Thank you so much for coming to our symposium. It is about a topic that is near and dear to my heart, which is CLL. It has been an interest of mine for the past 16 years. We are going to start off with a case.

Case 1: a 63-year old man with newly diagnose CLL

This is a 63-year-old man with newly diagnosed CLL. As is important with frontline and relapsed CLL, it is important to know what his risk status is. Upon biomarker testing, we see that he does have both a wild type for deletion(17p) and TP53. Those are two separate tests. You have to look for FISH and also a mutation test for the TP53 mutation. Next, he is mutated for IGHV. Overall we have a favorable risk patient. He has a past medical history notable for hypertension and diabetes, and he does have indications for therapy because he is symptomatic and he is cytopenic. He expresses though that he has a preference to be on a fixed duration regimen. He would prefer a pill-only regimen if possible, because he is busy with his career as a truck driver.

Pretest 4

With that being said, we have our next question. In your current practice, which of the following therapeutic regimens would you recommend for this patient?

1. Acalabrutinib;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax with obinutuzumab;
5. Venetoclax with acalabrutinib.

Great answers from our audience. Honestly, I do not think there is a single perfect answer, but the most common answer was venetoclax and acalabrutinib. I actually think that would fit this patient's goals and would be appropriate.

Poll 3

Let's tweak the case a bit. Instead of having mutated IGHV, what if he had unmutated IGHV? Maybe he does not require an all-oral regimen. In your current practice, which of the following therapeutic regimens would you recommend for the patient?

1. Acalabrutinib;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax-obinutuzumab;
5. Venetoclax-acalabrutinib.

The most common answer here is venetoclax-obinutuzumab, but some other votes for acalabrutinib, zanubrutinib, and pirtobrutinib. We will explore all the frontline options. I think the data continues to evolve. I think that is always a great option for patients to have multiple appropriate options.

Case 2: a 76-year-old woman with previously untreated CLL

Now we are going to shift to a different case. This is a 76-year-old woman with previously untreated CLL. She was diagnosed with CLL a couple of years ago. Initially, she was followed with watchful waiting, but now she has developed progressive disease and is requiring treatment. Upon biomarker testing, she has unmutated IGHV and also a deletion(17p) on FISH testing. She is a much higher risk patient. Her comorbidities are significant for controlled hypertension and CKD with a GFR of 40, her ECOG performance status is a one. Importantly, she also lives an hour away from the treatment center and she is the primary caregiver for her 80-year-old husband. With this very different case, let's see what you guys think.

Pretest 5

In your current practice, which of the following therapeutic regimens would you recommend for her?

1. Acalabrutinib;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax with obinutuzumab;
5. Venetoclax with acalabrutinib.
6. Venetoclax with acalabrutinib plus obinutuzumab.

Interesting. The majority of people are still going for time limited. Then 20% for zanubrutinib. That is different, and I do not think there is a right or wrong answer.

Panel discussion

As far as the panelists here, it looks like we, for the first case, preferred venetoclax-acalabrutinib unanimously. Nicole, why did you like venetoclax with acalabrutinib for the first case?

Dr. Lamanna: One is that the patient did express an interest to having an oral regimen, although that still leaves chronic continuous BTK as an oral regimen. However, he is young. He has favorable risk features, so I really, for a younger patient, would like a time limited approach, get them off of therapy. He wanted an oral regimen, so this would certainly give him great efficacy, time off therapy, reduced resistance because at some point he is likely going to need treatment again. That is why I picked acalabrutinib-venetoclax.

Dr. Coombs: Great. For the second case, it does look like we also have consensus regarding picking either zanubrutinib or acalabrutinib. It looks like maybe some are zanubrutinib fans, some are acalabrutinib fans. I think we split a lot of hairs in CLL because we have so many good options. Nitin, why did you pick a BTK inhibitor? You do not have to say why you think acalabrutinib or zanubrutinib is better, but what about that case made you prefer that?

Dr. Nitin Jain (University of Texas, MD Anderson): Right. The way the history was described and that lives a bit far away, she has unmutated IGHV, 17p deletion. Those are kind of the high risk genomics. She also has a CKD. GFR is 40, which is again not an absolute contraindication to use venetoclax-based regimen, but I think overall this is a kind of patient who will do with I think a single agent BTK inhibitor. Now I would say that 17p, I think the best frontline data, at least the prospective frontline data, is with zanubrutinib. You can certainly make a case for zanubrutinib. However, I think as all of us maybe said, if someone wants to prescribe acalabrutinib, I think that is not incorrect. Maybe they are based on insurance or whatever or cost or something. I think yes, zanubrutinib or acalabrutinib.

Dr. Coombs: Yes, I totally agree. There are some fights I will have with insurance, but between acalabrutinib and zanubrutinib, I just think they are both extremely efficacious. I do not think a patient is going to be served poorly by either one. I do not fight that fight because I will fight the fight if it is worth it, but I think they are both great drugs. I totally agree with you on that.

Indications for treatment

Now I am going to talk about frontline therapy and there is a lot to go through. I was telling my colleagues I am afraid of sounding like a broken record, but I do say something often when I talk about CLL, which is I really firmly believe there is not a one-size-fits-all approach for CLL. I think you could just offer a same therapy to every single patient, but I do not think that is the right thing because in 2026, we know the head-to-head data between our best treatment options. I do think patients have choices and I think it is behooves us as their treating clinician and people that care about them, would treat them as though they are our family, that we offer them the appropriate choices. With that being said, I always do consider whether a patient is eligible for a clinical trial. If they are not, of course, there are plenty of effective frontline regimens.

Because there is not a one-size-fits-all approach, I think it is important to get to know your patients, what is valuable to them, so the patient related factors. In addition to what their comorbidities, what are the con meds? Is there any absolute contraindication for any certain therapy? What are their lifestyle issues? I think the second case was important because I do not think it would have been wrong to offer a time limited, but I think that would have been hard given some of the social factors that we were presented with.

Also, it is important to take into account what are the disease related symptoms. Are they presenting, for example, with bulky adenopathy? Do they have any sort of end organ issues? That is not common with the CLL to have CLL related organ function issues, although I have certainly seen it. What are their counts? Who is this patient and what makes him or her unique?

CLL: dynamic monitoring versus treatment

I think one of the really important things about CLL is still in 2026 there is no indication to treat someone who's asymptomatic. Why is that? I think it is a lot of reasons. I think the most important reason is some people just do not get sick from the CLL. About one out of three patients with CLL literally just dies from something else. By treating everyone, we could certainly have the potential to hurt some patients by overtreatment and some of the side effects that can come with our treatments. There are, though, the majority of patients that do need treatment, two out of three. That could be right away, near diagnosis, or it could be after a period of watch and wait.

Genomic/molecular prognostic factors

There is not a single CLL that is identical, so I think the biologic features remain important. I do always test for the prognostic markers among my patients that are needing therapy, especially. I test for people on watch and wait, because it also helps me kind of understand, is this someone I want to watch closely or someone I could see a little less often? Definitely, it is important to send before you treat because there are differential responses, especially to our time limited regimens based on whether patients have high risk features such as 17p, unmutated IGHV versus totally favorable risk markers who honestly respond very well to everything.

Key Biomarker Testing to inform frontline CLL/SLL treatment

What are the key biomarker tests to inform frontline CLL treatment? Prior to treatment initiation, I would strongly recommend sending FISH testing, which must include 17p, and all the typical FISH tests do. Additionally, do not forget, you also have to send a separate test for TP53 mutation. Until I am blue in the face, I think this is something that still gets misunderstood. I do not think the FISH reports do anybody any favors. They will actually say TP53 normal. All that means is that TP53 is not deleted. It doesn't mean it is not mutated, and a mutated TP53 carries a similar adverse prognostic risk to a TP53 deletion, which is the 17p. That is a separate test that is important to be sent to understand the patient's prognosis and response to therapy

Additionally is IGHV mutation status which is another sequencing test. Where I work it is a send-out test though some places have it in-house. I also send beta2-microglobulin and CpG-stimulated karyotype. Complex karyotype is an independent predictor for adverse features. I think it is important. Is it as critical as the others, I would say not, but I do send it. B2M is important for the CLL IPI risk score. It is perhaps an indirect measure of disease bulk.

