Importance of individualizing CLL therapy. Next.

[00:09:29]

Prognostic Variables in CLL/SLL

These are the prognostic variables. We have seen this for a long time. CLL is not one disease. I think the problem that we run into is that patients come in with the thought process. Maybe you see them in your practice or somebody who does not do CLL a lot, or the primary care physician might have heard about it, or some other people who do not necessarily take care of CLL patients, they talk to the patients and say, “Hey, this is the best leukemia to have. This is a good leukemia. You will be just fine”.

You get lucky when you use that terminology, because yes, that is correct. 50% of the patients will have a slow moving CLL, but the vast majority of patients will need treatment during the life span, especially now that our patients are living well into their 80s. No cancer is a good cancer to have. CLL is not an exception.

Similarly, CLL is not one disease. CLL is multiple different diseases, all combined under one umbrella. As our understanding is growing, we are realizing that more and more, there are so many variables in the relapse setting that you have to consider when you are selecting which therapy to choose.

Historically, the couple of things that have been very important have been the FISH status and the IGHV status. I think those are the ones that we have been historically using and we still use it and still relevant. IGHV unmutated vs mutated status. Once you are mutated, you are always mutated. Mutated is good, unmutated is bad.

Similarly, on the FISH side, del 13q is the most common abnormality, which is the good prognostic marker, if it is without the unmutated thing. But if it is a mutated 13q deleted patients, [inaudible] repeatedly shows a worse prognosis is deletion 17p on FISH, not [inaudible].

TP53 mutation on genetic sequencing testing or a PCR assay. Del 17p on FISH and TP53 mutation on NGS, both of them combined will be worse than either one of them alone. Both of them are prognostically poor prognostic markers. This is why when you do the FISH, you also should sequence for TP53 mutations. Those are separate testing that has to be done in the current era in the US. In other countries where you may not have access to it, that is a separate discussion.

Similarly, there are other genes that we routinely test for ATM, NOTCH1, SF3B1, and so on. Some of them have a worse outcome. Some of them are slightly better.

On the relapse side, now we are trying to learn more and more about the resistance mutation. We know that the BTK cysteine 481 mutation is the most common mutation that we see in patients who get tyrosine kinase inhibitor. Similarly, for patients treated with venetoclax, they have this G101V mutations that we see most commonly in those patients if they are truly refractory to venetoclax.

Then there are a bunch of other genes, and I would not get into too much detail, but there is a few ones, especially the L528 and 474. The 528 is the BTK kinase dead mutation, which is the bad one. The 474 is the gatekeeper mutation. Both of them have different implications, and I will get to that at the end. But this is a learning process for all of us. How does the cancer evolve? How does the cancer become resistant? All of this information may be accessible to you. Sometimes you might have to find the right assay for this. Sometimes the assays may not be as good.

Next slide.

[00:13:23]

Management of Treatment-Naïve CLL/SLL

All right. How do we manage patients with treatment-naive CLL in the US currently?

Next slide.

[00:13:27]

First-Generation Covalent BTK Inhibitor (cBTKi): Earlier Role as 1L Therapy for CLL

This is the slide that you guys must have seen. But basically the bottom line is chemotherapy in the US has no role in the management of patients with CLL. I know people still argue 6 months of chemo and you are done. Again, there is no justification for that anymore in terms of progression-free survival, in terms of overall survival, in terms of low-risk disease, in terms of high risk disease, in terms of young patients, in terms of old patients. Every which way you look at it, chemoimmunotherapy is inferior to BTK inhibitors.

Yes, it is very attractive to do 6 months of chemotherapy and be done with it. Sometimes some of those patients may have a long remission. But in the modern day, this is not justified because the toxicity is not justified and people do end up getting secondary malignancy.

Next slide.

[00:14:17]

First-Generation Covalent BTK Inhibitor (cBTKi): Earlier Role as 1L Therapy for CLL

The first-generation BTK inhibitor was ibrutinib, obviously. Ibrutinib was the one that clearly showed an improvement over chemotherapy. Then different ibrutinib combinations with or without rituximab have been shown to improve outcomes in multiple studies, as compared to bendamustine-rituximab and as compared to FCR.

Next slide.

[00:14:37]

First-Generation Covalent BTK Inhibitor (cBTKi): Fewer AEs and Superior to CIT

The problem with the BTK inhibitors, ibrutinib specifically is, that it was a very effective drug. No doubt about that. It revolutionized, changed the way we take care of patients with CLL. But the problem is that when we only had ibrutinib, then we did not have a choice. We were able to get patients through treatment for a long period of time.

But as we got newer BTK inhibitors, which were less toxic, the justification for using ibrutinib declined. Over the years, that switched to acalabrutinib and zanubrutinib. As you can see, both of these again were compared to chemoimmunotherapy and again were shown to be less toxic and better than chemoimmunotherapy.

Across the board, old BTK inhibitors and new BTK inhibitors are not any inferior than chemoimmunotherapy. Chemoimmunotherapy actually is inferior to BTK inhibitor.

Next slide.

[00:15:35]

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

On that note, it just kept going on and on and on with venetoclax now, BCL2 inhibitors. Let us forget about the BTK pathway, which is the most important pathway for CLL. But if we focus on the BCL2 pathway and if we block it with venetoclax, even those patients did really well as compared to chemoimmunotherapy, both in the untreated setting and in the relapse setting.

