPINE: Cumulative Incidence of Any-Grase Atrial Fibrillation/Flutter and Hypertension

This is the APLPINE which is with zanubrutinib. Zanubrutinib vs ibrutinib. AFib was still better with zanubrutinib. However, hypertension in this randomized study, somewhat surprisingly, was similar compared to ibrutinib.

[00:46:34]

Relapse After Covalent BTK Inhibitor and BCL-2 Inhibitor Therapy

This was the data with the covalent BTK inhibitor and with BCL2 inhibitor. What about if a patient has received both of them and this is the scenario we are encountering more and more as more patients are getting these drugs in the front and the second-line therapy. So patients who has failed ibrutinib and also has failed venetoclax. That was the patient we presented to you in this case series.

[00:46:57]

Resistance to Covalent BTK Inhibitors

Now, for these patients we know from the work done by Jen Woyachand others over the years that these patients can gain resistance mutations when they are on long-term BTK inhibitor, for example, ibrutinib, acalabrutinib, and zanubrutinib. The most common is the BTK cysteine 481S mutation, which was described about 10 years ago.

[00:47:23]

A Growing Patient Population of Unmet Need

This has led to this concept of what is called these double exposed patients. Meaning that, patients who have received a ibrutinib-like drug could be ibrutinib, acalabrutinib or zanubrutinib and have also received venetoclax. Because these drugs have now been approved for almost more than 10 years for ibrutinib and venetoclax is almost coming up to 10 years as well, a lot of patients have received these drugs over their lifespan. Now we are starting to see more these patients who have received these 2 drugs and these patients are called double exposed patients. There is a specific definition, which is somewhat not a uniform definition across the board. There is also a definition of double refractory, which basically in general sense is the patients who have failed both BTK or BCL2 inhibitor and you do not think retreatment for them would help.

[00:48:20]

Outcomes of Patients With Double-Refractory CLL

Now studies have also shown and, again, 1 is an ERIC study which is a consortium in the Europe and a smaller study from Dana-Farber. Basically, the point here is that the so-called double exposure and especially double refractory patients who have failed BTK, covalent BTK, and venetoclax, those patients is a tough group of patients where we need better therapies and their progression-free survival to the next line of therapy is not very good, and their survival is not very good. A lot of effort is being made to develop new drugs for these double refractory patient population.

[00:48:57]

BRUIN: Pirtobrutinib (Noncovalent BTKi) for Previously Treated CLL/SLL

What are those drugs? We will talk about 2 drugs. We will talk about pirtobrutinib, and then we will talk about liso-cel which is a CAR T-cell therapy. Pirtobrutinib was approved for CLL for this double exposed patient population back in December of 2023, if I recall correctly. And really has changed the practice for these patients.

As you can see from the table, large number of patients, almost 300 patients with CLL were treated in this study, all patients had received ibrutinib-like drugs. Most of them were refractory to it, and about 40% had also received venetoclax in the past.

As you can see from the PFS curve, this drug first of all, works very well. Response rates are upwards of 80%. However, you can also see that the median PFS is just about 19 months. This drug works for a lot of patients but eventually patients will progress. I tell my patients when I am starting this drug that I expect a remission to last, maybe 1.5-2 years.

[00:50:01]

BRUIN CLL/SLL: PFS Based on Prior BCL-2i Exposure

This is also shown here where the left is BCL2 naive, and the right is the more traditional BCL2 exposed patients like our patient in the 86-year-old we discussed. Again, the median here is about 16 months.

[00:50:19]

BRUIN CLL-321 Trial of Pirtobrutinib vs Idelalisib or Bendamustine Plus Rituximab

More recently, pirtobrutinib was compared head-to-head in relapsed CLL compared to bendamustine-rituximab or idelalisib-rituximab. This is so-called 321 trial.