Approved targeted therapies for CLL

What are our options? They call it an embarrassment of riches in CLL because we have literally so many options that work so well. That is because of an improved biologic understanding of the CLL cell machinery, where we can target a lot of different aspects that cause the CLL cell to grow, to where either we inhibit proliferation or we outright just kill the cell via inhibition of the apoptotic pathway. Some of the most important targets are BTK, which is downstream of the B cell receptor, BCL2, which is part of the apoptotic pathway or anti-CD20 monoclonal antibodies.

Some that are less commonplace such as PI3 kinase, the target. Those inhibitors do work, but we do not use them as much because of unfavorable toxicity. We are really not using DNA damage chemotherapy agents really ever, unless we are totally desperate and have no other option, which I will tell you, almost never happens in my own clinic. I do not think I have used chemo in many years.

Novel agents are superior to CIT in first line

With that being said, let's go into just a smattering of trials to hopefully convince you why chemo is not good anymore. We have so many trials in the randomized setting, both in frail older patients, but also young fit patients that demonstrate the superiority of novel agent based approaches over chemoimmunotherapy. There really, in my view, is no role for chemotherapy in the US. Not to say there is not a global role, because of course, other countries outside the US do not always have access to these great drugs that we have in the US. However in the US, I do not use chemoimmunotherapy anymore.

Preferred regimens for treatment of CLL/SLL

With that being said, this is pulled from the NCCN guidelines, the preferred regimens for frontline treatment of CLL/SLL. It is still divvied up between patients who do have 17p or TP53 and those who do not. On the top is patients who do not have these aberrations. It is actually pretty simple. We just have kind of four big categories of treatments: acalabrutinib, zanubrutinib, or time limited regimen, acalabrutinib-venetoclax or venetoclax with obinutuzumab.

Now, in patients with deletion(17p), it is a little bit more complicated. It is totally appropriate to use continuous BTKI, acalabrutinib-zanubrutinib. Acalabrutinib can always be used with or without obinutuzumab. However, among patients maybe with 17p that do want time limited, there is actually now three listed regimens that are options. None are category one because the data in 17p are actually very sparse in the frontline setting due to the rarity of this abnormality in patients who are treatment naïve. However, you can do venetoclax-obinutuzumab, and there is also now listed acalabrutinib-venetoclax-obinutuzumab or zanubrutinib-venetoclax. Those two regimens are actually MRD guided. I do not personally use those off clinical trial, but there are data to support those, which we probably will not have time to get into, but could come up during our question session.

Acalabrutinib

Getting into acalabrutinib, excellent drug, very well tolerated. I have been using it for a long time. It is a second generation BTK inhibitor. It is quite a bit more selective for BTK as compared to ibrutinib. That then translates to fewer AEs, which has now been proven in a head-to-head study ELEVATE RR, where it showed that acalabrutinib was non-inferior with respect to efficacy, but definitely had better tolerability as proved by the lower rates of a-fib, a-flutter, but also much lower rates of hypertension, but also just less arthralgia, myalgia and less any grade bleeding, although the severe bleeding is probably similar. The drug can cause headaches, but otherwise I find it to be tolerated by almost all the patients I prescribe it, and it has been around since 2019 as an FDA approved therapy. It is a BID drug.

ELEVATE TN: Frontline acalabrutinib (continuous)+- obinutuzumab vs CIT

It can be given by itself or with obinutuzumab. The data that approved this agent in the frontline setting is the ELEVATE TN trial, where acalabrutinib is given either by itself as a continuous agent or with six cycles of obinutuzumab, which is started on cycle two, which does tend to lessen the infusion reactions as opposed to giving obinutuzumab before anything else. The standard of care regimen on this trial was obinutuzumab with chlorambucil. As you can tell by the PFS curve, acalabrutinib dramatically outperformed the control arm.

However intriguingly, with now six years of follow-up, there does appear to be an improved numeric PFS with the addition of obinutuzumab to acalabrutinib. However, I do not know about my colleagues, but I do not tend to use acalabrutinib with obinutuzumab, mainly because when you are going down the BTK treatment route, patients are really desiring that convenience aspect. Even though I do not think it is unreasonable to add obinutuzumab, I do it hardly ever, because the patients that I prescribe a BTK inhibitor do not want anything IV. You can see even acalabrutinib by itself leads to excellent PFS with six years of follow-up. This will likely continue as the study continues follow-up.

Zanubrutinib

The other option in the second generation BTK realm is zanubrutinib, another excellent drug that I use a lot of. Once again, it is more selective for BTK and a little different compared to acalabrutinib. The head-to-head study with zanubrutinib versus ibrutinib in the relapsed setting showed it was actually not only better tolerated with lower rates of a-fib, however, also improved efficacy. Acalabrutinib non-inferior, zanubrutinib had improved PFS and ORR. This agent was approved not only for frontline but also relapse use in January 2023. It has a unique aspect based on the pharmacokinetic data that support either twice-a-day or once-a-day dosing. For my younger patients who aren’t on a bunch of meds, it is actually very hard when you are kind of a med naive person, present company included, to take a med twice a day, so I like that daily aspect for patients who aren't already in that habit to do a drug twice a day.]

SEQUOIA: Frontline zanubrutinib (continuous) vs BR

SEQUOIA is the frontline trial that led to approval in treatment-naive patients. Big study, but the largest arm of the study, randomized patients to either get continuous zanubrutinib or standard of care bendamustine rituximab, and this arm excluded patients with 17p given it would have been unethical to randomize them to BR. And really just an impressive PFS with the continuous use of zanubrutinib, which, as you can very obviously tell, dramatically outperformed bendamustine and rituximab.

cBTKi comparisons

How do we compare these BTK inhibitors? I will tell you, I really hate these matched adjusted indirect comparisons because they are so artificial. I just think the best way to do good science and be a good clinician is to look at each randomized trial in isolation. Obviously, we can make some inferences, but the one thing I would not do is indirectly interpret that because acalabrutinib is equal to ibrutinib and zanubrutinib is better than ibrutinib, that zanubrutinib is better than acalabrutinib. I just do not think we can conclude that. What I conclude personally is zanubrutinib is an excellent drug, I think acalabrutinib is an excellent drug, and I think they are actually both very appropriate for patients with CLL, and I use both of them honestly. They have a little bit different in the way of side effect profiles. Acalabrutinib might have a little more headache if we are looking indirectly. It may also have a little less hypertension if we are looking indirectly, but in the end I think patients are served very well by either of these options. Of course, if a payer dictates which one, I do not think they are going to be served poorly most of the time. Obviously, there are exceptions though.

Fixed-Duration/Time-Limited Therapy

Now let's get into the fixed duration, time limited options. There definitely have been some changes here.

Venetoclax

The backbone of most fixed duration options is venetoclax. This has some very unique features. It is a BCL2 inhibitor. It is not anti-proliferative the way a BTK inhibitor is. It actually kills the cells, so it is cytotoxic to the cells that are so dependent on BCL2, which is CLL cells. Very highly effective. We do tend to see deeper remissions in patients that get venetoclax-based regimens. More CRs are achieved, more MRD negativity. In the frontline setting, it is paired with obinutuzumab. Of course, in the relapse setting, the traditional regimen is paired with rituximab, although we do generally favor using obinutuzumab in the relapsed setting based on superior efficacy extrapolated from a frontline trial of venetoclax-obinutuzumab versus venetoclax-r, among other regimens.

With venetoclax, we do tend to see differential activity among patients with high risk markers compared to those who do not have high risk markers. That could be IGHV unmutated, it could be TP53 aberrant. Venetoclax does tend to be well tolerated by most patients, although there are some side effects that can be seen. The biggest ones are cytopenias, specifically neutropenia and thrombocytopenia, and then some GI toxicity.