Next slide.

[00:15:59]

GAIA/CLL13: Time-Limited First-line Venetoclax + Anti-CD20 Ab ± Ibrutinib for CLL  

This is the CLL13 study, which was an important study for a couple of reasons, because this was the study that, again, kind of roundabout way, asked if the triplet combination of IVO, or ibrutinib with venetoclax-obinutuzumab. All 3 drugs, CD20, BCL2, BTK, put it all together. Compare it to venetoclax-obinutuzumab, venetoclax-rituxan and chemoimmunotherapy.

If they had ibrutinib alone arm, that would have been good, but that defeats the purpose of time limited therapy. If they had an I plus V arm, that would have been even better. Anyway, this is what we had. This study was important because we kind of knew what to expect that all 3 arms should beat chemoimmunotherapy.

[00:16:40]

GAIA/CLL13: Efficacy 

But what was interesting with this study is, in the next slide, that the response duration of the depth of the response, the undetectable measurable residual disease levels went up really nicely with the combination. The more you add in terms of novel therapy I plus V plus O, all the things that you add together, you get into a very deep remission.

Why is the deep remission important? Because the deeper the remission, the longer it lasts. No surprises there. This is kind of what was expected that the venetoclax-obinutuzumab arm, venetoclax-rituximab arm, and the IVO arm, all 3 novel therapy arms were better than chemoimmunotherapy. Absolutely no surprises.

But what was surprising here was that the ven-R arm was significantly inferior to the ven-O arm, and that was because obviously the only difference here was the obinutuzumab vs rituximab. The CLL13 is important primarily for this reason that the triplet gets you into a deepest remission. But ven-O is not bad at all.

Is it really justified to use 3 vs 2 and which 2? Because if you had added the I plus V, it would probably be fairly close to that 70%-plus with I plus V. You can argue about this. But one thing was important was obinutuzumab was better than rituximab. That is why for the vast majority of patients with CLL, if you want to use a partner CD20 antibody with whatever treatment you are using, obinutuzumab should be the go-to antibody.

Now, sometimes you run into insurance issues and that may be difficult, but typically obinutuzumab is the correct partner antibody for patients with CLL. The use of rituximab has gone down.

Next slide, please.

[00:18:30]

CAPTIVATE: Ibrutinib + Venetoclax for Untreated CLL/SLL 

All right. This is the I plus V study. We are talking about the CAPTIVATE study. Basically, it has ibrutinib for 3 cycles followed by the addition of venetoclax. Then if you had deep remissions, then you get randomized to continuing ibrutinib for another year or so. Then if you had detectable, then you continue both. One year minimum and then plus one.

Time limited therapy but stratified by MRD status. These are all relatively young patients who need therapy.

Next slide.

[00:19:00]

CAPTIVATE: 5.5-Yr Follow-up Survival Analysis From Fixed-Duration (FD) Cohort of First-line Ibrutinib + Venetoclax for CLL/SLL

All right, very interesting. All of these arms did really well. Patients with del (17p) still are not doing as well as the other cohorts. Over and over again, this is another thing that we are realizing that generally outcome across CLL, across all types of diseases has improved, except for patients with del (17p), and those are the patients who still perform inferiorly. They are still doing much better than they were before in the chemotherapy era, 11 months vs now 5, 6 years of average remissions.

With chemoimmunotherapy, the best remissions we got was in an 11-month PFS with FCR or alemtuzumab. But with these new treatments, we are looking at 5 or 6 years of median remissions, even in the high-risk patients. This is very impressive. People do really well with novel therapy combinations, even when they stop treatment after finishing the one year course of I plus V, which is ibrutinib or BTK inhibitor plus BCL2 inhibitor.

Next slide.

[00:20:03]

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

All right. This is why we have to talk about the venetoclax, BCL2 approach vs a BTK approach, right. Now when I am talking about BTK, I have to make one distinction. We are talking about covalent BTK inhibitor. What is the difference? The covalent BTK inhibitors are 3. Ibrutinib was the first one. Then acalabrutinib came about, and then we had zanubrutinib. All 3 are what we what we consider covalent BTK inhibitors. They bind to the cysteine 481 site and turn the switch off. That is it. They do not get off the molecule.

This is the first generation of drugs we have. Now, some people call it first generation, second generation, third generation or new and old, whatever. But the bottom line is all of them are covalent BTK inhibitors. In my opinion, all of them are the first-generation drugs. Some are different than the others. Toxicity profiles are different. One may be less toxic than the other. This is where the covalent BTK inhibitor should all be viewed as a class.

The problem with covalent BTK inhibitor was that it is definitely superior to chemoimmunotherapy. But you do require maintenance continuous dosing. You have very good data with 17p deletion and TP53 mutations with the use of BTK inhibitor. It is convenient. No infusions, no nothing. You go home. Thank you very much. Easy to follow. See you back every month or every 3 months.

It does have issues with cardiac issues and bleeding issues. Here is the problem with the BTK inhibitors. The cardiac issues, AFib and so on. Then they act like a blood thinner. You need to anti-coagulate these patients if they develop atrial fibrillation.

