Choosing Wisely in CLL: A Deep Dive Into Frontline Treatment

In this episode of Treating Together, host Marc Braunstein, MD, PhD, associate professor of medicine at the NYU Perlmutter Cancer Center, sits down with Adam Kittai, MD, associate professor and director of the CLL and Lymphoma programs at NYU Perlmutter Cancer Center, for a deep dive into the rapidly evolving frontline treatment landscape in chronic lymphocytic leukemia (CLL). As chemotherapy continues to give way to targeted and time-limited therapies, clinicians face an increasingly complex array of choices, each influenced by disease biology, patient preferences, and emerging clinical trial data.

Key Discussion Points

The episode focuses on the evolving frontline management of CLL and how clinicians can individualize therapy in an era of expanding options. Highlights include:

• Patient Evaluation and Diagnosis Considerations: Beyond traditional risk factors such as TP53 mutation and IGHV status, importance is also being placed on patient preference, comorbidities, and treatment goals (eg, time-limited vs continuous therapy) to guide treatment decisions.
• Therapy Selection and Sequencing Strategy: Dr Kittai offers his view on sequencing decisions in the front line: given the lack of robust comparative data, current evidence supports prioritizing the most appropriate upfront regimen rather than relying on uncertain sequencing strategies across agents.
• Insights From the AMPLIFY Trial (NCT03836261): With the recent February 2026 FDA approval of acalabrutinib (Calquence) plus venetoclax (Venclexta) in the front line, the discussion highlights progression-free survival (PFS) benefits seen in the AMPLIFY trial and favorable safety of the doublet.
• The Growing Role of Minimal Residual Disease (MRD): The discussion briefly pivots to the use of MRD testing in the clinic today, including data from trials like GLOW (NCT03462719) and FLAIR (EudraCT: 2013-001944-76), and its potential to guide treatment duration.
• Emerging Therapeutic Strategies in the Pipeline: The conversation looks to the future of CLL care, including Bruton tyrosine kinase (BTK) degraders, next-generation BCL-2 inhibitors, and novel combinations currently under investigation.
• Managing Richter’s Transformation: Dr Kittai covers evolving combination approaches for this aggressive cancer that aim to target both CLL and lymphoma biology, moving beyond chemoimmunotherapy.

Transcript

Braunstein: Welcome. I'm delighted to join Dr Adam Kittai, my incoming colleague at NYU Perlmutter Cancer Center, for this podcast on the evolving treatment landscape in CLL, particularly for frontline treatment. I'm Marc Braunstein; I'm associate professor at the NYU Perlmutter Cancer Center and practice in Mineola at the NYU Long Island School of Medicine. And I'll let Dr Kittai introduce himself.

Kittai: Hi, everybody. Also really happy to be here, especially presenting with Dr Braunstein to discuss CLL. As Dr Braunstein has said, I am joining faculty at the NYU Perlmutter Cancer Center as the director of CLL. So, this topic is on-brand, and really excited to be here to chat about all the updates on CLL.

Braunstein: Yeah, great. And so, the treatment landscape for CLL has moved away from chemotherapy, but even now with all the targeted therapies, it's becoming more and more difficult to keep track of all these studies, and so it’s really great to be joined by Dr Kittai, who's a true expert in this area. I thought we'd start the conversation about how we evaluate frontline patients. What are some of the features we're looking for as we're starting to think about treatment options? Certainly there's things I look at like performance status and age, but what are some of the other factors that you're thinking about when you evaluate and diagnose patients with [small lymphocytic lymphoma] or CLL?

Kittai: I agree, [Dr Braunstein], I think that one of the main things that I think about with CLL and frontline treatment is, many patients don't read the classic textbook that we talk about, so very often you will hear about how we should reserve high-risk patients such as TP53 mutation, deletion 17p, IGHV-unmutated patients for continuous therapy. And you may say, we should avoid patients with high-risk disease to give them time-limited therapy. But in reality, very often patients come in and they have comorbidities or true preferences on why they prefer a continuous therapy or a time-limited therapy.

So number one in my book is actually patient preference, and so I like to have a long conversation with my patients about what the current options are, which of those options I would prefer for that patient—for reasons such as comorbidity or risk of disease—and help the patient in terms of guidance, in terms of deciding what to actually treat that patient with. Because ultimately, we have a lot of good options for patients with CLL these days, and there are a lot of new data that show that even if you decide on one option vs the other, most likely your patient with CLL is going to do quite well no matter what you pick. So really, I think patient preference and a well-informed patient is the key to having good outcomes from both a patient perspective and how they view their outcome to be, as well as clinically, from both a survival standpoint as well as a safety standpoint.