TLS is a big worry about venetoclax, but I will tell you, when you pair it with obinutuzumab, you do not actually see TLS with venetoclax, you see it with obinutuzumab. It is important to do TLS monitoring, including during the obinutuzumab lead in. I do still do the monitoring with venetoclax because I do think it is still possible that it could happen, although it is not seen in the trials. It is generally with the obinutuzumab, but that is still part of the label.

CLL-14: First line Obinutuzumab + venetoclax (time limited) vs chlorambucil

The CLL14 trial led to the approval of frontline venetoclax in 2019. It was obinutuzumab-venetoclax versus chlorambucil-venetoclax. Obinutuzumab- venetoclax dramatically outperformed chlorambucil-venetoclax. The PFS now with mature follow-up for obinutuzumab-venetoclax, which is just a one-year regimen, is 76 months compared to chlorambucil-venetoclax, which is about three years. It is a regimen I have used a lot in the past seven year.

AMPLIFY: Fixed-duration acalabrutinib + venetoclax +- Obinutuzumab vs CIT for previously untreated CLL

But now we have one other fixed duration option, which is based on the AMPLIFY trial. This was maybe a slightly complicated study in that it had three arms, but the primary endpoint was to compare acalabrutinib-venetoclax versus the chemoimmunotherapy arm of FCR-BR. There was a third arm though, that actually was a triplet regimen. Acalabrutinib-venetoclax plus obinutuzumab. These are both time limited regimens with the acalabrutinib-venetoclax, where there is two cycles acalabrutinib lead-in, followed by 12 cycles of the doublet. For the triplet arm, it is just six cycles of obinutuzumab. The primary endpoint was AVA versus CIT, but one of the key secondary endpoints was then to compare AVO with CIT. Importantly, the study did exclude 17p and TP53 mutations.

AMPLIFY: PFS per IRC

The PFS looks great for AVO, which numerically has the highest percent of patients who are progression free and alive at that three-year landmark analysis, at 83%. AV also looks excellent 76%, and then chemo obviously is the loser here at 66%. Based on the stats, both AV and AVO were superior to chemoimmunotherapy. The study is not powered to compare AVO versus AV though, importantly.

AMPLIFY: OS

I think the OS though tells us a bigger story, and I think that is why it is important not to only look at PFS in isolation. You could have a drug that has great PFS, but it is so toxic that maybe it is not really benefiting some of our CLL patients. When you look at OS from the AMPLIFY trial, I think it is really interesting. What that showed is that AV was superior to FCR-BR, AVO was not. Those curves largely overlap. An important thing to realize about the AMPLIFY trial is that it accrued heavily during the Covid pandemic. The accrual period was 2019 to 2021, so during the worst part of Covid. Many patients didn't have any access to vaccines so there was a huge imbalance in the rate of Covid-related deaths, where numerically, the most patients died of Covid from AVO, second FCR-BR. That was 25, 21 and then not that many patients died from AV at ten patients. If you censor those deaths, and I always have somewhat mixed feelings about these censored analyses, maybe AVO doesn't look so bad as far as overall survival, but I do not think there is any way to say that if you didn't die from Covid, that you are somehow protected from any infection, right? I think AVO probably is just a quite immunosuppressive regimen.

AMPLIFY: Rate of uMRD (<10-4) in peripheral blood by flow cytometry

This is another very interesting by-product of this study, which looks at the rates of uMRD. The uMRD is not an FDA accepted endpoint in CLL. I think the study is a good reason why not, because uMRD is somewhat regimen dependent how well it is going to predict then for the more important future outcomes such as PFS, OS. The message here is AV was very good for PFS, looked great for OS, but yet it had low rates of uMRD, around 30%. AVO had very high rates of uMRD, look great for PFS, but not great for OS, and chemo actually looked not so bad for uMRD, but yet the PFS didn't look good. I think uMRD is important, but it doesn't tell the whole story. I would not use that as your only measurement of success with especially these oral doublet regimens.

CLL17 : continuous ibrutinib vs fixed-duration venetoclax + obin or venetoclax + ibrutinib for untreated CLL

I think the last big study I am going to look at is CLL17. I call this a practice affirming study. I do not necessarily think it was practice changing, but I think it was an important study because it was the only trial that we have had results on that randomizes between a continuous BTK inhibitor and then time limited regimens with novel agents.

It was ibrutinib versus venetoclax-obinutuzumab versus venetoclax plus ibrutinib. That regimen is approved in Europe and a lot of other places in the world, although it is not approved in the US. The idea is they wanted to see if the time limited regimens were non-inferior to continuous regimens, which is an important question because ultimately we have equipoise between offering our patients these types of regimens. Obviously, we are not using a lot of ibrutinib, but with ibrutinib being somewhat similar efficacy-wise to our current drugs, I obviously think it is still a reasonable study and obviously the patients got accrued a while ago because we had to follow them to see what happened.

CLL17: Progression-free survival

This was a plenary session at ASH, and it was published in the New England Journal. The results are impressive in the sense that the PFS curves just completely overlap. What we see here is that with albeit short follow-up of around three years, there is no difference in PFS whether you pick a continuous agent ibrutinib or one of your time limited regimens, venetoclax-obinutuzumab or venetoclax-ibrutinib.

CLL17: Response

ORRs are similar, but there are differences among patients who have high risk markers versus those who do not.

CLL14: PFS by TP53 and IGHV mutation status

I am going to show you first the CLL14 trials. This is now looking at venetoclax-obinutuzumab. Among patients with TP53 mutation, they do have shorter PFS among patients who do not. Similarly, shorter PFS for patients with unmutated IGHV versus those who do not. I do not think that is a reason to totally take this regimen off the table, but I do think it is a reason to more appropriately and extensively counsel your patients who have high risk markers, especially TP53, if you are considering one of these time limited regimens, such as venetoclax-obinutuzumab.

ELEVATE-TN: PFS in patients by IGHV or del(17p)/TP53 mutation status

These are the data for ELEVATE-TN, where unfortunately, you would hope that the addition of obinutuzumab would help with the TP53 mutation patients which were included in this study. It didn't seem to make any difference at all. I think obinutuzumab addition is not unreasonable, but I especially would not recommend it in someone with 17p because those PFS curves totally overlap.

SEQUOIA 5-yr follow up: PFS with zanubrutinib vs BR

These are the SEQUOIA results, kind of split whether patients do or do not have mutated IGHV. When you are using continuous zanubrutinib, the unmutated patients do almost as well as the mutated patients. The continuous BTK inhibitor use really almost takes away that negative impact of the unmutated IGHV. You see the BR patients in the blue. There is a huge difference among patients who got BR that were mutated. They still do okay. Still not as well as zanubrutinib versus the unmutated BR patients. They do terrible.

AMPLIFY: PFS subgroup analyses

AMPLIFY being the last and most recent study, I think it is important for the case we discussed. I think you could do AV in someone who's unmutated, but the PFS doesn't look great so far from what we know of AMPLIFY. The median PFS is currently estimated at 51 months for AV whereas it is not reached for mutated. This is an early follow up though, so I do think this PFS is subject to change. A lot of times when you have early follow-up, these late time points are very unstable. Right now I think AV is most exciting for my mutated patients. I think we are going to do well with anything I give them. Unmutated, I would like to see longer follow-up.

CLL17: PFS by subgroup

These are the CLL17 groups. For time, I am going to skip it, but long story short is the 17p didn't do quite as well with time limited, although we need longer time to follow them as well.

What do we do with all these great options?

We have a lot of great options. I think it is very important to individualize the conversations, taking into account the patient's unique CLL disease biology, but also the characteristics that make them unique, such as their comorbidities, preferences, access to care, etc.

Let’s Return to Our Cases

With that, I think I get to hand it back off to the cases. Maybe skip those for time. Let's see if you changed your answers and then I will hand off.

Posttest 4

To remind you of the prior case, this is a 63-year-old truck driver, favorable risk markers including mutated IGHV. He says, hey doc, I want something fixed duration, but I just want pills, if that is possible. What would you give him?

1. Acalabrutinib;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax with obinutuzumab;
5. Venetoclax with acalabrutinib.

