Optimizing CLL/SLL Care: Expert Strategies for APPs to Integrate New Targeted Therapies and Practice-Changing Evidence

Let us just talk about CLL/SLL. It is the most common leukemia in the Western world—23,000 new cases per year, and you are mostly going to see people in their middle-aged or older adults.

SLL and CLL are both considered the same hematologic malignancy arising from indolent slow growing cells. What is differentiating them is the CLL arises from mostly the blood and marrow, and the SLL cancer cells are mostly in the lymph nodes.

[00:02:52]

Prognostic Variables in CLL/SLL

What about prognosis? When you are looking at prognostic variables, what makes people more likely to do better or worse than others? What we are seeing here is that this slide lists the prognostic variables. TP53 is the most important thing to consider, and these mutations are in all cancers, primarily blood cancers as well. It is more prognostic than anything in my opinion.

It really looks at the mutational status. The IGHV mutation status refers to the changes in immunoglobulin therapy. These somatic cells as they develop, are there going to be changes to those cells, where then the blueprint of those cells are going to be not as good. When you have those mutations and so you will hear a lot about a mutational status; those are the things that we think about in terms of prognosis, along with these other on the slide.

[00:03:41]

Let's Consider a Patient Case

Let us consider a patient case.

[00:03:44]

Therapeutic Choices in Treatment-Naïve CLL/SLL

Patient Case 1: A 76-Yr-Old Woman With Previously Untreated CLL

Here is a patient case. A 76-year-old woman with previously untreated CLL; 76 years old is a very common age for CLL. She was diagnosed in 2023 Rai stage I, IGHV unmutated status. She had a long history of hypertension controlled with 3 medications: coronary artery disease controlled medically, and atrial fibrillation which was controlled, and a baseline creatinine of 1.2.

Now, initially, she had been watchful waiting, where you are looking for the doubling of the lymphocytes, thrombocytopenia. If it is SLL, you look for bulky adenopathy. A CT scan did reveal some bulky axillary lymph nodes, that she became symptomatic with about 7 cm bilaterally. We are talking about treatment now, but she is worried about her cardiovascular health and a defined treatment period. Those are her priorities.

[00:04:33]

Therapeutic Choices in Treatment-Naive CLL/SLL

Let us go into therapeutic choices.

[00:04:35]

Algorithm for Frontline Therapy

Here is an algorithm that was taken from the National Comprehensive Cancer Network version 3.2025 guidelines. This is the general algorithm. First of all, to treat or not to treat, that is the question. Sometimes you want to wait as long as you can until the treatment is needed, and if there is no indication, then you can observe. Watchful waiting that is what our case study started with.

 Once you decide in that little orange block, in that an indication to treat is present, then you look at the mutational status. Do they have del(17p) with that TP53 mutation or the IGHV unmutated status? Then you are looking at BTK inhibitor and combinations. Venetoclax is reasonable, and we will talk about that in a little bit, or the TP53 wild-type and/or the other mutations, and so very similar combinations.

[00:05:29]

First-Generation Covalent BTK Inhibitor (cBTKi) Ibrutinib: Earlier Role as First-line Therapy for CLL

How would you decide with all these drugs available what to give this patient? Think about the first-generation covalent. Most of you, even if you do not do CLL for a living, will have familiarity with ibrutinib. This is our first-generation covalent BTK inhibitor. I mentioned covalent because we are going to talk about the noncovalent one in a little bit. This is a slide that illustrates outcomes with ibrutinib in combination with rituximab in CLL.

What we are seeing in these more recent trials, not the recent, in 2012. Sorry, guys. What we are seeing in these studies is that when you are giving ibrutinib, it is better than chemoimmunotherapy. When we are looking also at some additional studies, this is the RESONATE-2 trial. Then the A041202 study. Sorry, I am having eyesight problems today, and it is very small on my screen so please excuse me. You probably can see better than I can.

The first-generation ibrutinib is still better than chlorambucil chemoimmunotherapy in all of these studies. You can see the curves up there. The blue curves is ibrutinib, the BTK inhibitor. Again, very well-described safety profile. Generally pretty easy to deliver, but we are going to talk about toxicity and considerations in a minute.

[00:06:49]

Next-Generation cBTKis Acalabrutinib and Zanubrutinib: Fewer AEs and Superior to CIT

Next, we have another covalent or cBTKi, which is a acalabrutinib, and then another one called zanubrutinib. Again, a little bit of less of the off-target effects as we get newer drugs. Acalabrutinib plus or minus obinutuzumab was shown to be superior to chemotherapy in the ELEVATE-TN study. Then we have the SEQUOIA study, which is done most recently, and that looked at zanubrutinib vs bendamustine-Rituxan.

Again, you can see the separation of the curves in these randomized trials that the newer BTK inhibitor was superior to the chemoimmunotherapy combination. You are going to see in your frontline NCCN guidelines. Most commonly these days we are going to give something like acalabrutinib or zanubrutinib. Acalabrutinib and obinutuzumab is a very common combination or zanubrutinib, and we will talk about how to figure that out in a minute.

[00:07:40]

CLL14: PFS and OS With First-line Obinutuzumab + Venetoclax or Chlorambucil (Time Limited)

The CLL14 study, this is one of the most mature data studies. This is time-limited. You can see here to the left they are looking at progression-free survival and overall survival. Patients were getting a fixed duration of obinutuzumab plus venetoclax or chlorambucil. You can see the patients that had the venetoclax-obinutuzumab in the blue line was superior to the chlorambucil-obinutuzumab. The take-home point here is venetoclax is better.