[00:50:31]

BRUIN CLL-321: IRC-Assessed Progression-Free Survival

This also showed that pirtobrutinib was superior to this more aggressive randomized trial, but not the regimens we are using these days idelalisib-rituximab or BR, but nonetheless it is statistically superior with a median PFS of 14 months.

[00:50:54]

BRUIN CLL-321: Time to Next Treatment or Death in Venetoclax-Naive and Venetoclax-Treated Patients

Now the next question here, again is the same trial talking about pirtobrutinib. Again, showing that the pirtobrutinib is superior to your more conventional idelalisib-based regimen or bendamustine-rituximab.

[00:51:09]

Select Ongoing Phase III Studies of Pirtobrutinib in CLL/SLL

There are several ongoing studies with pirtobrutinib, currently, right now, both for actually frontline as well as relapsed/refractory. Actually, press release have been issued that they have met the primary endpoint, but hopefully we will see some of this data at the upcoming ASH meeting.

[00:51:31]

Expert Sequencing of Novel Therapies in CLL

That is 1 option for you pirtobrutinib. When you are trying to think how to use these drugs, and again, this is a complicated slide where a lot of options are listed there. But my general recommendation would be that there is a lot of permutation and combination you can use these regimens. I do not think anyone can tell you if 1 is absolutely the right way to do it.

I think the good thing is many of these regimens last for a long, long time, remission duration. As patients are living longer and we have new drugs coming along, including BTK degraders and others, I think for most of these patients, the long-term survival will really be excellent, given all these multitude of options we have for these patients.

Also, when we talk about this retreatment, we talked about the retreatment with venetoclax in terms of the ReVenG study, which is coming up. Also when we are using these BTK-venetoclax combinations in the frontline and with the upcoming AMPLIFY approval, we should see more of it being done. There is ample data now, but some data from our group, as well as CAPTIVATE and other group that you can retreat once you do a time-limited frontline ibrutinib-venetoclax, you can retreat at the time of progression with either ibrutinib and venetoclax.

It is an important point to remember. If you progress when you are not taking the drug, it is unlikely that you will be resistant to the drug. I think that is just a general rule.

[00:53:00]

TRANSCEND CLL 004: Lisocabtagene Maraleucel in Relapsed/Refractory CLL/SLL

Now, the second very important concept is the CAR T-cell therapy. Or not concept, it is an approved strategy. It was approved in March of last year and this is liso-cel, which is approved for DLBCL for quite a while.

Now, in this particular trial, the investigators, obviously gave CAR T-cell therapy for relapsed/refractory CLL. Patients received FC lymphodepletion, which is pretty standard. Then you get the CAR T-cell therapy.

This is the data which is combining with ibrutinib. There is also data with liso-cel alone and this is more data with liso-cel plus ibrutinib. When you combine with ibrutinib, the data actually is much better. You have a much higher response rates and you have a much better PFS. If the liso-cel was alone given, you can have the response rates and also the PFS is about 18 to 20 months. Adding ibrutinib to liso-cel really improved the response rates for these patients.

[00:54:05]

TRANSCEND CLL 004: PFS by Best Overall Response at DL2

This is again the same data. This is with combining it with ibrutinib, and when you combine with ibrutinib, these patients are doing really, really well. I just say as a standard of care practice outside of a clinical trial, in our practice we are also combining it with BTK inhibitors when we are using liso-cel as standard of care therapy.

[00:54:24]

TRANSCEND CLL 004: Tumor Burden Correlated With ORR

Some of the more recent data which was presented basically correlates tumor burden with response. It also makes sense that if you want to give CAR T-cell therapy, you want to debulk the patient before you give CAR T-cell therapy, which is pretty much what they show that if you have bulky lymph nodes, those patients tend to do less well.

[00:54:45]

TRANSCEND CLL 004: Select AEs With Lisocabtagene Maraleucel

Very important things, CRS and neurotoxicity, which any CAR T product you have to look at. This product was actually pretty safe in terms of the CRS, though, if you look at the grade 3 or 4 neurotoxicity, about 19% risk. That is something you have to be watchful for if you are using liso-cel in your practice.