Braunstein: Right, it really is gratifying to have all these options at our dispense to manage patients with different variables. And before we get into the different regimens and talk about studies like the AMPLIFY study, I'm wondering, do you think about sequencing therapies when you're selecting a first-line therapy? Are you thinking, “Well, I'm going to start here and possibly go to the next line,” or just saying, “What is the best regimen upfront, and then we'll think about it once we have to address it down the line, what their next line of therapy will be”?

Kittai: I think about what the best frontline therapy is at this point. And the reason why I focus and hone in on that is because no matter the risk of the disease, no matter what we pick, on average, that patient's going to have probably around 5 years on average on their first line of therapy alone. Many patients go way past that, but in general, it's about 5 years. And so when I'm thinking about 5 years into the future, I don't even know what might be approved 5 years into the future. Additionally, there's not many studies that have looked at the sequence of novel therapy, such as BTK inhibitor- or venetoclax-based therapy, and then novel therapy such as BTK inhibitor or venetoclax-based therapy. And so we don't really know which sequence is the best sequence. We are really reliant on real-world data because a lot of our current approvals occurred in patients who had many prior lines of therapy in the relapsed setting and have also been treated with chemoimmunotherapy, which we've largely abandoned. And so in reality, I don't really have the data in sequencing to support thinking about sequencing in the front line.

Braunstein: That's a great point that there isn't as much guidance on how to sequence. I think what the guidelines and the consensus suggest are that we potentially sequence the mechanism. And so we have various BTK inhibitors; we have venetoclax, a BCL-2 inhibitor; [and] monoclonal antibodies like rituximab [Rituxan] or obinutuzumab [Gazyva]. These have all been studied in the first line and later lines of therapy, and more recently, have been studied in the upfront setting with time-limited options, so maybe we can transition to the phase 3 AMPLIFY study.

For the listeners, just for context, this was a randomized phase 3 study with 3 arms. One arm was acalabrutinib plus venetoclax; another arm was acalabrutinib plus venetoclax plus obinutuzumab; and the third arm, which was the control arm, was chemoimmunotherapy, which could have been [fludarabine-cyclophosphamide-rituximab; FCR] or [bendamustine-rituximab]. This was for a fixed duration in patients who were untreated. The study did exclude patients with deletion 17p or TP53 mutation but did include patients with unmutated IGHV. So how have you viewed these data, and how are you incorporating it into your algorithm for clinical care?

Kittai: In this study, what they found was that both acalabrutinib-venetoclax and acalabrutinib-venetoclax-obinutuzumab led to a PFS benefit compared with chemoimmunotherapy—but there are a couple of caveats to this. Number one is that patients in the [triplet] arm were actually more likely to die and had a worse overall survival [OS] than [the doublet], and this was because of COVID-19. This is one of the biggest caveats to the study—that this study was mostly enrolled during COVID-19, and so some of the outcomes are surprising, especially with that increased risk of death with the triplet combination. Now, this wasn't the only study that showed increased risk of death with the triplet combination. There was also a cooperative group study—an Alliance study [NCT03737981] that compared ibrutinib [Imbruvica]-venetoclax-obinutuzumab with ibrutinib-obinutuzumab—and [in] that particular study too, [which] was also enrolled during COVID-19, there were more deaths than expected in the ibrutinib-venetoclax-obinutuzumab arm.

When I look at the [AMPLIFY] study, number one, I think a take-home point is that patients who you are thinking about treating with the triplet should be younger and also have a higher risk of infection. So that's something to consider for the triplet, and to know is that the triplet was not approved by the FDA due to this higher risk of death with the triplet. Now, the patients who were receiving acalabrutinib plus venetoclax did quite well. The safety profile looked fantastic, to be honest, and there was a PFS benefit compared with chemoimmunotherapy. Now, the one interesting thing about the acalabrutinib-venetoclax combination too, was that for patients who had IGHV-unmutated disease, it appeared that these patients actually did worse when treated with acalabrutinib then venetoclax than those patients who did not, which is not something that we always see with novel therapies. And so, when I'm thinking about the combination of acalabrutinib plus venetoclax, I'm thinking that it would be good for a patient who wants an all-oral time-limited therapy, who also has good-risk disease, IGHV-mutated disease. That being said, if somebody wants an all-oral time-limited therapy, I don't think that I would exclude it for patients who have IGHV-unmutated disease; I would just inform that patient that I wouldn't expect them to have as long of a PFS than not.