Then, when you look at the overall survival, there is still a separation of curves. The blue line is the venetoclax-obinutuzumab, and then the orange line is the chlorambucil-obinutuzumab. We are seeing an improvement in survival of those patients.

[00:08:21]

AMPLIFY Trial of Acalabrutinib + Venetoclax ± Obinutuzumab vs CIT

Now, the AMPLIFY study, because we have not talked a lot about studies yet. It was so funny because 15 years ago, I remember hearing Amy Goodrich present on these topics, and she used this description, this buffet of options. How do you select from the buffet? There is lots of great choices, but these studies are illustrating why they are good choices. Again, anything seems to be better than chemoimmunotherapy.

I know we have a lot of slides, and I just wanted to pause a minute and remind you that you can download these slides. We have great references on these slides. We will not go into every detail about the study design or how we decided to design the study, but you can always reference that later. That said, the AMPLIFY trial was the acalabrutinib plus venetoclax plus or minus obinutuzumab vs chemoimmunotherapy. They were randomized to any one of these 3 arms. There was a crossover included for patients that progressed.

[00:09:19]

AMPLIFY: PFS per IRC

The Independent Review Committee, the IRC, were the committee that determined the progression-free survival. This was a big study. We had an independent community. The take-home point is the AVO did better than the FCR, bendamustine or the AV. Again, we are looking at these newer therapies and it still was a fixed duration of therapy. You had the stopping point at the fixed duration therapy, which is, incidentally, what our case study is interested in is a fixed duration of therapy. You are seeing the superiority of the newer combinations compared to chemo-immunotherapy.

[00:09:57]

AMPLIFY: Rate of MRD (<10^-4) in Peripheral Blood by Flow Cytometry

Now, we did not talk too much just yet about the MRD status. Minimal residual disease is a method to detect the presence of remaining CLL cells. To 10^-4 is a very common threshold. We do this by obtaining peripheral blood, by flow cytometry. You can see that there was a better rate of MRD status in the newer combination vs the chemoimmunotherapy.

I am going to pause there, and I am going to turn the baton over to my friend Amy Goodrich. She is going to take us into individualizing treatment, considering safety with covalent BTKis and BCL2 agonists.

[00:10:35]

Individualizing Treatment Considering Safety: Covalent BTKis and BCL2 Antagonists

Amy Goodrich: Thank you, Beth.

[00:10:39]

Pretest 2

Let us start with a pretest question. Allopurinol and hydration are important risk-mitigating strategies for which of the therapies used in CLL management? Is it:

A. BTK inhibitors;

B. CAR T;

C. Obinutuzumab; or

D. Venetoclax;

[00:11:05]

Pretest 3

Then pretest number 3. Based on all available evidence from head-to-head comparative phase III trials, which of the following pairs of BTK inhibitors would you tell a patient is associated with a similar risk for hypertension? Which of these combinations have a similar risk of hypertension? Is it:

A. Acalabrutinib and ibrutinib;

B. Acalabrutinib and zanubrutinib;

C. Pirtobrutinib and zanubrutinib; or

D. Zanubrutinib and ibrutinib;

If you know, you know. If you do not, just guess. Then hopefully everybody gets it right on the posttest.

[00:11:52]

Ibrutinib/BTK Inhibitor-Related Toxicities of Interest

Let us talk about ibrutinib and toxicities of interest. Beth talked about this being our first-generation drug, and in general, all BTK inhibitors have a risk of bleeding, cardiovascular toxicity, both atrial fibrillation and flutter. Very low incidences of ventricular arrhythmias, but those do exist, hypertension as well, and infections. What you are going to see is that the rates of those are different from agent to agent.

[00:12:23]

Comparison of E1912 and Alliance 041202 Trials: Median Age and Grade ≥3 TRAEs on the IR Arm

If we look at this comparison of a couple of trials here, that E1912 looked at ibrutinib and rituximab vs FCR, and RA041202 was a phase III of ibrutinib-rituximab vs just ibrutinib vs bendamustine and rituximab. If you just bring your eye along here, you can see that the ages are not the same. Right there, these are not created equally, but you can see that there was a definitely infection risk for both of them, higher in the older patient population.

The atrial fib rates were generally pretty similar, as were bleeding. Where you can see the hypertension rate was higher, again, this was older patients. There were more deaths in this arm, and there are lots of reasons why that happened that you can pull this paper and look at. Again, older folks, so not created equally.

[00:13:28]

ELEVATE-TN 6-Yr Update: AEs of Clinical Interest

If we look at ELEVATE treatment naive, which looked at acalabrutinib with obinutuzumab vs acalabrutinib alone. This is 6-year follow-up. You can see that the percentages are in parentheses. Atrial fibrillation was relatively equal. The combination of ibrutinib or acalabrutinib and obinutuzumab did not make a huge difference.

Major bleeding, you can see that there was a lot of low-grade bleeding, but not a significant amount of high-grade bleeding, really in either arm. Hypertension was pretty equal as well. Infections, the same story. Really not a huge difference in toxicity from arm to arm in this trial.

[00:14:23]

SEQUIOA: Safety Analysis

Let us look at SEQUIOA. SEQUIOA randomized patients to zanubrutinib vs bendamustine and rituximab, and then this is split out into those without a deletion 17p and those with. This is a lot of data. If you can just put your eye across this, certainly there were high rates of toxicity in general, most being low-grade contusion.

One of the frustrating things for me, as somebody who sees a lot of CLL patients, the way bleeding and bleeding events are described from paper to paper are very different. Some of them call them bruising. Some call it bleeding. This study called it contusion.