[00:55:04]

Now, let's go back to our patient case

Let us go back to the case.

[00:55:07]

Patient Case: An 86-Yr-Old Man With Relapsed CLL

You may recall 86-year-old who has failed BR, venetoclax-rituximab, acalabrutinib. Has developed BTK resistance mutations while on acalabrutinib.

[00:55:17]

Posttest 2

What would you do next? Same choices as before. Please vote. Maybe let us see the responses. Pirtobrutinib went from 50% to 68%, which is good. Some people voted now for CAR T-cell therapy. Duvelisib is still an option, but probably I will not use it in a very old gentleman when pirtobrutinib is available. Time-limited venetoclax-rituximab could be reasonable, but this patient progressed within 1 year of stopping venetoclax so may not be the best option. No one picked zanubrutinib which is appropriate. Patient has a BTK cysteine 481S mutation and zanubrutinib will not work.

[00:56:12]

Posttest 3

I have maybe 2 or 3 more slides just talk before I hand it back to Dr Gaballa. How confident are you in your response? Maybe we can quickly vote as well. Let us see the responses. At least 1 person is very confident. There was no one in the previous poll.

[00:56:45]

Emerging Therapeutic Approaches

Maybe want to talk about maybe 2 or 3 slides on some emerging therapeutic options just to cover all bases?

[00:56:52]

BELLWAVE-001: Nemtabrutinib for R/R CLL

I should mention we talked about pirtobrutinib, but there is another noncovalent BTK inhibitor called nemtabrutinib, which data has been presented at EHA meetings recently. This again seems to work for patients who have failed previous covalent BTK inhibitors. Again, this drug is already in the randomized phase III studies, and we are waiting for those data, and maybe we will see if this drug gets eventually approved as well.

This just shows the data again in relapsed/refractory CLL, the number of patients, relatively smaller compared to what pirtobrutinib studies have shown. This is again an important drug which we are waiting for more larger data set in phase III studies, and see if this gets to the market as well.

[00:57:38]

BELLWAVE-001: Nemtabrutinib AEs of Special Interest

This showed the adverse events. Again, pretty similar drug I would say to the other BTK inhibitors that we have used.

[00:57:51]

BGB-11417: Sonrotoclax + Zanubrutinib in CLL

I should also mention that there is emerging data with the drug called sonrotoclax, which is like venetoclax, a BCL2 inhibitor, and zanubrutinib. This regimen is being pursued in the frontline setting as well. Then what you show here is relapsed/refractory data, 2 oral drugs together. What I want to emphasize on the bottom right is that this regimen is pretty particularly effective and leads to high rates of MRD negative remission as you see in the blood.

Again, we are waiting for more data with this regimen in the frontline setting. Hopefully, we can see an approval down the line. Again, we will see how the frontline trials read for this regimen.

[00:58:37]

Effectively Managing BTK Inhibitor Associated AEs

I will hand back to now Dr Gaballa for the rest of the talk. Thank you.

[00:58:42]

Pretest 3

Dr Gaballa: Thank you, Dr Jain. Pre-test question here, how confident are you in the ability to educate your patients receiving BTK therapy about the associated adverse events?

A. Not confident;

B. Low confidence;

C. Modest confidence;

D. Confident;

E. Very confident;

Please go ahead and vote. Let us take a look at the results.

[00:59:14]

Ibrutinib/BTKi-Related Toxicities of Interest

Let us go through the BTK toxicity. Obviously, there are BTK toxicities, particularly with first-generation BTKs, less so with second generation BTKs. There are general side effects. And there is this just some toxicities of interest. There is things like diarrhea, arthralgias, low blood counts, increased infection risks, which again, some of them are due to off target toxicities. Some of these can be lower with second-generation BTK inhibitors like acalabrutinib and zanubrutinib.