I like the post answer for venetoclax-acalabrutinib. I like that for him. It is not the only right answer, but in line with his preferences, that is a very appropriate option that fills his goals of time limited oral. It is also reasonable.

Revisiting case 2: a 76-year-old woman with previously untreated CLL

Next question is now our older woman 76, high risk disease, unmutated IGHV, 17p, some comorbidities, hypertension and CKD. And she also has some access-to-care issues, lives an hour away and she cares for her 80-year-old husband. A lot on her plate.

Posttest 5

What would you recommend for her?

1. Acalabrutinib;
2. Zanubrutinib;
3. Pirtobrutinib;
4. Venetoclax with obinutuzumab;
5. Venetoclax with acalabrutinib.
6. Venetoclax with acalabrutinib plus obinutuzumab.

I think acalabrutinib and zanubrutinib would by far be the easiest thing for her. Would it be wrong to give her time limited? No. Would that be pretty difficult socially? I think it might be, but you could always talk to her about that. All right. I am going to hand it back to Nicole. Thank you.

Panel Discussion: Perspectives in Frontline Treatment for CLL/SLL

Dr. Lamanna: Excellent talk. Let's try to catch up a little bit.

Poll 4

Which of the following questions would you like the experts to discuss further regarding frontline treatment of CLL? So here's where you get to choose and then we will talk briefly about this.

1. What is the role of MRD in prognosis and treatment?
2. When might you consider adding obinutuzumab to a BTK inhibitor containing regimen?
3. Would you consider chemoimmunotherapy for any previously untreated patients?
4. What are key AEs you watch for with contemporary regimens, especially novel combination regimens?

So if you guys can choose, then we will talk about it.

A little smattering. Very quickly, most people ask, when might you consider adding obinutuzumab to a BTK inhibitor containing regimen? Callie, you mentioned you rarely do that, but under what circumstance might you do that?

Dr. Coombs: I definitely have done it. I would say the obvious situation is someone who presents with an autoimmune cytopenia that has failed other therapies, and you want to get control of the disease, but you also need to treat the underlying CLL. I have added obinutuzumab in that setting. The other time I have used it is in a patient with just bulky disease, especially cytopenias that just needs a little bit more rapid response. BTK inhibitors are great. They just take a while. I have also sometimes used obinutuzumab to kind of hasten the response.

Dr. Lamanna: I just want to go back very quickly just to address, Nitin, the role of MRD.

Dr. Jain: I think the MRD role, I would say, in the context of time limited approaches, I think there is a role for MRD. To clarify, I think if your patient is on continuous BTK inhibitor therapy long term, probably they will still be MRD positive when you check MRD down the line. Maybe not a specific role, I would say to check MRD for prognosis or treatment. I think for time limited approaches, whether it is venetoclax-g, or acalabrutinib-venetoclax these days, I think it is very clear from multiple studies that the MRD at the end of treatment, most of the studies we have done in the peripheral blood by flow cytometry, or you can do next generation sequencing. I think that will predict for long-term PFS, at least most of the studies have said that. I think at least in that sense you can use the MRD for prognosis. I think the big question which I think gets asked is that okay, if a patient is MRD-positive, what are you going to do? Is it actionable at this time? And I think some of the data suggests that there are some trials we are waiting, I think phase III studies, MAJIC study and others. I think we will have more information about it. However at least for prognosis standpoint, I think it is very clear. At least in my practice, we do it at the end of treatment, but I would say maybe that is not the standard across the board.

Dr. Lamanna: Okay. I will skip the AEs for now, but we can hopefully catch up and talk about that a little later.

Audience Q&A

Feel free again to add in some audience questions. If there are, please type them in. We are happy to answer those. Let's see if we can move on.

Patient Insights: The Critical Role of SDM in CLL Selection

Brian, I am going to have you talk about shared decision making in CLL. This is important for all of us.

Dr. Brian Koffman (Chief Medical Office, CLL Society): Thanks to everyone for this opportunity. Thanks to Decera and this chance to talk. The one thing I will add to talking about who I am is also, I am a CLL patient for the last 20 years with 17p deletion, complex karyotype, IGHV unmutated, ZAP 70, 11q, complex karyotype, NOTCH1. You name it, I have got it and here I am 20 years later, because of the breakthroughs that have happened in CLL and because I have been in clinical trials. I am going to present both the patient's perspective and my work as a patient advocate and also my feelings as a retired physician.

Principles of excellence in caring for patients with CLL

To start with, I am going to talk about what the basic things are for a CLL patient. I think every patient needs an accurate and definitive diagnosis. CLL is a relatively easy diagnosis to make with flow cytometry, but as my colleagues around the table, sometimes it can get mixed up with mantle cell and other things and sometimes there can be some important differentiations that need to be there.

This second one is important, and especially the part of tailoring this to the patient. It is a complex disease, but it is usually for most patients a slow moving disease. It is an iterative learning process for patients. You have to meet the patient where they are at. You have to give them the kind of high quality information to grow, and that is what the CLL Society is there for, to help you, because I practiced medicine for almost five decades, and I know what the time pressures are like. Any kind of aids and things you can do to help you educate your patients, we are there to help with that.

As you heard, there is a lot of great treatments out there. We have an embarrassment of riches. At the CLL society, we say, if you know one CLL patient, you know one CLL patient. While there is a lot of factors that Dr. Coombs and others will talk about in terms of how you make the decision: what are the comorbidities? What are the patient's social circumstances? What are the patient's biomarkers? Another is, as was illustrated in some of these cases, what are the patient's personal preference? No way I am getting a shot. No way I am getting an IV. Or I want something that is over with in the next year or two years, or I just want a pill therapy. That is all that I want. That is very important that the patient share in those decisions.

Because of the breakthroughs in therapies, we have had the ability to keep our patients alive. A patient diagnosed with CLL, even who needs treatment now, has the same life expectancy as someone who doesn't have a CLL diagnosis. Issues of survivorship. That patient with the CLL, make sure they are not going to die of an infection because we are at high risk. We are all immunocompromised. Do you need an immunologist on your team? Do you need an infectious disease specialist? Make sure they are getting their gender and age-appropriate cancer screening. All of these things. Make sure that you are working with your team to make sure this patient, because likely the CLL isn't going to be the final factor in their life. Make sure they have access to those specialists.

It is an emotionally difficult disease. I remember there is this cognitive dissonance. “Dr. Koffman, you have cancer. It is incurable. We are not going to do anything about it.” “Are you really a doctor? You just told me I have cancer and it is incurable, and you are not going to do anything about it?” So helping patients understand the value of active surveillance. We prefer that term to watch and wait, because it sounds like the other shoe is going to drop. Active surveillance, active observation is a more proactive kind of term.

You have to understand that holistic approach to the patients. That is again, what the CLL society is there for, and I am going to talk about some of our services a little bit later.

Patient preferences: factors that influence patient treatment decisions in CLL

This is some research that we did in terms of what is important to patients. I think you are going to be surprised here by how similar what is important to patients is important to physicians in terms of this treatment. If you look really at the top three, it is all about how well the treatment works, how effective it is. If you look at the other kinds of things, the next most important thing is what are the side effects? Not so much short-term side effects, but what are those long-term side effects? Then you get into cost and then you get into limited duration and all oral, but they are way down the line. The most important thing is how well does the therapy work from the patient's point of view? This is the largest survey at the time done in CLL patients. We presented this data at ASH several years ago.

How about the patient's involvement in that shared decision making? There is a significant group of patients, in gray there who say, whatever you say, doc, I am aboard. I am just going to go with you, but that is a small number of patients. There is a number of other groups that say, I am going to put my input in here, but I am going to rely on you. But if you look at that big slice of the pie there, well more than half of the percentage of patients, patients want to be actively involved and a large number of patients are going to walk in, and this is before the era of AI, and are going to tell you, I want this therapy doc, you talk me out of it. That is the reality of what we are dealing with now.