Now on the other hand, venetoclax plus obinutuzumab is very attractive, 12-month and you are done. But it does have a possibly inferior - not a possibly. We definitely know that in patients with unmutated disease, IGHV and patients with mutated TP53 or del (17p) disease, venetoclax had an inferior outcome.

The first question we talked about was specifically addressing that issue, that if you have a patient with del (17p) or TP53 mutation, the preferred option in the modern era, in this country where you have access to all the different options is a BTK inhibitor for high-risk patients.

Now, why do not we use ibrutinib in patients above 70? Well, we do not use ibrutinib as much because ibrutinib has been shown to be the most toxic. It has the most side effects. That is why we prefer to use acalabrutinib or zanubrutinib. That was the whole idea of that question was to focus on what we can do to select out the best option for that person.

If somebody has 17p disease and del (17p) on FISH or TP53 mutation, those are the patients who should initially be treated ideally with BTK inhibitors.

Now if you say that, hey, BTK inhibitors are bad for this patient for XYZ reason, in that case it is not wrong to use venetoclax, but it is not the preferred option. Venetoclax does give you a time limited option. It does potentially save money in cost, but then the monitoring cost is high. The cytopenias can be an issue.

Tumor lysis, at least lab tumor lysis can be a problem, but all of these can be managed. The point of all of this is there is no better option. Both of them have some advantages, some disadvantages. This one does not have the cardiac issues, the hypertension issues, but the cytopenias are more pronounced with venetoclax. Diarrhea might be there too. This is why it has to be weighed with the situation that you are in. You need to have a good team that can monitor the patient well. You have to do it safely.

If that is the case, you can use one over the other. It does not mean that one is better. It is a different philosophy. It is a different approach.

Now another way to look at it is let us say if your goal is to keep the disease in remission for 10 years, how many times will I have to do venetoclax? One time 5 years, 6 years; another time, 3, 4 years, and then you are done. After 10 years, it probably would not be effective.

On the other hand, if you keep on a BTK inhibitor, you may get 8 or 9 years anyway. That is the whole argument of using continuous therapy vs venetoclax, provided that the toxicity can be justified.

All right. Let us keep moving.

[00:24:28]

AMPLIFY Trial of Acalabrutinib + Venetoclax ± Obinutuzumab vs CIT

All right. This is the AMPLIFY study, which is the most important study that was recently presented. It was a 3-arm study. Same question. Can we stop a BTK inhibitor? What is the best partner for a BTK inhibitor? Because ultimately you want to use very effective treatment upfront front-line because that is where you will get the most bang for your buck. But at the same time, you do not want to continue therapy.

Nobody wants to continue therapy if you had a good option, but you do not want to jeopardize long-term outcomes by using time limited therapy. This is an important study because it compared chemoimmunotherapy vs AV vs AVO. Acalabrutinib plus venetoclax with or without obinutuzumab.

There was no surprise. I do not think anybody was surprised when it showed that AV arms were better than chemoimmunotherapy. That was not really in doubt, if I may say so, because we knew what was going to happen. I would have been nice to have a VO arm in it. That would have been even better. But it is what it is.

Big study, multi-center study, international without 17p deletion. That is an important point to note. These are not high-risk patient traditional criteria. They looked at various outcomes.

Next slide.

[00:25:44]

AMPLIFY: PFS per IRC

Very interesting. The AVO arm had the best progression-free survival. The triplet as compared to A plus V. As expected, they were better than FCR or BR.

Next slide.

[00:25:56]

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

If you look at the depth of response, the triplet had the best response in terms of the depth if you look at uMRD 4. That is why this was clearly performing better in the long run.

Next slide.

[00:26:12]

AMPLIFY: OS 

Then in terms of overall survival, AV actually had a better overall survival. Why is that? Why did the patients with AVO, the triplet who were doing better in terms of depth of response, in terms of the response rates, in terms of progression-free survival, why were those not doing better in terms of overall survival? That is because of the COVID-related mortality.

Almost exclusively, the mortality was higher in the triple therapy arm because of COVID. As a result, there was no difference in survival outcomes between AVO and chemoimmunotherapy. But there was improvement with AV vs chemoimmunotherapy. But if you censor for COVID-19 deaths, there was no difference in overall survival if you used any of the 3 arms.

This is why it is important. Yes, I am getting into a deep remission. Yes, I am getting into a better PFS, but at the cost of substantial mortality, that is not justified. You lose a person in remission. These are the questions that you have to debate. Are you ready for triple therapy or is double enough, because you have less toxicity? Is survival a good endpoint? Survival is very hard to demonstrate a difference in CLL because luckily our mortality is not that high.

These are the big questions that are there. Will everyone get 3 drugs or will everyone get 2 drugs? Maybe it is a young patient. Maybe we can do a better job. This was done during the height of the pandemic. Nowadays, maybe with the vaccines, we can have a better outcome.

These are the decisions that we would like to make. But the bottom line here is, obviously, if you combine the 3 drugs, you get into a better response. You get into a deeper response which lasts longer.

Next slide.

[00:28:06]

Safety: BTK Inhibitors BCL2 Antagonists

Okay. That is that with the AMPLIFY study. Now we will talk about the BTK inhibitors and the BCL2 inhibitors in terms of their activity. Let us move on.