Again, not apples to apples by any means. As you can see, much more contusion with the zanubrutinib arms than with the BR arms. Infections were not grossly different. Diarrhea not grossly different. Interestingly, there was more neutropenia with BR than with zanubrutinib, because you will hear here in a bit that zanubrutinib one of the hallmarks is neutropenia.

[00:15:38]

SEQUIOA: Safety Analysis (cont'd)

If we look at those adverse events of interest, the hypertension rate, you can see not grossly different at this point. Headaches were also common, thrombocytopenia. But if you go to the bottom and look at all bleeding and all cardiac events, and I am going to give you a second for your eye to come here. All bleeding events were clearly higher in the zanubrutinib arms than BR and then the cardiac events, and again, the parentheses are the percentages. They were higher in the zanubrutinib arms, but really not heads and shoulders higher. This really points to good safety compared to bendamustine and rituximab, which is why we are using so many of these BTK inhibitors.

[00:16:30]

CLL14: Most Frequent Grade ≥3 Adverse Events With Obinutuzumab + Venetoclax or Chlorambucil

Let us now switch gears and go to obinutuzumab with venetoclax. This study looked at venetoclax-obinutuzumab vs chlorambucil, and so taking your eye to the red boxes here, you can see that neutropenia was not grossly different, thrombocytopenia not grossly different. The take-home here is that even though there are relatively high rates of neutropenia, there are very low rates of febrile neutropenia, which is great. Then, TLS was not grossly different either for these 2 arms.

[00:17:11]

AMPLIFY: Most Common AEs

AMPLIFY, which Beth just talked about which is acalabrutinib with venetoclax vs acalabrutinib, venetoclax, and obinutuzumab vs chemo of choice BR or FCR. Looking again, neutropenia not grossly different. You will see higher rates of headaches with acalabrutinib, because that is really one of the most common toxicities that is unique to acalabrutinib.

Infusion-related reactions, of course, when you are giving a monoclonal that is going to be an issue vs 2 oral drugs only. Then again, if you look at the febrile neutropenia rates, those are still quite low. We really do a good job of controlling those. They are higher with the chemo arms, but not super high with those, but definitely lower with our novel therapy arms.

[00:18:14]

AMPLIFY: AEs of Clinical Interest

Then, if we pull out our cardiac events and our hemorrhage, if you look at the AFib, aflutter, ventricular arrhythmias, hypertension, you can see here that in the acalabrutinib-containing arms, there are more cardiac events than in the chemo arms. Again, most of those are very low grade and not serious.

Then, in terms of hemorrhage, there were very few patients had major hemorrhage. Those numbers were low all the way across.

If you are looking at neutropenia, again, that was relatively common in all the arms, more so in the 3-drug arm than the 2-drug arm. Then infections were also relatively common in all of these arms. Really this shows that there is good safety. We are really used to using FCR and BR, or we were, and this is really why we are moving away from those things, because we have new drugs that are more well-tolerated and just as efficacious or more.

[00:19:30]

Venetoclax: Adverse Events and Management

Venetoclax. It is impossible to think about venetoclax or talk about venetoclax without thinking about this ramp-up and tumor lysis monitoring. Those of you who use venetoclax know that you are establishing tumor lysis risk based on lymphocyte counts and bulk of adenopathy and renal function. The vast majority of patients can be monitored safely outpatient, but there are folks who do need to go inpatient. We follow the package insert religiously.

Everybody gets hydration and allopurinol, and then follow the package insert and your institutional guidelines. Once you get through this ramp-up and you get through those frequent visits, patients really tend to tolerate this well.

There is a 43% and 42% incidence of diarrhea and nausea. Those tend to be very, very mild. Patients definitely can develop neutropenia. They may require growth factor. Follow the prescribing information for dose reductions, but really, tumor lysis syndrome is the hallmark of this drug. I do not know if anybody knows the history of this, but in the early clinical trials, they started with the full 400 milligram dose, and a few people died of tumor lysis syndrome.

Since this ramp-up was instituted, this has become very safe. There have been no deaths, and this is really a very useful drug.

[00:21:07]

Management of Venetoclax-Associated Toxicities

Toxicity management. Those of you who are using this drug or work in the heme malignancy space full-time, you know what tumor lysis syndrome is and how you are managing tumor lysis syndrome. One of the great things about venetoclax and obinutuzumab is upfront therapy is that they get 3 weeks of obinutuzumab before they start the venetoclax. There is nice debulking, and maybe patients are higher risk starting out, but by the time they get to their venetoclax, they are debulked and they are much lower risk.

I do use this risk assessment, and I look at this, and I do not try to remember anything because there is so much to remember. I always go back and look. Again, we talked about for low and intermediate-risk outpatient with allopurinol and hydration, and for these high-risk folks, they really do need to get admitted.

[00:22:06]

Venetoclax: TLS Management

Again, I have talked about this. This just gives you a little different view of this, and the schedule of the tumor lysis monitoring. Again, those of you who do this all the time, you have gotten good at this, and you know how to make this as easy as you can for patients while keeping them safe, for sure.

[00:22:28]

Patient Case 1: A 76-Yr-Old Woman With Previously Untreated CLL

Let us go into a case. Again, this is our 76-year-old woman. She was diagnosed in 2023. She has early-stage disease, unmutated, which is high risk. She has got hypertension, coronary artery disease. She has a history of AFib. Her creatinine is on the high side of normal, but it is normal. She was watched. She progressed in 2024. Beth told you about her count is heading in the wrong direction.