Patient preferences: fixed duration vs continuous therapy

This is another way to slice some of this data. The pie chart is a forced decision. You can see again, the most important thing to patients, half the patients, was overall survival, which I feel as a patient should be the most important thing for the patient. Maybe not if you are 92 years old, it may be quality of life and other things, but for most patients, I think that is most important. Also, patients are very anti chemo. There is always the bias that is built into this, isn't there? These are the patients who are answering a survey. These are the patients involved, engaged, are coming to our website or doing these things. We have to understand that we are dealing with a more educated group of patients, but still that is the most important thing. The other things are much smaller: reaching MRD, limited duration, good future options.

Now another way of slicing that data is looking at these factors in terms of how important they are to you, if they are extremely important or moderately important. In patients who are thinking the long game and they are thinking I need to have options down the line, it is important that they avoid chemo. Reaching MRD is also important to patients, maybe more important to patients than it is to physicians, because it is still a research tool. What is also interesting is if we look at that chart below that, is that they are very keen that their therapy stop based on uMRD, which is still a research goal, not a clinical goal. Patients are eager to do that. They like the idea of not having any measurable disease. They are excited by that.

Panel discussion: Shared decision-making in CLL

I am going to stop there and turn to the panel and ask a couple questions. When you have this embarrassment of riches, to use your term, how do you work with your patients to involve them, to engage them in those treatment decisions? You showed that CLL17 data, they are all kind of overlapping lines. I will start with you, Callie.

Dr. Coombs: Yes. I think it is important to meet the patient where they are. I think the blessing we have, as CLL focused clinicians, is time. I am not meeting a patient like an AML patient in the hospital where we have to start therapy the next day or two. I often have a warning of months, if not a year or two, once I see that they are progressing. My move is generally to say, hey, it looks like we are moving in this direction. We will have a visit just to talk about the global options of time limited, continuous. No rush. Let's see how things go. See you in three months. Things get a little worse. Have you thought a little bit about which one you prefer? Then it is an ongoing process, but it is important to just realize there is almost never a single right answer, but choices are important.

I am not a good predictor of what my patient wants. I sometimes think I can predict because I have gotten to know them over a few years, but sometimes I get really surprised. I think young people are going to like time limited. It turns out that young person is so in love with their job, they do not want to take the time off, they want the simple thing, they want the BTK inhibitor. Or it could be the older person who says, oh, I really just hate the idea of ever getting a-fib, so I'd rather do the venetoclax-obinutuzumab, and I can take the appointment. I think we aren't mind readers, but it is important to just spend that time and we have that blessing with long-term follow-up and longitudinal practice.

Dr. Koffman: Nitin?

Nitin Jain: Yes, no, very similar thoughts. I think in the clinic generally it is a decision over multiple visits, at least two or three visits where we are starting to talk about it. These are the different options. If I think one will be maybe better for them based on either lymph node tumor burden, maybe need for kidney function or their recent cardiovascular history. I may say, okay, these are all the options. For you, this may be a preferred approach based on these factors, but all these options are available. Generally, it is not a one-time discussion where we finalize treatment that very day. Generally, it is like, okay, let's regroup maybe in a few weeks or a month or two months when they come back. Then if the disease continues to progress, we will talk more about it. As Callie said, in that time course, I think patients are able to make decisions. Completely agree that there are situations where you think they will pick one, but for whatever reason, maybe the logistics, family, whatever, they want to go with a certain option.

Dr. Koffman: Nicole, you get the last word.

Dr. Lamanna: I agree. Because the sake of time, I think the beauty is we have time to talk to our patients. I think that is really important.

CLL Society’s Test Before Treat Campaign

Dr. Koffman: So I am going to go through a couple other things here. We have a program at the CLL society for test before treat. Callie covered all of this earlier, but we have a wristband that we have handed out thousands of which simply says if you have unmutated IGHV or deletion(17p) or mutated TP53 equals no chemoimmunotherapy. We have patients walk into their doctor's office with these wristbands. We have one pager. On your way out, you can stop at our booth and pick up some of these papers and things that can help you with this and other topics. We are very big on this.

Test Before Treat: Pretreatment testing for key biomarkers is associated with improved outcomes

This is a paper that we presented at ASH last year, which shows something remarkable. In the interest of time, I am going to go through it really quickly. What it shows here is if you are a patient and you see a doctor who orders the appropriate biomarkers, you are going to do better. It is a surrogate marker for the quality of your care. Just having the proper test, whatever the results of the tests are, you are going to get better care and live longer. You are going to get more likely to get NCCN guidelines. What still bothers me as a patient and as a patient advocate, is to see that almost 15% of patients who test positive for 17p deletion are getting chemoimmunotherapy, and patients who aren't tested, 20-something percent are getting chemoimmunotherapy. And the numbers are even worse with IGHV when there is no indication. We have study after study after study that says this shouldn't be done. It is heartbreaking to see this as a patient advocate.

Summary of resources at a glance

I am going to talk a little about the organization that I am so proud of. We have more than 40 support groups. We do a lot of education. These meet virtually. This can really help when a patient meets somebody like me who has this very aggressive CLL, and they see I am 20 years out and I do not look so bad. That is more powerful than anything any hematologist or oncologist can tell them. They say, hey, maybe I am not going to die of this in the next six weeks. It is incredibly important.

We have a medicine cabinet that goes over very practical advice. What if I get a headache with this medication? What if I get diarrhea with it? Very practical advice written by physicians and nurses and stuff to help with this.

We have second opinions. We have all kinds of on-demand webinars. We have all kinds of things on infection control and Covid personalized. Patients can send in questions. We have doctors, nurses, pharmacists, lab scientists answering those questions. We talked about the test before treat. I am a CAR-T patient myself. We have all kinds of education on that. We have a primer. What is a spleen? What is a lymph node? What does a lymphocyte do? We have handouts on all of that stuff to help you do your job better.

All of this stuff is available to you. If you stop by the booth, we can help you with that. This is stuff you can download, that we can mail to you, we can help you to hand out to explain to patient what a lymphocyte is. We have all kinds of things helping with labs.

Spiritual counselling, really important. We set up this chaplaincy service. I never expected it to be used to the extent that it has been. It is an incredibly popular service and most of it isn't religious. It is more about the existential things. What am I doing with my life? What is important to me? How has this cancer affected me? And we have individual counselling that is available.

The CLL society is there to help you help your patients, make your job easier and make it go faster. We have a ton of resources. Please stop by our booth just outside the door and make sure that we can get in touch with you and help you. I will move on to my friend, Dr. Jain.

New Advances in Second-Line Treatment and Beyond

Dr. Jain: All right. In the last part of the talk, we will talk about relapsed/refractory CLL. I think if some of the slides we are not able to finish, these will be available in the handouts or it is downloadable on the website. You can refer to them later.

Case 3: Patient with CLL previously treated with ibrutinib + rituximab and venetoclax + rituximab

We will start with a case as we did with the first half of the session. You have a 64-year-old male in your practice with CLL. Patient is unmutated V gene, deletion 11q by FISH, no p53. The patient got ibrutinib plus rituximab as a frontline therapy from 2016 until 2020, disease progressed while on ibrutinib. Now you gave the patient venetoclax based on the MURANO study starting 2020. Here it looks like you have continued maybe even longer than two-year duration, but now patient is progressing and needs treatment. You do a repeat testing as would be advised. The patient is TP53 mutation negative but has now a BTK C481S mutation.

[00:56:52

Poll 5

For the poll, in your current practice, which of the following therapeutic regimens would you consider for this patient?

1. Retreat with venetoclax-obinutuzumab;
2. Switch to acalabrutinib;
3. Switch to zanubrutinib;
4. Switch to pirtobrutinib;
5. Switch to liso-cel CAR-T cell therapy.

Please vote. All right. Retreat with venetoclax-obinutuzumab, I think would have been a reasonable option. In this case it looks like the patient is continuing venetoclax, so patient is progressing on venetoclax. However I think if the patient had previously stopped venetoclax and in the previous progress I think venetoclax would be considered an appropriate choice, but certainly pirtobrutinib would be good as well. All right.

Panel discussion: How would the experts manage this patient?