[00:28:16]

Ibrutinib/BTK Inhibitor–Related Toxicities of Interest

This is the ECOG. Basically we are talking about bleeding toxicities, cardiovascular toxicity. Just a minor point here is the cardiovascular toxicities are important for BTK inhibitors. Having said that, the cardiovascular toxicities should not be lumped into one. It should be very distinct. Atrial fibrillation, ventricular arrhythmias are more debatable. Lastly, it should be hypertension.

Why is that? I would like to take one second to make the point for this is because hypertension has nothing to do with atrial fibrillation in this setting. Yes, in the normal patient population that we see in our practice, cardiology practice, primary care practices, you have hypertension for 10, 20 years. You have cardiac remodeling. You end up with AFib. Completely different beast.

In this case, atrial fibrillation happens in the first 2 months. It kind of peaks. By the sixth month it peaks and then it plateaus. You do not see a lot of new AFib after 6 months. Most patients who do well after 6 months or 1 year, they will not have any problems. The hypertension is the same. It happens in the first 6 months, plateaus. AFib happens in the first 6 months, plateaus.

The point is, it is not AFib that is being caused by the hypertension. They are unrelated. They are mechanistically different processes. That is why lumping cardiovascular toxicities is not the smart thing to do because the mechanisms are different. You have to look at hypertension separately, then atrial fibrillation. This is why it is important to tease those apart. But those are fairly important toxicities of BTK inhibitor. Infectious complications is another one that we see. Let us move on.

[00:29:58]

Comparison of E1912 and Alliance 041202 Trials: Median Age and Grade ≥3 Treatment-related Adverse Events (TRAEs)on the IR Arm

This is the chemotherapy comparison. Essentially, we saw that patients who got BTK inhibitors, ibrutinib primarily, if they were 70 years of age or older, those patients had the highest risk of sudden cardiac death. This was one of those things. Then similarly for older patients, this was a very prominent signal for younger patients. We do not see that in the ECOG study vs the Alliance study, which were sister studies, one for young, one for old.

Similarly, atrial fibrillation rates were higher in older patients, as expected. Now in clinical trials, the patients are super selected. The adverse event rates are higher from natural, real world databases. This is as high as 30%. In some cases, bleeding risk is as high as 30%, but obviously higher in the elderly folks. Hypertension 33% with the ibrutinib.

Across the board, the older you are, the less the reason for using ibrutinib. That was what was addressed in the previous question that we asked. Ibrutinib should be avoided, at least in the US for patients, who are older than 70, it should not be used. There is no justification for its use because we have better drugs unless you are in a very unique situation. This is the reason why nobody recommends, nobody uses patients or starts patients on ibrutinib above 70 because of the especially high risk of cardiac toxicities and hypertension with ibrutinib.

Next slide.

[00:31:24]

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

This is again A plus O vs A. This is the ELEVATE study. You see atrial fibrillation rates in the 1.7. This is on the low side because you do have grade 3, which is clinically relevant or higher events are pretty low. Bleeding is still an issue but the atrial fibrillation rates are lower. Hypertension is a very low, almost like background noise but still there. Infection remains the biggest issue. Did we make a difference between ibrutinib and acalabrutinib?

Next slide.

[00:31:55]

SEQUOIA: Safety Analysis

Let us look at SEQUOIA, which is the zanubrutinib data, which essentially shows fairly similar results that the hypertension rates are actually there. But more importantly, neutropenia becomes more pronounced in patients with zanubrutinib. That causes more cytopenias. That was something to look out for. Unique to the BTK inhibitor, zanubrutinib probably causes more neutropenia than other drugs.

Next slide.

[00:32:21]

SEQUOIA: Safety Analysis (cont’d) 

If you look at the hypertension rates, zanubrutinib also caused significant hypertension risks. Again in terms of overall cardiac risk, it is very low. Atrial fibrillation rates are much lower with zanubrutinib as compared to ibrutinib. But hypertension and neutropenia are important risks of zanubrutinib. You have to keep that in mind when you are deciding how to proceed.

Next slide.

[00:32:56]

BTKis: Impact of Safety Concerns/Cardiovascular Risk 

This is our consensus that we publish that if you have a patient who is high risk for hypertension, you might want to go with something like acalabrutinib, which may be less hypertension inducing rather than ibrutinib. If it is an older patient, definitely avoid ibrutinib. If it is somebody with a very high risk of atrial fibrillation, both acalabrutinib and zanubrutinib are not unreasonable options. Patients who do have underlying heart issues, those need to be optimized, work with cardiology, work with cardio and oncology, but develop methods to stratify patients, optimize the cardiac issues and then do it.

Another important thing. Can you use blood thinners with BTK inhibitors? Absolutely. You just have to be careful. You can use blood thinners. It is actually the antiplatelet therapy like the aspirin and the Plavix, which actually causes more of a bleeding issue with BTK inhibitors. If you can get somebody on off of aspirin or Plavix, that is actually a bigger, a more important thing than getting them off of apixaban. We frequently have patients on apixaban and they do just fine.

Next slide, please.

[00:34:00]

BTKis: Expert Recommendations for the Management of Bleeding and Cardiovascular Issues

All right. This is what we do if you have to take them for a minor procedure, stop the BTK inhibitor for 3 days. If it is a major procedure for 7 days. Why? Because that is how long it takes for the platelets to recover. This is an antiplatelet effect of the BTK inhibitor. That is why you do not combine BTK inhibitors with antiplatelet therapy. Be aggressive with monitoring hypertension. If somebody is complaining of palpitations, do not ignore it. Pay attention to it. Get an EKG and move on from there.