It is important to image these people because part of the tumor lysis risk factor calculation is bulk of adenopathy.

Ten cm is the cutoff, but she has got bulky axillary node 7 cm, and she has got abdominal nodes up to 9 cm. She is worried about her cardiovascular health, and she would like a defined treatment period. I am going to tell you one of the nicest things about treating patients with CLL is that this day does not come unexpected. It is very common that you are talking out options with people for months and months and months before the day comes that they actually need therapy.

This lady is somebody who had looked at BTK inhibitors and heard about BTK inhibitors and knew she was high risk, so she was worried about that. She also wanted a defined treatment period.

[00:23:56]

Poll 3

Which of the following would you recommend as best first-line therapy? Would you recommend:

A. Ibrutinib as our first-generation BTK inhibitor;

B. A second-generation, either acalabrutinib with or without obinutuzumab or single-agent zanubrutinib;

C. A third-generation BTK inhibitor pirtobrutinib; or

D. Venetoclax with obinutuzumab;

[00:24:32]

Algorithm for Frontline Therapy

Beth, I think this is where you take over.

Beth Faiman: Talking about frontline therapy, we saw this algorithm before, and honestly, it is just really dealer's choice. You have all these good options, but she is unmutated. She wants a limited duration of time therapy. She does not want to be on treatment forever. You want to have those discussions.

As Amy said, you have time in many of the cases. You still see people that come in with a high white count, and you are working them up for all different leukemia. It ends up being CLL, and then you decide on your treatment options. Basically, following the algorithms, if you are not doing this for a living, go to nccn.org. These are free guidelines you could reference, and then you can use them in your practice.

[00:25:30]

Frontline Covalent BTK Inhibitor (cBTKi) vs Venetoclax + Obinutuzumab: Factors to Consider

Frontline covalent BTK inhibitor vs venetoclax and obinutuzumab. These are the factors to consider. It is a balancing act. The covalent BTK we know they are superior to chemo immunotherapy. We saw the CLL14 trial and all these other studies that support. We should not be using that. No FCR for these people. It requires continuous dosing. There is more data in the population with del(17p), TP53 mutation. There is convenience. You are not going to worry about the ramp-up, tumor lysis syndrome monitoring, but it is associated with more cardiac and bleeding events.

Now on the other side of the scale in the orange box, you have the venetoclax and obinutuzumab or ven-obi. That seems to be also superior to chemoimmunotherapy, but this is a 1-year time-limited therapy. For somebody who has cardiovascular concerns, this is less worrisome for cardiovascular. As Amy said, if you work them through the ramp-up and you risk-stratify for low, high risk, again, go to the package insert. If you do not do this for a while, there are no known cardiac or bleeding risks, which is super important.

[00:26:37]

Factors Guiding Therapy

What are some of the factors guiding therapy? We already discussed that. Does your patient prefer time-limited therapy or ongoing therapy? If yes, then venetoclax and obinutuzumab is done in 12 months, and so that is something to consider. Does your patient want to avoid infusions? Then yes, the covalent BTKi or venetoclax and acalabrutinib are all oral drugs. Sometimes we worry about reimbursement and approval through the drugs, but you can work through that.

Most of these times patients can get on assistance programs if they are not covered by their insurance. There is lots of copay assistance programs out there now. Does your patient have significant renal impairment? That is a little tricky. With venetoclax, you almost want to try to avoid the venetoclax. If you are worried about tumor lysis syndrome, it can complicate things. She has adequate kidney function.

Then does your patient have del(17p) or p53 mutation? The covalent BTKis seem to be superior, but she has an unmutated status.

[00:27:22]

Summary: First-line Treatment of CLL/SLL Considering Safety

In summary, frontline treatment considering safety, monitoring patients. The majority of them do well with monitoring these novel therapies. Then obinutuzumab is more effective in CLL than rituximab, but associated with greater infusion-related reactions and TLS risk because you are giving it with venetoclax.

Consider the patient and disease characteristics to determine if the patient is suitable, and then risk-stratify for tumor lysis syndrome. There is such beautiful tools out there for you to determine what risk. Like Amy said, she does this for a living. She is always still referring back to those prescribing information and recommendations, because you do not want to guess when you are risk-stratifying somebody and then have a mistake. Many institutions have a check-off list and a double checklist that we go through.

Infusion-related reactions with obinutuzumab can be reduced by BTK inhibitor pretreatment, of course, as well.

[00:28:28]

Posttest 2

I am going to go back to Amy just for the questions, and then she is going to do the pretest, and then I am going to take it off in a couple more slides.

Amy Goodrich: Sure. This is a posttest. Allopurinol and hydration are important risk-mitigating strategies for which of the following therapies used in CLL management? Is it:

A. BTK inhibitors;

B. Liso-cel or CAR T;

C. Obinutuzumab; or

D. Venetoclax;

Beth Faiman: I hope they get this right, Amy.

Amy Goodrich: Beth, it is going to be your fault if they do not.

Beth Faiman: It will be because that was in my section.

Amy Goodrich: I am kidding, Beth. Beth and I do a lot of these programs. Sorry about that, everyone. The venetoclax. Yes. Again, you cannot think about venetoclax without thinking about tumor lysis syndrome and that ramp-up and the risk mitigation strategies that include allopurinol and hydration.

Beth Faiman: Amy, did you see the pretest, posttest? The pretest, it increased from 30% said venetoclax to 61% said venetoclax. You got it right. Congratulations, audience.