I am going to be focusing here on the toxicities of interest, including bleeding, cardiovascular toxicities like AFib, ventricular tachyarrhythmias, hypertension, and infectious issues.

[01:00:10]

Comparison of E1912 and Alliance 041202 (Ibrutinib): Median Age and Grade ≥ TRAEs on the IR Arm

Let us start with the ibrutinib. This is a summary from the ECOG study as well as the ALLIANCE data. It summarizes some of the grade 3 or higher toxicities. We could see that there is about 10% to 20% of patients who have sometimes grade 3 or higher infections. AFib, grade 3 or higher was seen in 4.5% or 5.5%. Hypertension also is seen. It seems to be sometimes underreported with some of the trials, but it is in the neighborhood between 10% to 30%. Sometimes you could see deaths from toxicities, particularly early on. Sometimes patients could have significant bleeding episodes. Luckily, that is something that is very rare.

[01:01:02]

ELEVATE-TN: Safety of Acalabrutinib ± Obinutuzumab

Acalabrutinib, a second-generation BTK inhibitor, has less cardiovascular toxicities. We saw that with the head-to-head data between acalabrutinib and zanubrutinib, as Dr Jain had shown. Typically here, the grade 3 or higher AFib rates are lower, around 1.7%. Beeding remains an issue with all of the BTK inhibitors. Luckily, severe bleeding is not common. It is typically around the 5% range.

[01:01:38]

SEQUOIA: Safety of Zanubrutinib

You can also see hypertension, infections, and second primary malignancies have been also reported.

In terms of zanubrutinib, zanubrutinib has been compared head-to-head with ibrutinib in at least 2 trials. The AFib rates with zanubrutinib are less compared with ibrutinib but they still can happen. You need to educate your patients about the side effects and what to look out for. Hypertension seem to be similar to ibrutinib.

However, things like rash, arthralgias, these are typically less with zanubrutinib compared to ibrutinib. Headaches are less with zanubrutinib. They are more reported with acalabrutinib. In terms of AFib rates, these are significantly lower, again, with zanubrutinib compared to acalabrutinib. Here, with the SEQUOIA study, the reported rates were less than 1% that were grade 3 or higher.

[01:02:57]

BRUIN CLL-321: Safety of Pirtobrutinib

Pirtobrutinib has not been compared head-to-head yet with acalabrutinib or zanubrutinib, but it has a very favorable toxicity profile, although it seems to have more cytopenias now. It is unclear if this is because these patients who are on the BRUIN study are extremely heavily pretreated, or it is something intrinsic to pirtobrutinib. Typically, this is something that you want to keep an eye on for patients on pirtobrutinib because you can sometimes see neutropenias that can be easily managed with dose interruptions and dose reductions.

However, AFib rates are very low grade 3 or higher 1.7%, overall, 2.6%. Bleeding can also be seen but again, severe bleeding is very uncommon. Rates of hypertension are also relatively low. Again, for pirtobrutinib make sure you just watch out for neutropenia.

[01:03:59]

BTKis: Impact of Safety Concerns/Cardiovascular Risk

When you are seeing a patient that you want to initiate on a BTK inhibitor, what are the things that you want to look out for? Obviously, look at their blood pressure at baseline. Do they have hypertension at the get go? Do they have any cardiovascular risk factors? Do they have diabetes, obesity, hypertension, high cholesterol, renal disease? Do they already have heart disease? Do they have arrhythmias? Do they have heart failure? Do they have valvular heart disease? Do they have ischemic heart disease?

When you are doing the first evaluation and the history and physical, these are the things that you want to evaluate in the beginning. For patients that have risk factors for cardiovascular disease or they already have cardiovascular disease, these are the patients that before starting a BTK inhibitor, I would get an echocardiogram, and consider a referral to 1 of your cardiology colleagues who would monitor these patients with you.

Now, if the patient has no cardiovascular risk factors whatsoever, then technically any of the BTK inhibitors can be considered. If there is any concern, again, favor more selective drugs like acalabrutinib or zanubrutinib or a BCL2 inhibitor, if there is significant cardiac risk.