All right. Next slide.

[00:34:30]

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

These are some of the other side effects that we see. Headache is very prominent with the acalabrutinib. That is why caffeine works very nicely. It typically resolves very quickly. Similarly for zanubrutinib. You can always hold drug but you can also give growth factors, just a minimal amount of growth factors to control the disease.

Moving on to venetoclax. Next slide.

[00:34:51]

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

As you can see, venetoclax causes a lot of thrombocytopenia and neutropenia and febrile neutropenia is luckily not that bad. But it also causes cramping. It also causes diarrhea. These are real side effects that have to be paid attention to and managed. Those are the ones that we commonly see in practice.

Now the scare with venetoclax is tumor lysis. Actually, we do not see a lot of tumor lysis, if you control it better. If you start with the CD20 antibody, get them down in a nice disease control state, debulk them, then it should be fine using obinutuzumab with venetoclax and venetoclax should not cause the tumor lysis if you ramp it up nicely.

Next slide, please.

[00:35:36]

AMPLIFY: Most Common AEs 

These are the most common side effects we saw with the AMPLIFY study. AMPLIFY study showed that the neutropenia was highest with the AVO arm and the chemoimmunotherapy arm. The triple therapy causes more cytopenias as expected. Headaches were more common with the acalabrutinib arm. You do not see the headaches with the ibrutinib or the chemotherapy arm infusion reactions, again, if you use obinutuzumab, you will have infusion reactions.

Then febrile neutropenia rate actually is also slightly higher with AVO, but not significantly higher. Just a couple more patients. But that is the reason why if you are going to use a triplet to get the patient into a nice deep remission, you are increasing the toxicity.

Look at the COVID risks. It is significantly higher in terms of severe grade 3 or 4 COVID-related infections with AVO. This was actually the big issue back then. Is COVID here to stay? What about vaccines? They do not really work in our patients. We know that. Then what do you do? These are all issues that we have to deal with.

Let us move on to the next one.

[00:36:44]

AMPLIFY: AEs of Clinical Interest 

Then similarly, if you look at atrial fibrillation rates, very low rate as expected with acalabrutinib. Hypertension is also relatively low, almost slightly above background that you see with the chemoimmunotherapy. Bleeding does remain an issue. We have to be careful with that. Neutropenia infections are an issue.

We do get more problems with the increasing depth of response if we combine all 3 drugs.

[00:37:12]

Let's Revisit Our Question

All right. Let us revisit our question then.

[00:37:13]

Posttest 1

All right. This is the first one. In the AMPLIFY study, which of the following is demonstrated in the interim results of AVO vs FCR or BR for untreated CLL without del (17p).

1. Survival rate was lower;
2. Hypertension was higher with AV or vs AVO;
3. Similar rate of febrile neutropenia with AVO and FCR/BR; or
4. Significantly prolonged progression-free survival with AV vs FCR or BR.

Please vote.

[00:37:58]

Posttest 1: Results 

All right. Significantly improved progression-free survival with AV vs FCR/BR was the correct answer. The higher rates of hypertension. There was not a big difference in the acalabrutinib arms in terms of hypertension. The febrile neutropenia rates were also higher with chemoimmunotherapy.

Essentially, the AV vs FCR PFS was the difference in this, which both of them were better.

All right. Let us move on to the next question. This was the rate of hypertension and so on.

[00:38:33]

Management of Venetoclax-Associated Toxicities 

Okay. We talked about tumor lysis syndrome with venetoclax. We have seen this. Basically, debulk the patient before starting venetoclax. Now, in the BTK inhibitor plus BCL2, BTK ibrutinib, acalabrutinib, zanubrutinib plus venetoclax, you start with the BTK first. Then you debulk in 2 to 3 months, and then you start the venetoclax and you do not have any problems whatsoever. That is why it is such an exciting approach.

Let us move on.

[00:39:04]

Expert’s Algorithm for Front-line Therapy 

This is our management. Like I said before, is it wrong to use venetoclax plus obinutuzumab? Probably not a wrong option in the unmutated and the del (17p) patient, but it is not the preferred option. The preferred option for patients with del (17p) or TP53, untreated CLL or IGHV unmutated. Any high-risk features, the therapy of choice is a BTK inhibitor, acalabrutinib with or without obinutuzumab or zanubrutinib and venetoclax plus obinutuzumab would be the second and then TP53 wild-type, no del (17p) in those all 3 is a toss-up.

Then you can decide if you want to continue. Now you can ask me, hey, why aren’t you adding doublets here? Because the doublets in the United States is not approved in Europe. It is approved in the US. It is not approved until we get the doublets or triplets approved of novel therapy. Right now we have only the acalabrutinib plus obinutuzumab-zanubrutinib as continuous option for untreated upfront CLL. Otherwise, you should not be stopping these therapies because we do not have good data to support that approach.

Let us move on to the relapsed setting now very quickly.

[00:40:20]

Summary: First-Line Treatment of CLL/SLL

Summary of this. We have talked about this. Select the BTK inhibitor for high-risk venetoclax for low-risk, time limited. Talk to the patient. Be careful about side effects and you will be just fine. Let us move on.