[00:29:39]

Treatment and Safety Considerations in R/R CLL/SLL

Amy Goodrich: Thank you, everyone, for your attention. Treatment and safety considerations in relapse/refractory CLL.

[00:29:52]

Patient Case 2: A 68-Yr-Old Woman With CLL Harboring del(17p)

Again, this is our lady. This is a different case, 68-year-old, so similar demographic. She has got a 17p deletion. She comes and her white count is 90. Remember, there is no magic white count. This is all about what is their hemoglobin doing? What is their platelet count doing? What are their neutrophils doing? What are their lymph nodes doing? She is anemic, and she is thrombocytopenic.

She has depression. She receives an SSRI. She has got headaches that are controlled with medications. She has also got AFib, and she is on a direct oral anticoagulant or a DOAC. She gets triplet therapy with venetoclax, acalabrutinib, and obinutuzumab along the AMPLIFY study.

She has some mild headaches on acalabrutinib that resolved with acetaminophen. Her best response is a partial remission. She has detectable measurable residual disease throughout treatment, and within 18 months of starting therapy, she now presents with progressive lymphadenopathy. Her counts are heading in the wrong direction. She is becoming cytopenic, and her next-generation sequencing revealed a C481S mutation.

[00:31:15]

Pretest 4

Considering available information, what is the next best line of therapy? This lady got triplet therapy. She has got a 17p deletion. Do you think you should be talking to her about:

1. Venetoclax and obinutuzumab;
2. CAR T;
3. PI3 kinase-based inhibitor therapy, something like idelalisib with rituximab;
4. Pirtobrutinib; or
5. Zanubrutinib.

[00:31:45]

ELEVATE-RR: Ibrutinib vs Acalabrutinib in Patients With High-Risk Relapsed/Refractory CLL

Beth Faiman: Many options, Amy.

Amy Goodrich: I know.

Beth Faiman: I will go through them in a few minutes, too. Actually, next slide, I will go through them. Back to me again. This is what we try to make it interactive because it is boring when you just listen to the same speaker, but you get a comedy team over here. I do not know. I just really enjoy speaking with Amy, though. Thank you for putting up with us this morning.

Let us talk about ELEVATE-RR. Again, if you are not familiar with clinical trials, we had the ELEVATE-TN, treatment-naive. ELEVATE-RR is the relapsed/refractory. This is also ibrutinib vs acalabrutinib. The idea was, gosh, these are both covalent BTK inhibitors. Which one is better? Which one should we decide?

This was a noninferiority study where patients were equally randomized to ibrutinib or the acalabrutinib. That you could see here that the trial described that there was no difference in the patients who had one vs the other. What you are looking for is the safety.

[00:31:55]

ELEVATE-RR: Cumulative Incidence of Any-Grade AEs of Special Interest

Was there a difference in safety, though? This slide describes the cumulative incidence of any grade AEs of special interest. We are looking at atrial fibrillation and flutter, hypertension, bleeding events, diarrhea, and arthralgia. All these things you can see with the covalent BTK inhibitors. What you can see here is that you still saw some more cardiovascular adverse events with the ibrutinib and the higher safety profile, the risk profile, I should say, with that drug.

[00:33:15]

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

It is not the first one that we go to. It is not the second one we go to the ibrutinib, but it is noninferior from a safety standpoint, but there are more toxicities compared to acalabrutinib, where patients did much better. That is the one that you are going to pick if you needed to give a BTK inhibitor in second-line based on the ELEVATE-RR study.

What about ALPINE? We heard about this before. It is a phase III zanubrutinib vs ibrutinib in relapsed/refractory CLL/SLL, and again, we are randomizing patients to zanubrutinib or ibrutinib. Again, another noninferiority study trying to figure out, is ibrutinib really better than the zanubrutinib or vice versa?

[00:33:57]

ALPINE: PFS at 43.5-Mo Follow-up and ORR

What is super cool about these studies is now we have this long-term follow-up and the progression-free survival, the amount of people that are staying in remission at 42.5 months was reported recently, as well as the overall survival in 2024 by Dr. Brown. You saw the blue line. The thick blue line is the zanubrutinib, and then the orange line is the ibrutinib. What you saw also is patients with or without the Tp53 or the del(17p) mutation still did really, really well. Again, better than the ibrutinib with the deletion.

[00:34:30]

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

Again, we are looking at not only the noninferiority, but we are looking at the toxicity. This slide highlights the cumulative incidence of any grade atrial fibrillation, and you saw obviously that we know that can be caused by ibrutinib, so the orange line on top is the ibrutinib, and you saw an incidence of 17% AFib, flutter, and hypertension. With zanubrutinib, it was only 7.1%. The hypertension was on top of each other, so no difference in hypertension, but worry about the atrial fibrillation rates.

[00:35:02]

ALPINE: Cardiac Safety Profile

In terms of the safety cardiac profile, zanubrutinib was associated with lower rates of atrial fibrillation, cardiovascular events. For somebody like our first case study or some of the other ones that we are discussing here, zanubrutinib is really a pretty well-tolerated drug. You can see here all of the events there were 24.7 of all cardiac events vs 34.6 in the ibrutinib arm. Again, ibrutinib set the stage for BTK inhibition in CLL/SLL. It might not be the best choice if we have access to other options. Zanubrutinib was clearly a superior in that study in terms of adverse events and noninferior.

[00:35:46]

MURANO: Phase III Trial of Venetoclax + Rituximab vs BR in Previously Treated CLL/SLL

In the MURANO study, this is a phase III trial of venetoclax and rituximab vs BR, bendamustine and rituximab in previously treated CLL/SLL. Again, I will not go into great detail about the study design, but the blue box here, the venetoclax and rituximab the doses are highlighted there for when you download the slides later and share them with all your friends at your workplace, vs the bendamustine and Rituxan in the orange box.