For patients who do have already some cardiac risk factors, for example, AFib, that is well-controlled, hypertension, heart failure, valve disease, a BTK inhibitor is not contraindicated. You could still have them take it. Again, you get a baseline echocardiogram. You have 1 of your cardiology colleagues see the patient with you. Again, consider a second-generation BTK inhibitor like acalabrutinib or zanubrutinib, which have less cardiovascular toxicities than ibrutinib.

[01:05:57]

BTK Inhibitors: Expert Recommendations for the Management of Bleeding and Cardiovascular Issues

Just some tips when managing these patients. To avoid bleeding issues, try to avoid antiplatelets and anticoagulants as much as possible. They are not contraindicated. They can be used. If you have to use them, that is perfectly fine. You just have to watch out a little bit more closely if they have any bleeding risk factors.

Warfarin should not be co-administered with these BTK inhibitors. It has not been studied in the trials, but other anticoagulants can be used with some caution.

If the patient needs to go to surgery, so you would hold the BTK inhibitor 3-7 days, depending on if it is a minor or major surgery before and after the procedure. You educate the patients on the signs and symptoms of cardiac arrhythmias, palpitations, dizziness, syncope, whatnot. You want to work with your cardiology colleagues. Hypertension should be aggressively managed with these patients and it is usually subtle, so you just have to pick it up. And it is 1 of those things that can develop later on. Early on, some patients develop bleeding problems, but later on these patients can start to develop hypertension late in the course.

[01:07:21]

Managing AF and Cardiac Arrhythmias

Always look at the concomitant medications because there is always drug-drug interactions. I typically review all the medications for interactions with my pharmacists when I am starting a new patient. Patients who have AFib or cardiac arrhythmias, again, you can use a BTK inhibitor in these patients as long as the AFib is controlled. Acalabrutinib, zanubrutinib, and pirtobrutinib, they all have lower AFib cardiovascular risk factors compared to ibrutinib.

Again, these are the patients that you want to work with, your cardiology colleague. You get an opinion from them and they usually would co-manage these patients with you. Obviously, if they need an anticoagulant, as I mentioned, you would want to not use Coumadin. You could use 1 or the other anticoagulants, but just educate the patients that, ”Hy, there is a higher risk of bleeding, obviously, and these are the things to watch out for.”

[01:08:21]

Expert Recommendations: Special Considerations for the Management of BTKi-Related AEs

Moving on To acalabrutinib, specifically, has a little bit more headaches. These typically happen early on within the first month or 2. They are very easy to manage, typically with acetaminophen and caffeine supplements. Coffee usually does the trick. Try to avoid nonsteroidals again because they would inhibit the platelets. For zanubrutinib, sometimes neutropenia can be seen, and this is something that not necessarily happens early on. It can happen later on. It is typically very easily managed with dose interruptions. If it is recurring, you would dose reduce. It is rare that we would have to permanently discontinue zanubrutinib because of cytopenias.

[01:09:08]

Patient and Caregiver Discussions: What AEs to Expect/Monitor While Taking BTK Inhibitors

Of course, you could sequence those medications. Meaning that if someone has a headache that is not controlled for some reason, they could go on zanubrutinib. If someone is not tolerating zanubrutinib, they could go on acalabrutinib and so forth.

It is important to educate the patients and their caregivers about what to look out for and what the symptoms are. You want to talk to them about the bleeding and bruising. Again, bruising is fairly common, especially early on so you just have to educate the patients on that.

You have to educate them on bleeding, like blood in the stools, blood in the urine. They want to let you know about that as well. Again, these patients should just make sure that they maybe carry a wallet so that when they go to their other physicians, they know that they are on a BTK inhibitor. If they need to start on another medication, they have to check with you regarding the interactions. For infection risks, it is recommended to stay up to date with vaccinations as much as possible.