We will talk about the case of a 76-year-old person. Next slide, please.

[00:40:38]

Let's Revisit a Patient Case

Next one.

[00:40:42]

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

This is again the patient that we talked about initially. She had high-risk 17p disease, del (17p). Thrombocytopenia, anemia, bulky lymph nodes, renal failure, 3 hours away, does not want to come back. How would you treat this patient?

Next slide.

[00:40:56]

Posttest 2

These are the options. Please pick an option:

1. Acalabrutinib ± obinutuzumab;
2. Ibrutinib;
3. Pirtobrutinib;
4. Venetoclax-obinutuzumab.

[00:41:21]

Posttest 2: Results 

All right. Pirtobrutinib is not the right answer. The correct answer would be acalabrutinib. Venetoclax is not wrong, but good luck managing this patient because she is 3 hours away, so she may not be able to show up in your clinic. The correct answer is acalabrutinib plus obinutuzumab. That is one.

All right. Let us move on.

[00:41:43]

Aligning Current Clinical Practice With NCCN CLL/SLL Guidelines

Then let us talk about NCCN guidelines. What did the NCCN show. Let us look at that.

[00:41:51]

NCCN Guidelines Version 1.2025

NCCN shows the same thing. You start off without the high-risk mutation the del (17P) or TP53. You start with acalabrutinib or venetoclax and can consider venetoclax plus obinutuzumab, but that is not a category one recommendation. That is what we were asking about. Pirtobrutinib should not be used in the front-line setting? Absolutely not, unless we know the data that it is okay to use. Because if you start with pirtobrutinib, by the way, this was the second generation BTK inhibitors that I was going to talk about. This is the non-covalent BTK inhibitor.

The first 3 bind here. These 2 bind here. Both pirtobrutinib and nemtabrutinib, there are 2 of them that work very nicely. They bind to another site. They bind on and off.

They come off the kinase. This is why they are called non-covalent BTK inhibitors. Pirtobrutinib should not be used in the front-line setting. Then let us move on to the next one.

[00:42:47]

NCCN Guidelines Version 1.2025

This is when patients with del (17p). If somebody has del (17p), venetoclax-obinutuzumab, should be the less preferred option. Then BTK inhibitors is the first option. If you do not have a del (17p), all 3 are perfectly reasonable. I might have said it differently earlier.

But for subsequent line of therapy, it is very important to see what they had in the front-line setting. If they had chemoimmunotherapy, then everything goes. If they have BTK inhibitors, then you switch to BCL2 inhibitor. If you had BCL2 inhibitors, let us say they had venetoclax plus obinutuzumab, how soon after will you do venetoclax-obinutuzumab again? Now, there is a disagreement in this approach, but from the data that we have, it is almost 50% of the responses if you reuse venetoclax.

If the response rate is less than 2 years, it does not make sense to use venetoclax. Again, it is not wrong to use it, but it would not give you any bang for the buck, so it is probably not useful or worthwhile using venetoclax again if your first remission was less than 2 years.

Let us move on.

[00:43:55]

Expert’s Algorithm: Therapy for Relapsed/Refractory CLL/SLL After CIT, cBTKi or BCL2 Inhibitor (BCL2i)

This is how we summarized it. If you had prior chemoimmunotherapy, you can use all 3 options: ibrutinib, venetoclax, or acalabrutinib-zanubrutinib. If you had a prior covalent BTK inhibitor, you then go to venetoclax or pirtobrutinib, or you can go to something else like a PI3 kinase inhibitor, but we do not really use it.

If you had prior BCL2, you can reuse it if you had a good remission in the front-line setting, otherwise you go from BCL2 to BTK.

All right. Next slide.

[00:44:29]

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

This is the ELEVATE-RR study with acalabrutinib vs ibrutinib. This is kind of the studies that established the superiority or lack of inferiority of these drugs over one another. There is no difference in outcome. Acalabrutinib was fine, and so was ibrutinib. But the issue was toxicity. Next slide, please.

[00:44:49]

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

This is the toxicity curve as you can see. Atrial fibrillation was higher with ibrutinib, both in patients with or without a prior history. Then in terms of hypertension, ibrutinib was higher, acalabrutinib was lower, bleeding events were higher, diarrhea was higher, arthralgias was higher. Across all groups, atrial fibrillation, hypertension, bleeding events were worse in patients on ibrutinib.

Our discussion, if you have worse toxicities, let us move on. Next slide.

[00:45:22]

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

This is the ALPINE study, zanubrutinib vs ibrutinib in a different patient population. Cannot really make any arguments about which one is better again.

Next slide, please.

[00:45:32]

ALPINE: PFS at 42.5-Mo Follow-up and ORR 

Zanubrutinib had an improvement in PFS across all subsets as compared to ibrutinib. Next slide, please.

[00:45:41]

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

It also showed worsening of the atrial fibrillation with ibrutinib as compared to zanubrutinib. Zanubrutinib was better in terms of atrial fibrillation. But when you talk about hypertension, they are both equally bad.

Next slide.

[00:45:55]

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

Similarly, venetoclax plus rituximab vs bendamustine-rituximab chemotherapy. This is an older study, the MURANO trial.

Next slide.

[00:46:04]

MURANO Update: Sustained Benefit of BCL2i 

This slide clearly showed venetoclax was better in the relapsed setting as compared to BR.