[00:36:10]

MURANO Update: Sustained Benefit of BCL2i

We have heard before about the improved survival or improved benefit of adding these newer drugs, and this was also seen in this study. When patients had venetoclax, which is the blue line, they had a 53.6 months progression-free survival vs 17 months. Patients are staying in remission longer when they get the venetoclax and Rituxan in relapsed disease.

[00:36:34]

BTK Inhibitor Switch to Mitigate Adverse Events

What about BTK inhibitor switch? We talked about the 3 covalent BTK inhibitors. Ibrutinib is the first one, acalabrutinib, and zanubrutinib. You can see this was a list of the studies in patients with CLL, and these are various studies. The first box is the 33 patients that were intolerant to ibrutinib and had adverse events switched to acalabrutinib, and 72% had no recurrence of adverse events, and only 13% recurred at a lower grade.

Patients with CLL, again, you can see in this 41 cohort of patients that had AEs, and they switched to acalabrutinib. You had a recurrence of a lower grade of 41% no recurrence. Then, patients with just general B-cell malignancies, which could have included Waldenström's, I think in this study; 67 patients intolerant. Again, you can switch to BTK inhibitors and not necessarily have an adverse event.

[00:37:28]

Expert’s Algorithm: Therapy for Relapsed/Refractory CLL/SLL After CIT, cBTKi or BCL2i

What is an expert’s algorithm? Amy and I were not invited to be on the NCCN guidelines, but I think we do this enough that we would probably agree with what the other experts had said. Just like our newly diagnosed algorithm, or the relapsed/refractory, is the treatment indicated? Are they relapsing, and that if it is not indicated, they are doing okay? We observe closely. If there is a purple box in the bottom indication present, then we say, “Did they have prior chemo immunotherapy? Do they have prior covalent BTK inhibition, or did they have a prior BCL2 inhibitor?” That is your decision-making after your relapse refractory.

[00:38:07]

Outcomes With Covalent BTK Inhibitors

What about patients who have progressed on both venetoclax and a covalent BTK inhibitor? What are the options for them? This is a slide that shows the different outcomes of BTK inhibitors. These cells are super smart. They are going to find a way around anything. There is this idea about acquired resistance.

We discussed again the several BTK inhibitors, the newer ones, the covalent ones. The original covalent BTK inhibitors work by binding irreversibly to a specific amino acid. That is that cysteine at position 481, or C481, and the BTK protein. A mutation at that site, the C481S prevents the drug from binding again. They no longer can bind. The drug does not work. The cancer cells go. We need new drugs for these patients.

[00:39:09]

Acquired Resistance to Covalent BTK Inhibitors Is Generally Driven by Mutations in BTK at C481 Site

The acquired resistance is real to these covalent. Again, as I described, when you get mutations at the C4A1S, which is the site, acalabrutinib, ibrutinib, zanubrutinib cannot do their drugs. Resistance is an issue with the covalent.

[00:39:24]

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

Fortunately, we have another class of drugs, the noncovalent BTK inhibitors that are now available. The BRUIN CLL-321 study of pirtobrutinib vs idelalisib vs bendamustine-rituximab. Again, you can see patients were randomized to the pirtobrutinib vs the other arm.

[00:39:43]

BRUIN CLL-321: IRC-Assessed PFS (Primary Endpoint), TTNT or Death

You can see in this analysis that Independent Review Committee assessed the progression-free survival or time to next treatment or death. You can see the pirtobrutinib was better than the idelalisib. It decreased the risk of starting the next therapy or death by 63%.

[00:39:58]

BRUIN: Efficacy of Pirtobrutinib Regardless of Prior Exposure of BTKi and/or Other Therapy

You can see on this study here the efficacy of the pirtobrutinib regardless of prior exposure. It did not matter if they had ibrutinib, zanubrutinib, or acalabrutinib. This plot shows that they still were able to respond to the pirtobrutinib, probably because the different binding site.

[00:40:15]

BRUIN CLL-321: AEs of Interest

In terms of adverse events of interest in this 116 patients, any great adverse events, you can see them listed here. You still have some bleeding, and Amy already shared how each study tends to report this a little bit differently. Hemorrhage, what is that? How severe was the bleeding? How do you grade that? Those are always the challenges I have in clinical research. Anyway, bleeding still can be a thing. Anemia, neutropenia, and infection as well. The atrial fibrillation rate was pretty low of any grade, as you can see here.

[00:40:48]

BRUIN CLL-313: Pirtobrutinib vs B+R in Untreated Patients With CLL/SLL

What about the CLL-313 study with pirtobrutinib vs BR in untreated patients? Now we are moving it into an international phase III larger study, randomizing to a standard of care BR vs the pirtobrutinib. Stay tuned for additional insights. There was just a report, but I think ASH 2025 there is going to be a paper on this, hopefully presented. We did not get the abstracts definitely out yet, but stay tuned, because this is really the future of medicine.

[00:41:18]

TRANSCEND CLL 004 (Combination Cohort): Liso-cel + Ibrutinib in R/R CLL/SLL

What about CAR T-cell therapy? Why did we wait until so long in the presentation? Well, because for relapsed/refractory patients and we wanted to provide you with a lot of the good stuff that is out there that anybody can pretty much give.