All of us talk about pirtobrutinib and liso-cel. Maybe I will ask Dr. Lamanna to very briefly comment on it and then we will move on. What are your thoughts about this case? You selected pirtobrutinib followed by liso-cel?

Dr. Lamanna: Yes. Obviously the data with pirtobrutinib after this particular person was on BTK and then venetoclax continuous therapy, the concern is, the pirtobrutinib from the BRUIN data may only last so long. It will help but the patient is still young, so we have to think what is the next step? That is outside of other clinical trials and novel agents, which you'll discuss, but that is the concern is pirtobrutinib will work, but you should start getting that patient evaluated for CAR-T cell.

Dr. Jain: I think that is very, very appropriate. I think pirtobrutinib obviously is an oral pill, so you can start a patient right away. Certainly for liso-cel for many of the centers, you have to send to a center where they have the program. It takes some time. I think if you need something immediate debulking, I think pirtobrutinib is a good option. We will move on.

R/R CLL represents many different clinical scenarios

Relapsed/refractory CLL. One thing is that it represents many different scenarios, right? You have patients who are relapsing maybe after just antibody therapy. They got rituximab some time ago, or up until recently, patients have relapsing after chemoimmunotherapy, where actually most of the relapsed/refractory data up until recently was from all the major studies we talk about, RESONATE, ASCEND, MURANO, ELEVATE RR, ALPINE. All these studies were really done in chemotherapy-exposed patients who had minimal target therapies prior to getting the target therapies in these studies. Then we have patients who are failing after covalent BTK inhibitors, then we have patients after failing frontline venetoclax-based therapy. And then we have patients, so-called double exposed patients who are failing after both BTK and BCL2. Relapsed/refractory CLL is not just one bucket. There are so many different buckets. I think knowledge about the prior therapies, response to prior therapies is very important for individual patient as you are trying to make treatment decisions for their future.

An approach to R/R CLL

This is shown in this schema from a review paper where based on what the patient has received previously, you can have many different potential options for them to consider. Like in the first bucket here, patient who had no prior BTK event, so these are chemo-exposed patients. They got FCR seven years ago, or BR some years ago. For this particular patient, you can certainly go back to covalent BTK inhibitor or venetoclax-obinutuzumab or venetoclax-rituximab which will be based on the MURANO, but these days I think obinutuzumab is the favorite drug. Venetoclax-obinutuzumab would be an appropriate regimen.

Summary of key studies with BTK inhibitors and venetoclax in R/R CLL

I think as was mentioned before, some of the major key studies we have in the field which have been running for the last many, many years and now have been reported for the last many years, were really done in chemo-exposed patients. Practically all those studies, and we will go through some of them, really showed that the experimental arm was better than the control arm, which maintenance was chemotherapy or idelalisib-rituximab or bendamustine-rituximab based regimen. At the bottom, you see the MURANO study, which was a major study in the field, which compared with bendamustine-rituximab in relapsed/refractory setting and really put venetoclax-rituximab or venetoclax as a very potent regimen in relapsed/refractory CLL.

Guidance for covalent BTK inhibitors and venetoclax

Covalent BTK inhibitors, Callie talked about them, ibrutinib, acalabrutinib, zanubrutinib. They are all approved. The thing with them is that you have to still give them continuously, if you are using single agent, as is the case in the frontline setting. In relapsed/refractory setting, venetoclax approval is for venetoclax with rituximab based on the MURANO study. Venetoclax is given for two years irrespective of the MRD. You are supposed to stop treatment at the end of two years. Now I think given the frontline data we have with obinutuzumab, there is an increasing extrapolation, I should say, and this is already in the NCCN guidelines, so you are able to prescribe it, that obinutuzumab is a preferred CD20 antibody over rituximab. One thing to remember, whenever you are using a venetoclax-based therapy, whether it is venetoclax with rituximab-obinutuzumab or venetoclax with a BTK inhibitor, I think neutropenia, which can be sometimes 40% to 50% grade 3 or 4 neutropenia, ANC of less than one, can occur, diarrhea. When you are starting the treatment with venetoclax, you have to monitor for tumor lysis syndrome, which is also a very important aspect.

An approach to R/R CLL

Now if you look at patients who received covalent BTK inhibitor and now they are kind of relapsing, here I think it is important to figure out if the patient relapsed on a BTK inhibitor or the patient had a side effect to BTK inhibitor. This sometimes comes in the clinic. We had a recent patient where, when we were talking to the fellow or the resident who evaluated the patient and maintenance, maybe the treating physician stopped the ibrutinib because they had a-fib. Three months later or six months later, they progressed and they may be labeled as, patient has failed ibrutinib, but actually he has not really failed ibrutinib. They had side effect to ibrutinib and they progressed on the off-therapy phase. I really try to get that history out of the patient directly many times. Were you taking ibrutinib BTK inhibitor when your white count started to rise or the lymph nodes started to worsen?

Here in this situation, especially if you had a patient on ibrutinib, which was discontinued for toxicity, there is good data with all BTK inhibitors with acalabrutinib, zanubrutinib and also with pirtobrutinib that you can switch to a different agent. However, if the BTK was discontinued for progression, in that case, the only BTK inhibitor which could work with pirtobrutinib or you have to switch to a venetoclax-based therapy.

Dose modification or interruption of covalent BTKi

Many times this question comes up in the clinic where a patient is on covalent BTK inhibitor, for example, ibrutinib. You have toxicity. You want to stop the drug. What median time, what average time patients can stay in remission? At least from the E1912 trial, which was an important trial in the field some years ago, it looks like on an average, patients may stay in remission for about two years, once you stop a BTK inhibitor for toxicities. However I think there is a lot of variables in the clinical practice. Sometimes these can go for many, many years without needing treatment.

Intolerance to ibrutinib: Does switching to second-generation covalent BTKi work?

As I mentioned before, there is now multiple data sets. The data set on the left is for zanubrutinib, data set on the right is with acalabrutinib, where if a patient is having really the toxicity from ibrutinib and you switch to a second generation BTK inhibitor, most of those toxicities actually do not recur or they recur at a lower grade, so it is better tolerated. That is a strategy which I think has been used in the clinical practice quite a bit. Maybe it will be less of an issue moving forward as we have less and less number of patients, at least in the CLL, getting ibrutinib these days, but certainly we have patients who have been receiving ibrutinib for the last many, many years and are having these toxicities.

Venetoclax after prior covalent BTK inhibitor

Most of the data with venetoclax, the MURANO study, as I said, the main trial was in chemo-exposed patients and really had very little targeted therapies, but here are a couple of data sets looking at venetoclax in the context of prior covalent BTK inhibitors. You can see here in these patients, the left is a retrospective analysis and the right side is a prospective study of venetoclax in heavily pre-treated relapsed/refractory CLL, where the median PFS is about two years.

BRUIN CLL-321: Pirtobrutinib for R/R CLL/SLL previously treated with cBTKi

Now more recently we are seeing encouraging data with pirtobrutinib. Pirtobrutinib, for everyone, is a non-covalent BTK inhibitor which works for patients with ibrutinib failure. Here is the so-called BRUIN 321 study, where patients who had failed prior covalent BTK inhibitor or treated with BTK inhibitor, ibrutinib, acalabrutinib or zanubrutinib, they are randomized on progression to pirtobrutinib versus acalabrutinib, rituximab or BR.

BRUIN CLL-321: PFS and OSS

Here we see the PFS and the OS curves for these patients. In the PFS, you can see that the pirtobrutinib was superior with a median PFS of 14 months and that comes to Dr. Lamanna’s point previously where when you are starting patients on pirtobrutinib, most of the time it is not going to last forever, but you can get a good nice debulking and a partial remission for these patients. However, it was certainly better than idelalisib/rituximab and bendamustine-rituximab and led to approval, as is said in the box on the top right. In December of last year, FDA granted approval of pirtobrutinib, that you can use pirtobrutinib with just a prior treatment with a covalent BTK inhibitor. The label has been broadened with this recommendation back in December of last year for pirtobrutinib.