Next slide.

[00:46:12]

Sequencing Therapy for Patients With CLL/SLL

This is how we derived our sequencing for patients with CLL. What do you do one after the other.

Next slide.

[00:46:19]

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

What happens now that patients have had both venetoclax and failed a BTK inhibitor? What do you do for those patients?

Next slide.

[00:46:30]

NCCN Guidelines Version 1.2025

This is the NCCN guideline which basically talks about this fact after both double failures. These are patients who failed BTK inhibitors and BCL2 inhibitors. In those patients, pirtobrutinib is an option. But while you are doing that, if it is a true refractory. I am not talking about intolerant patients. Intolerant patients have a better biology. They actually do better in terms of their outcome.

But in terms of the truly resistant patient who failed BTK inhibitor and BCL2 inhibitor, those patients should be considered for CAR T-cell therapy. This is the most important tool that we have right now. Not perfect, but definitely a step in the right direction. Pirtobrutinib can be given to control the disease, possibly for a few months, possibly for up to 2 years. It is an excellent option, but it does not last very long in those patients with an average of around a year and a half to 2 years in the true refractory patients.

It is a great option to control the disease. But what is the next step? That is the issue.

[00:47:40]

Outcomes With Covalent BTK Inhibitors

Especially in a younger person, that is the issue because this is the problem. Most of the problems that happen in patients who progress on BTK inhibitors is because of their CLL progression and other events, infections and so on. Those are the reasons why people stop and then people stop because of progression.

Now, it is not an exact science. We only know maybe around 80% to 60% of patients why they get progression. The most common mutations are BTK mutations, cysteine 481C and PLC gamma 2 mutations. Then there is a bunch that we do not know about. Both of those mutations make the cells resistant to BTK binding. This is what happens. This is the cysteine 481 mutation.

The cysteine 481 is now not available to BTK inhibitors binding. That is how the cells get resistant. That is where pirtobrutinib comes in and it binds at a different site and turns the switch off.

Next slide.

[00:48:35]

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

This is the tool. Now the problem also is we are getting more and more newer mutations identified. I was talking to you earlier about it.

Next slide.

[00:48:47]

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

These are the mutations that are called kinase dead mutations like the L528, in which nothing works. This is something that you have to be careful. This is where pirtobrutinib is important because pirtobrutinib works in BTK cysteine 481-resistant patients. It is a very promising drug. Prior to this, we had no other option. Pirtobrutinib was a major advance. These are the reasons why it is important to have this tool, which gives us around 18 months of disease control, progression-free survival.

These are the patients who ordinarily would have been dead in 3 to 6 months. This is why the importance of pirtobrutinib is significant. This is why it is such a major advance in the field. But you also have to plan at the same time about what to do after this patient. Now, in terms of outcomes, obviously if the patient does not have true double refractory disease, those patients do the best. Now, if you have just one BTK or BCL2 patients, those are obviously the ones that will do better as compared to true double refractory.

Next slide.

[00:49:56]

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

Unless it gets approved in the front-line setting and so on, it will be hard to justify its use in the front-line setting. But we do have more data in the relapse setting, pirtobrutinib was compared to idelalisib plus rituximab and bendamustine plus rituximab.

Next slide.

[00:50:12]

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

We do not really use idelalisib plus rituximab. Basically, pirtobrutinib was significantly better in terms of progression-free survival as compared to idelalisib with rituximab or BR. It was an important data set that came out that established the effectiveness of time to next treatment with pirtobrutinib was significantly longer than idelalisib or BR.

Next slide.

[00:50:39]

TRANSCEND-CLL 004 Phase I/II Trial of Lisocabtagene Maraleucel in R/R CLL/SLL

This is what I mentioned in passing was the CAR T-cell therapy for CLL. This is again an important study, basically for patients who failed everything. It was promising, but unfortunately, in the first iteration, we only saw around 20% responses in terms of CR rates.

The other problem was that if you do get into a CR, you had the best outcome obviously, that is also important. Then also, if you had undetectable MRD, those patients also had a better outcome. But the point of this whole discussion is that we are only looking at 20%, good outcomes with CAR T-cell therapy. Is there anything we can do to improve the effectiveness of CAR T-cell therapy? That is what was presented at this ASH meeting.

Next slide.

[00:51:33]

TRANSCEND CLL 004 (Combination Cohort): Study Design

Yeah. This is the study design. We look at the Flu/Cy chemotherapy followed by CAR T-cell therapy. Then in the updated results, the ibrutinib was combined prior to the CAR T-cell collection, which improves outcomes for CAR T-cell therapy.

Next slide.

[00:51:51]

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

This result basically led to a much, much higher response rates when you combine ibrutinib with CAR T-cell therapy. Now we went from like a 20%-ish to almost 80%-plus response rate with a 45% CR. We doubled our outcomes of CAR T-cell therapy just by combining ibrutinib for a few weeks prior to CAR T-cell collection, harvesting and then post CAR T.

Now, the problem is ibrutinib is not the most active drug in terms of the activity in this setting, because these patients have invariably failed both options. But the point was not to use ibrutinib necessarily as therapy against CLL. The point was to improve the T-cell health. This is what is reflected. You are looking into very promising undetectable MRD rates in the blood. You are looking at very high rates of CRs and CR incomplete.