This is the TRANSCEND CLL 004 study with liso-cel and ibrutinib in relapsed-refractory SLL. Again, the CAR T-cell therapy is where you have to harvest the T-cells and manufacture them to be fighters. You can get this bridging therapy while you are waiting for manufacturing, and the patients get flu/cy lymphodepletion. Then that opens up space for these cells to expand in their blood, and then they get the liso-cel. The primary endpoint at dose level 2 was complete response and such.

[00:42:04]

TRANSCEND CLL 004 (Combination Cohort): Response, Undetectable MRD4, and DoR

Anyway, we are seeing some impressive rates of responses. They have here the response by investigator, and then this is the overall response rate was 86%. Again, stay tuned for more updated results from this study, which I think should be coming up soon. These were data from last year ASH.

[00:42:23]

TRANSCEND CLL 004 (Combination Cohort): Safety

The TRANSCEND CLL 004 combination cohort. Again, why am I forgetting what they combined it with? Liso-cel ibrutinib. It was ibrutinib. Thank you. The cohort safety is listed here as well.

[00:42:42]

Liso-cel Infusion and Monitoring in Outpatient Setting

Just so for those of you that are not familiar with the CAR T-cell therapy, this is just a cartoon that depicts the process of manufacturing. Again, it takes time to manufacture CAR T-cells. You have to have this discussion ahead of time. You cannot be rapidly progressing when you decide you want a CAR T-cell therapy because of the time that it takes to get the cells out. Once they are a candidate, financially cleared, they have the T-cells harvested, then manufactured, then reinfused. It is a process.

Common side effects of the CAR T-cell therapy are cytokine release syndrome, neurotoxicity we worry about and then infection risk. The short-term and long-term side effects which will be covered in another section. Not today, but I did want to introduce that to you.

I think I have talked way long enough. I am going to flip it back to Amy. She is going to go over our questions.

[00:43:38]

Posttest 3

Amy Goodrich: Thank you, Beth. Here is a posttest. Based on available evidence from head-to-head comparative phase III trials that Beth just told you about, which of the following have a similar risk for hypertension? Is it:

A. Acalabrutinib and ibrutinib;

B. Acalabrutinib and zanubrutinib;

C. Pirtobrutinib and zanubrutinib; or

D. Zanubrutinib and ibrutinib;

Which have similar risks of hypertension?

Beth Faiman: I can just describe what the pre and post was to Amy, if you do not mind.

Amy Goodrich: The correct answer is zanubrutinib and ibrutinib. Beth showed you that the BRUIN trial, where there was a separation of curves in the AFib, aflutter, but they overlapped in the hypertension category. Beth, do you want tell us what they are great for?

Beth Faiman: The pretest showed that the 12% was pirtobrutinib. Hold on. I think I am in the wrong question. What was the correct answer? Can you see the polling on the side? I forgot the question.

Amy Goodrich: I do not see.

Beth Faiman: Acalabrutinib, 38%. The pretest was 23% and then it increased knowledge to 38%. Good job.

Amy Goodrich: We will take it.

Beth Faiman: I clicked on the wrong button. Now I know where I am at for the next question.

[00:45:10]

Patient Case 2: A 68-Yr-Old Woman With CLL Harboring del(17p)

Amy Goodrich: That is okay. Our case study 2. Remember, she was the lady who has a 17p deletion and she got triplet therapy with venetoclax, acalabrutinib, and obinutuzumab. She progressed pretty quickly after stopping that therapy. She has a C481S mutation.

[00:45:32]

Posttest 4

Considering this lady, which of the following is the best next line of therapy? Is it:

A. Venetoclax with obinutuzumab;

B. CAR T;

C. Idelalisib with rituximab;

D. Pirtobrutinib; or

E. Zanubrutinib;

Beth Faiman: Amy, I hope they get this right. I do.

Amy Goodrich: It has been a long day for these attendees already.

Beth Faiman: Thiry-four percent pre pirtobrutinib and the posttest was 21%. Now, remember, pirtobrutinib is the one that you have that fancy mutation, the C mutation. That would have been the best one. I did a bad job describing that. It is me, not you. But D was the correct answer.

Amy Goodrich: I think if people were confused about pirtobrutinib vs liso-cel, liso-cel is third-line and beyond. Remember, this lady got triplet therapy, and so she is not third-line or beyond. Anyway, pirtobrutinib is our noncovalent. Once people progress on a covalent, pirtobrutinib is the option. This lady really progressed pretty quickly. If she had progressed 5 years later, we would probably be thinking about this very differently, and we would have 10 new drugs.

Beth Faiman: I know, right? It is so exciting.

[00:47:20]

Optimal Strategies to Partner With Patients in Their Care

Amy Goodrich: Optimal strategies to partner patients with their care. We talked a little about this shared decision-making, and really understanding patient expectations, and talking them through that watch-and-wait, and making sure they understand what triggers are for therapy. Really understanding their goals, and some people are very articulate about whether they want infusions or they do not, or they want time-limited therapy, or they want just the fewest visits humanly possible.

Then, really, compliance is really important here. I really try to tell patients that we dose-reduce if they have side effects. Reporting those symptoms, not only does it allow you to get on them quicker and get them under control quicker, but it is important for patients to know that sometimes we really do need to dose reduce these drugs, and they still can be very effective. Then there are lots of things in the lots of resources in the literature for adverse event management at this point, which is a real positive as well.

[00:48:31]

Tools and Resources to Share

We do have some of them here at CCO. We have got CLL tool for healthcare providers, and we have the BTK inhibitor adverse event management tool. If you have not looked at these and you are not familiar with using these drugs, and you are starting to use them, or even if you do, just to make sure that you are up to date on how you are managing people.