An approach to R/R CLL

Now if you look at the patients who have prior venetoclax-based therapy, this will be like venetoclax-g in the front line. Maybe they received some chemo in the remote past. Here I think again the issue will be why the venetoclax was discontinued. If they had toxicity to venetoclax, then certainly you have to go to a BTK inhibitor based approach. However, if they had a long-term duration of response to venetoclax-based therapy, then I think, as we discussed, retreatment with venetoclax-based therapy would be appropriate or certainly you can go to BTK inhibitor approach.

Retreatment with venetoclax

What are the data with retreatment with venetoclax? So there are some prospective trials happening in this scenario, but what we have right now is some of the kind of ad hoc analysis from many of the randomized studies. On the left is MURANO study, on the right is the CLL13 and 14 studies, where you can retreat with venetoclax for these patients, especially when you have a long treatment-free remission or treatment interval from when you completed the therapy.

On the right side, you also see there is a mention of REVENGE study, which is an ongoing study looking at this very option of retreating with venetoclax-g in a prospective manner.

Poll 6

We will go to a poll now. In patients with relapsed/refractory CLL who progress after a covalent BTK inhibitor therapy, how often do you assess resistance mutation? The patient I described had a persistent C418S. That is the question. Are you checking for these mutations in clinical practice? The choices are listed. Please vote.

All right. Maybe I didn't expect that. Most of you mentioned that you routinely test in practice. I would say many times it is not checked in the routines, but I think that would be something to consider, especially I think if you are failing a covalent BTK inhibitor and you are going to another BTK inhibitor right away, I think some of those mutations may help decide, certainly if you have a non-cysteine 418 S mutation, which can lead to resistance to noncovalent BTK inhibitors.

An approach to R/R CLL

Lastly, we have this tougher group of patients who have failed both covalent BTK inhibitor and venetoclax or at least have used them. That was the case in question which we discussed. Here the options really are pirtobrutinib or liso-cel.

A growing patient population of unmet need: double refractory and double exposed

This is a group of patients which is increasing. Patients are living longer, which is great obviously. However, these therapies, patients are on it and eventually we are seeing more and more of these patients, so called double exposure, double refractory. Depending on who you talk to, maybe there is a difference in the terminology of what exactly is called double refractory. Double exposed, I think, means that patients have at least some exposure to both of these classes of drug. The point here is that I think these patients have relatively poor outcomes and we have therapies approved, but we are talking about median PFS of maybe one to two years, which I will talk in the next few slides.

Mechanisms of disease resistance to targeted agents in CLL

Here it talks about the mutations I was briefly mentioning about. You can see in the middle here, if you look at the BTK cysteine 481 S, which is kind of the second part. There are other mutations, so-called T474I, L528W, which if you do a BTK mutation analysis, you have to look at the codon which is affected. It is not just you say patient is BTK mutated. You really have to know what site because that can help maybe what exactly you may decide to do next for that individual patient.

Key biomarker testing to inform R/R CLL/SLL treatment

Now coming back to the biomarker question, which Callie also mentioned in her talk, whenever a patient relapses, I think it is important to recheck for FISH testing, also TP53 mutation testing. One thing which I think is in highlight here at the bottom of the slide is that the IGHV test for individual patient doesn't really change over time. You do not need to check IGHV again and again. If a patient is unmutated, they will remain unmutated for the rest of their life or the same way for the mutated, they will remain mutated. That test doesn't need to be repeated. In fact, in our center, if we resend the test, they will decline to process it. They will say a patient had it before. Why do you want to test it? Certainly the other ones, 17p, FISH, p3 mutation. As we talked about the BTK PLC gamma 2 mutations I think are important to test in this scenario.

BRUIN: Pirtobrutinib for previously treated CLL/SLL

The two drugs we are going to talk about briefly are pirtobrutinib, which is a non-covalent BTK inhibitor. This is the original BRUIN study which led to the original approval of pirtobrutinib. Here single agent pirtobrutinib, and these are very tough patients to treat in a way. Tough in the sense that tough disease to treat where they have multiple prior therapies, but you see a high overall response rate of 70% to 80% in this patient population.

BRUIN update: PFS

And this is the PFS curves where same thing Dr. Lamanna mentioned, you can look at the PFS on the top curve is 18 months. This is among patients who received a prior covalent BTK inhibitor. The bottom one is our patient in question where patient had both BTK and BCL2. Here the median PFS is about 15.9 months. It works, but eventually patients will progress and you have to start thinking about what next for an individual patient.

BRUIN CLL-314: pirtobrutinib vs ibrutinib in treatment naïve and R/R CLL/SLL

Now pirtobrutinib has also been studied more recently versus ibrutinib. This was the data presented at ASH. It was a head-to-head comparison both in relapsed/refractory, but also a subset of patients who were treatment naive. It was a trial which has both patient populations in the same trial. On the left, you see the overall cohort where you can see that the pirtobrutinib was superior to ibrutinib. On the right, you see the relapsed/refractory subset of that cohort where the p value was not significant, but in the overall cohort was significant.

BRUIN CLL-322: fixed-duration pirtobrutinib + venetoclax + rituximab vs venetoclax + rituximab for previously treated CLL

Then there is another relapsed/refractory trial which is happening. We just know the press release back in April that the trial met the primary endpoint. This is relapsed/refractory CLL, where the venetoclax-rituximab has been the standard in a way based on the MURANO study. However, this study combined venetoclax-rituximab with pirtobrutinib. This is looking at triplet actually versus doublet in relapsed/refractory CLL. We know that the trial met the primary endpoint of improved PFS, but we are looking forward to the data presentation.

TRANSCEND CLL-004: Lisocabtagene maraleucel in R/R CLL/SLL

Now besides pirtobrutinib, the other aspect is the liso-cel, which is the CAR-T cell therapy, also approved in CLL a few years ago. As any other CD19 CAR-T cell therapy, you give flu/cy lymphodepletion.

TRANSCEND CLL-004: PFS by response in BTKi progression / venetoclax failure subset at DL2

Here on the left, which is highlighted on the top as well, that the median PFS was about 12 months. That was in the patients who were so-called double refractory patient population.

Overall, I think just the CAR-T kind of works for patients and they will be tailored to the curve. There will be patients who hopefully will be cured with this particular CAR-T cell therapy, but a large majority of the patients will ultimately end up relapsing. I think that is where the unmet need is, how we can increase that bar, how we can increase the outcomes as maybe there are some CAR-T cell therapies in lymphoma space which are doing very well, whether it will be novel targets and things like that. That is where I think some of the field is looking at the outcomes for these patients.

TRANSCEND CLL-004: Liso-cel plus ibrutinib outcomes

Important point that if you use CAR-T, at least the prospective data is, with ibrutinib – the same trial, they had a separate arm with ibrutinib – adding ibrutinib with CAR-T really improved the outcomes. The CR rate went from 20% to 45%. The overall response rate went from 50% to about 85%. MRD rate went up, PFS improved, everything improved. At least in the clinical practice, at least in my practice, and I think that is pretty much every CLL physician is doing these days, when we are doing CAR-T cell therapy for patients, we are combining with the BTK inhibitor. The trial was done with ibrutinib, but in practice, I think a lot of these patients are being combined with pirtobrutinib or other second generation BTK inhibitors.

Posttest 1

We have a posttest question now. We talked about a patient with CLL who is unmutated V gene, had ibrutinib and now he is progressing. What biomarker approaches would you recommend for this patient before choosing the next treatment? The patient is failing ibrutinib. What would you test?

1. Would you repeat testing for p53 mutation only?
2. Would you test for IGHV only?
3. Would you test for p53 deletion(17p) as well as consider BTK resistance?
4. Would you test for everything including IGHV?

Please vote.

All right. Very nice. Completely, I think big switch from pre and post in the in the third choice which will be the appropriate thing to consider here. Okay, let's move on. We can move to the next one.

Posttest 3

All right. Based on the recent clinical trial data guidelines update, which of the following would be most accurate to tell a patient about current indication for pirtobrutinib in CLL SLL?