Very promising. Early results from the use of ibrutinib in combination with CAR T-cell therapy for patients with CLL.

Next slide.

[00:52:57]

TRANSCEND CLL 004 (Combination Cohort): Safety

Yeah, in terms of side effects, again, the side effects are luckily not that bad. The vast majority of patients had a mild grade 1, grade 2 CRS, which basically means fevers requiring tocilizumab, which some of the patients needed and luckily not a whole lot. That is actually better than what we would expect for a large-cell patients in terms of neurological effects. Most of them were grade 1 and grade 2 neurological effects. Then obviously the vast majority of patients died because of progressive disease.

Next slide.

[00:53:34]

Recent FDA Approval of Lisocabtagene Maraleucel for CLL/SLL

As a result, CAR T-cell therapy was approved in March of last year for patients who have received at least 2 prior lines, including a BTK inhibitor and a BCL2 inhibitor. It is an important tool for our patients.

[00:53:49]

Expert’s Algorithm for Relapsed/Refractory CLL/SLL

This is the next slide. As a result of this, if you had a prior covalent BTK inhibitor, you consider alternate BTK inhibitor or venetoclax, if discontinued because of intolerance. All right. But if discontinuation is because of resistance, you switch to pirtobrutinib. This is the difference. If you had a prior BCL2 inhibitor, you can use the BTK inhibitor, or you can use a BCL2 inhibitor after BCL2 after 2 years of remission.

If you had prior chemo immunotherapy, you can use whatever. Once you fail all of this, only then you should go to CAR T-cell therapy. It is not indicated earlier. Then similarly, pirtobrutinib should not be used in the front-line setting. It should be only reserved for patients who are intolerant to covalent BTK inhibitors or resistant. Then ideally 2 plus lines of therapy.

Next slide.

[00:54:42]

Let's Revisit a Patient Case

Let us visit our last case again.

[00:54:45]

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

This is an 86-year-old person with relapsed CLL, initially diagnosed in 2013. Had chemotherapy followed by a venetoclax-rituximab for 2 years. Two years of venetoclax-rituximab only gave you a one year remission. This is not the person that you want to repeat venetoclax. Again, eventually they were started on a BTK inhibitor, but it is an 86-year-old. So CAR T, no CAR T.

Not a CAR T candidate generally, possibly, but not usually. But acalabrutinib gave him 5 good years of remission. Now they are becoming resistant to acalabrutinib. In this person who had a very short remission to venetoclax bendamustine-rituximab, unmutated disease, responding nicely to acalabrutinib. What is your next option?

Next slide.

[00:55:31]

Posttest 3

1. Duvelisib;
2. Pirtobrutinib;
3. Venetoclax;
4. Zanubrutinib.

Please vote.

[00:55:50]

Posttest 3: Results

Excellent. The best answer is pirtobrutinib. Venetoclax will not be of any use in this setting. It is not wrong to use it, but you may not get a lot. Zanubrutinib is unlikely to work in this setting. All right. Next slide. This is the correct answer.

[00:56:08]

Role of MRD in the Management of CLL/SLL

What about the role of MRD? People keep talking about MRD. What is MRD? Just the last couple of slides. Let us look at this.

[00:56:11]

Predicted Correlation of Undetectable MRD and Relapse

This is how we think about it. When do you get cured? Ten to the minus 7. Possibly 10 to the minus 9. This is kind of the whole concept. The deeper the remission, the longer it lasts. Unfortunately, our detection method can only go up to 10 to the minus 6 or reliably. But we cannot detect all of this disease below that. But I think we all are thinking that maybe 10 to the minus 9 might be the cure rate. That is kind of the whole idea.

This is the thing that when you do regular flow cytometry that you do in your hospital, you only get to 10 to the minus 1, 1.5 in that ballpark. If you use the sensitive flow MRD assay, which is only available in a few places in the country, then you get into the 10 to the minus 3, minus 4. But if you really want to get to the minus 6, that is where you get into the NGS or clonoSEQ assay, which is available, in our country.

Next slide.

[00:57:07]

CLL14: PFS and OS According to MRD Status in Venetoclax + Obinutuzumab Arm

The deeper the remission, the better it is. This is what we see with venetoclax. If you get into a less deep remission, people relapse very quickly. If you get into a deep remission, then you get into a pretty nice outcome. But the problem is it is we are not seeing the flat line, why do not we see the flat line? We did see the flat line with FCR chemotherapy, which were MRD negative patients.

We never get into that kind of depth. We do not get into 10 to the minus 7 or eighths, possibly with venetoclax. That is why we are not seeing the curve flattening out. That is what we see. It is still the first 8 years, so maybe by 10, 12 years, we might see a small group of patients who might have a flat line. But we are not seeing that right now.

The other important point is that if you get into a deeper remission, you actually live longer. This is why it is important to do this and MRD testing and have the patient get into an MRD. If that is your approach, it helps you to predict outcomes. But will it change our management? Probably not. Because if you are using time-limited therapy, because you want to stop, you have more confidence in stopping if you are MRD negative.

Next slide.

[00:58:19]

Optimal Strategies to Partner With Patients in Their Care

This is what I have been talking about. It is not a one-way street. It is a discussion with the patient. You look at the patient side effects. That is when you decide how to treat these patients.