[00:48:53]

Posttest 1

Let us jump into posttest number one. How confident do you feel in counseling patients with CLL to engage them in their care with the goal of promoting adherence to their treatment plan? Everything from not confident to very confident.

Optimally, everyone would be confident or very confident. This tends to be a savvy patient population. A lot of them come with a lot of very good questions. We do need to be on our toes, and the ones that do not come with good questions, we really need to figure out how to engage them and make sure that we are increasing their health literacy.

[00:49:40]

Poll 4

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

A. Yes;

B. No; or

C. Uncertain;

[00:49:50]

Poll 5

Then if you can just take a minute to enter one key change that you plan to make in your practice based on this education.

[00:50:00]

Audience Q&A

Then we are going to dive into the question and answer. We do have some questions here. How long after being on a BTK covalent inhibitor do patients become resistant? Beth, do you want to take that one?

Beth Faiman: Yeah, it varies. Patients can be on fixed duration or they can be on a longer duration, but it really depends on the disease biology and the patient itself. Regular monitoring of labs and making sure that they are taking the drugs so for oral adherence, those types of strategies I think are things that we can employ but it really varies. When you look at the clinical trials, look at the duration of response. These drugs work for a long time.

This acquired resistance over time varies according to the mutational status, the risk of the status, and if patients are taking their medicines or not. Amy, what do you think about that? Do you have any other thoughts about resistance? It varies.

Amy Goodrich: I feel like everybody does well initially, and then it does vary widely. It does. Even if people have an initial response, they can quickly become resistant. Most people are on it for a number of years before they become resistant. Then someone is asking, can you talk again about the C481S mutation in relationship to pirtobrutinib vs zanubrutinib?

Beth Faiman: Yeah. I feel like the biggest thing is the reversibility of the binding; the BTK binding with the covalent ibrutinib, acalabrutinib, and zanubrutinib is one way. They all do the C481, but the pirtobrutinib becomes distant from that as a reversible binding. I do not know, Amy. Maybe you have a better way of describing it.

Amy Goodrich: When I explain it to patients, I explain it that the ibrutinib, acalabrutinib, zanubrutinib, they all hook in the same way, and they hook into that C481S. When that mutates and they can no longer bind in, the drug stopped working. Then the pirtobrutinib binds in a completely different space. It does not matter if this is working normally or not working normally. The pirtobrutinib does not need this binding pocket.

Beth Faiman: It binds really separate.

Amy Goodrich: That is how I think about it.

Beth Faiman: That is a better description, and it is a separate pocket binding site. If it is mutated and it does not work anymore, and it lost that power to when it mutates. I think of a mutant. For a long time, I was trying to figure out what is it? A mutant. They are just not normally forming cells, and so they cannot do the job that they are supposed to do.

Amy Goodrich: Yes. We have some more questions. If a patient is on acalabrutinib and develops progressive disease, but they do not have a C481S mutation. Do you ever go to another covalent? Do you go to zanubrutinib before moving to pirtobrutinib? How do you handle that?

Beth Faiman: I think that we shared our little diagnostic algorithm, and that is when I go back to the NCCN guidelines. I say, okay, so what is the recommendations for somebody once they are progressing? You can go to another covalent.

Let us say a lot of people now they are progressing, and they were on chemoimmunotherapy or ibrutinib. You can try acalabrutinib or zanubrutinib in combinations or by itself. There are a lot of different options, and I just go back to the guidelines. I do not know if we can pull up that algorithmic approach in the guideline. I will go back and circle back here. We go slide 57 is our expert algorithm.

You can see here that if you had an indication as the purple box in the bottom, you decide. Did they have prior chemoimmunotherapy then it is dealer's choice? The prior covalent BTK inhibitor is the middle box, so the best choices are venetoclax plus or minus an anti-CD20 such as rituximab or an alternative covalent BTK inhibitor. If it was discontinued due to intolerance, maybe it did not stop working and they still have the ability to respond or the pirtobrutinib, which is if they had the prior covalent or intolerant, or resistant.

Venetoclax BCL2 inhibitor class switch. Maybe they stopped it for a variety of reasons. You can definitely go to acalabrutinib or zanubrutinib as well if you stopped it for another reason, and it might still work. What do you think, Amy?

Amy Goodrich: Then you have got all these slides, and Beth did show you a pie chart of C481S is just one of several mutations. It is the most common one, but it is not the only one. This is a very much emerging area of interest to try to figure out why people stop. Other than really, why do people stop? What can we do about stop responding?

I have another question, Beth. Because of these cardiovascular risks with BTK inhibitors, do you baseline screen all patients with an EKG if they have no cardiac history, or just those at high risk? What are you doing?

Beth Faiman: I like to get a baseline EKG, especially if giving them ibrutinib. Usually, I am not using ibrutinib upfront. Acalabrutinib still harbors some risks, though, but I like to know the cardiac status ahead of time. The question I get a lot, Amy, is echocardiograms. Do you want to see if they have had a prior echocardiogram? In your practice, is that important to you?

Amy Goodrich: We are trying to do screening EKGs on everybody, not necessarily ECHOs, because the toxicity is not with the squeeze. It is with the electrical system.

Beth Faiman: We do not do ECHOs on everybody, and so usually you are going to know because these patients are middle-aged and fifth to seventh decades or older is how they will present. They are going to probably know if they have hypertension or hyperlipidemia or if they have had an atrial fibrillation episode. Then we are just going to closely monitor them.