1. It is approved for newly diagnosed and relapsed/refractory.
2. It is approved for relapsed/refractory after prior treatment with a covalent BTK inhibitor.
3. Approved for relapsed/refractory CLL after covalent BTK inhibitor and a BCL2 inhibitor.
4. Or you have to have more than two priors of therapy and also have a BTK inhibitor and BCL2 inhibitor.

I think the correct answer is the second choice from the top, which I think a lot of people switched to that. That is the new approval back in December we talked about where it is approved after a covalent BTK inhibitor. We can move to the next slide.

Posttest 2

Now I am confident in my ability to engage patients with CLL/SLL in shared decision making. Do you agree with that statement? Strongly disagree? You have the choices there. Please read and vote.

All right. Excellent.

Emerging Treatment Approaches

So I have a few more minutes. There is a very important point to talk about BTK degraders. We will really quickly run through some of the slides before I hand off to Dr. Lamanna for kind of final panel discussion.

Nemtabrutinib: Reversible noncovalent BTK inhibitor in CLL

In terms of the emerging treatment approaches, we want to be complete in terms of what we are covering for you today. Besides pirtobrutinib, just to kind of let you know there is another drug called nemtabrutinib, which is also a non-covalent BTK inhibitor, is not yet FDA approved, but is in phase III studies, which has also shown some promising data, as is shown here, which was presented now, I think last year.

BTK degraders: Mechanism of action

The new class of drugs which has come along in the last two or three years really rapidly in the field of CLL is the so-called BTK degraders, which actually degrade the BTK protein completely, as opposed to inhibiting it. It removes them from the surface of the CLL cells. It also has a scaffolding function where some other proteins are not able to bind to that mechanism as well. This class of drugs are oral drugs like BTK inhibitors and have come along very quickly in the field.

BGB-16673: BTK degrader in CLL/SLL

There is a drug called BGB-16673. This has been presented in multiple meetings in the last few years. We have heard sequential updates. This is the last update where, with single agent drug in a very heavily treated patient population where many of these patients have also failed non-covalent BTK inhibitors, showing quite high efficacy in terms of response rates, as you can see, highlighted up to 80% to 90% patients responding to treatment.

Bexobrutideg (NX-5948): BTK degrader in CLL/SLL

NX-5948 has a name now of bexobrutideg, also another BTK degrader. In a very similar fashion, has been shown with multiple studies at multiple meetings over the last few years, and also very similarly high rates of overall response rate across the spectrum of patients with CLL, very heavily pre-treated patient population. So these two classes of drugs are the foremost right now in terms of the development, though there are others in early phase trials where the data has not been presented.

Epcoritamab: Bispecific antibody (CD3 x CD20) for R/R CLL/SLL

Another important class of drugs is CD20 bispecific antibodies, which have also come somewhat slowly in the field of CLL as compared to DLBCL space. Epcoritamab, I think, has the best data in the field where single agent, this Epco bispecific antibody led to high rates of good remission, overall response rate, but also importantly, both MRD4 and MRD6 response in some of the patients, which was quite remarkable.

Sonrotoclax (next generation BCL2 inhibitor) + zanubrutinib for R/R CLL

Also, we now have a new generation of BCL2 inhibitors, sonrotoclax which actually was just approved for mantle cell lymphoma a few weeks ago. This is a new BCL2 inhibitor, but is also in studies in CLL and multiple combinations including with zanubrutinib, which is shown here with high rates of remission.

Select ongoing/recent phase III trials in previously untreated CLL

There are many other phase III studies ongoing in the context of CLL. This is frontline CLL. Some of these we may see at ASH or in future meetings.

Select ongoing/recent phase III trials in R/R CLL

In the second slide is relapsed/refractory CLL. A lot of active clinical trials data emerging I think in the next few years with many of these studies coming to fruition. All right. With this, I will hand it back to Dr. Lamanna.

Panel Discussion: Perspective in Treatment for R/R CLL/SLL

Dr. Lamanna: Thank you for catching us up. Time for you guys to ask questions to us.

Poll 7

I apologize because the tablet I have, I am not getting the online questions. Maybe you'll be able to also submit them and we can answer them after too, but just having difficulty with that.

1. What would you like to talk to the panel about? We talked a little bit about role of MRD.
2. We talked a little bit about is there a time you would consider rituximab versus obinutuzumab with venetoclax? I think we addressed that, but if you want, we can talk about that.
3. Would you ever consider pirtobrutinib immediately after progressive disease following venetoclax-obinutuzumab versus a covalent BTK inhibitor?
4. When might venetoclax retreatment be considered after progressive disease following venetoclax and obinutuzumab?
5. When do you typically refer for CAR-T?
6. And are you testing most or all of your patients who experience disease progression on a covalent BTK inhibitor for mechanisms of resistance?

And I know we talked about that, but please vote.

It seems like a large number of folks still want to talk about when do you refer for CAR‑T? Nitin, do you want to talk about that a little bit?

Dr. Jain: Sure, yes. I think in my practice, typically in some sense, certainly the double-exposed patients. We are talking about patients who had a prior BTK inhibitor, ibrutinib-acalabrutinib-zanubrutinib, had venetoclax exposure as well, either maybe in combination, maybe after a relapse of that. I think in those patients, certainly a referral to a cardiac center would be an appropriate strategy. I think certainly we have pirtobrutinib in the mix there as well in double exposed patients we can use. I would certainly think about CAR-T cell therapy after they have received at least two lines of therapy and they have been exposed to covalent BTK inhibitor and a venetoclax-based therapy. I think that is where the group of patients, at least we start thinking about CAR-T cell therapy. In a practical sense, many times for the same group of patients, you also have pirtobrutinib available. Many times it is like, oh, let's start a patient on pirtobrutinib and then kind of make plans for when we may do CAR-T cell therapy, either when the patient is progressing after pirtobrutinib, or do you want to maybe do while the patient is responding to pirtobrutinib? I think those are some of the things in practice we are looking at.

Dr. Lamanna: Yes. Fair enough. Callie, you alluded to that as well.

Dr. Coombs: Yes, I totally agree. I definitely would not think about it prior to failure of a covalent BTKi and venetoclax. I would amend maybe double exposed to once I am convinced they are refractory, I'd try them on a different BTK inhibitor if it was intolerance. If they had venetoclax retreatment as an option, I'd try that. The published data from TRANSCEND CLL 004 do not look great, but I will say some of the real world data look better. There is actually a poster at ASCO. There was also an oral presentation at ASH. I do think pirtobrutinib bridging is probably going to lead to better outcomes. Not to mention the patients on TRANSCEND CLL 004 were particularly difficult. They had six prior lines of therapy. But even these real world experiences, the oral at ASH, the poster at ASCO, they were still very pre-treated. They had six prior lines of therapy, but they had likely more effective bridging because I think pirtobrutinib is just so good at debulking. We know at least one of the independent predictors for higher response is going in with non-bulky disease and pirtobrutinib is excellent at debulking. No, it doesn't lead to deep responses like CRs, but it can significantly reduce lymph node burden, maybe lead to better responses. I do not think about it for my 90-year-olds, but in my young patients who I think they are going to need something more than pirtobrutinib to kind of get them past hopefully into the stage of life where they are not going to die from their CLL, I definitely would think about pirtobrutinib more as the bridge. That is why I answered pirtobrutinib as a bridge to liso-cel for the case because he was only 64. If he was 84, pirtobrutinib was good enough, but then maybe we will see an approval for a degrader for next go around. The field is always changing, but I think we have a lot of options.

Dr. Lamanna: Brian, you wanted to add a comment?

Dr. Koffman: Yes. Just to add, I think from a patient's perspective, that bridge, because if you go into CAR-T with bulky disease, you are not going to do well. It cannot be your ultimate therapy. There has got to be a penultimate. You have got to have something in your back pocket, even if it is only for three to six months or something. It might be pirtobrutinib or it might be a PI 3K, kinase inhibitor. Maybe you can get away with one despite their toxicity for three to six months or something, but that is one of the things that when I talk with patients about is you have got to have something there because if you go in with bulky lymph nodes or an ALC that is sky high, it’s cellular therapy, it is not going to work if there is a high disease burden.