Now, one of the main questions that I think a lot of people ponder on with these results is, will acalabrutinib-venetoclax take patients who otherwise would have gone on continuous BTK inhibitor, or will it take from patients who would otherwise have gone on venetoclax plus obinutuzumab? I've heard a lot of conflicting opinions on this. I'm curious to know, [Dr Braunstein], what are your thoughts on this?

Braunstein: Yeah, that's a great question. And just to your point, the FDA approval in February of this year was just for the acalabrutinib and venetoclax combination, not the one with the obinutuzumab. I think the FDA viewed the data similarly, that there were worse outcomes with the triplet. But yeah, your question is really interesting, because now we have these 2 very effective regimens. I think for obinutuzumab and venetoclax, I think the patients who had unmutated IGHV did benefit in that group, so maybe I favored that for the subgroup that has the unmutated IGHV. I think that in my experience, for patients who have bulky disease, they tend to respond a bit faster with the monoclonal antibody, so I might consider venetoclax-obinutuzumab in that group. But clearly, we don't have head-to-head data available yet for these 2 regimens, and I think they both have somewhat distinct [adverse] effect profiles. With the BTK inhibitor, you have to pay attention to comorbidities like arrhythmias and bleeding risk and things like that. But I don't think there's a clear winner between the 2 regimens. So I think I would sort of just individualize it based on comorbidities and molecular features. What's your thought process?

Kittai: I agree. I think that I might still use venetoclax-obinutuzumab for a patient with IGHV-unmutated disease. There are a couple of other things that came out recently, too, that are of interest and sort of play into this phenomenon. So one is the CLL17 study [NCT04608318], which was the first randomized study to compare continuous ibrutinib vs ibrutinib-venetoclax and venetoclax-obinutuzumab as a time-limited therapy, and the Kaplan-Meier curves for PFS were overlapping. So the efficacy of these 2 regimens are pretty similar. And so my take-home point from that particular study is that I think it's in the eye of the beholder. I think that…providers who are more used to giving covalent BTK inhibitors continuously will look at the CLL17 study and say, “I'm going to continue using continuous BTK inhibitor, because it's just as effective as time-limited therapy,” whereas the academic centers, who are more used to giving the time-limited therapy because they have the logistics and the ability to get all the labs and [tumor lysis syndrome; TLS] monitoring that's required, might look at that data and say, “Patients who get time-limited therapy have equal outcomes to continuous therapy, so I'm going to continue giving time-limited therapy.”

When I look at the AMPLIFY data and I think about the CLL17 data, I think the same holds. I think that the AMPLIFY data may not sway somebody to not use continuous BTK inhibitor because it's just so easy. But at the same time, someone who might be somewhat familiar with the venetoclax sees that there is not much TLS on the AMPLIFY study [and] sees that the safety profile looked pretty good. They may actually switch from using a continuous BTK inhibitor to the all-oral acalabrutinib-venetoclax, just because the ease of it looks pretty good, as opposed to the classic difficulty in giving the obinutuzumab infusions. So we'll see how this plays out into the future. I do know that since the approval of ibrutinib plus venetoclax in Europe, that [combination] has been adopted pretty widely, as opposed to the venetoclax-obinutuzumab and the continuous BTK inhibitor. We'll see how time plays out over the next few years, to see what the uptick is in terms of use of acalabrutinib and venetoclax across the United States, but it is really nice to finally have an all-oral time-limited therapy with acalabrutinib and venetoclax.

The last thing too is that the MAJIC study [NCT05057494] is studying acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in a randomized phase 3 study; we'll see what that data look like, hopefully soon.

Braunstein: Yeah, that’s a great point. That study will be very practice-informing. And I guess we can all hedge our bets on which one will be the winner in that study, if there is one.

And so, I think for continuous BTK inhibitor therapy, for which there's a wealth of data showing benefit in various higher risk categories, it’s still [unclear] where that fits in. Because the first question patients often ask are, “How long do I have to be on this therapy? When can I stop it?” And all the single-agent BTK inhibitor studies have been pretty much given until progression. Would you consider then switching a patient over to…one of these time-limited regimens by adding in the second agent, in a patient who's recently diagnosed, but intended to get an indefinite therapy with a single-agent BTK inhibitor?

Kittai: I think we have 2 questions in 1 here. So, I think that how the study was designed is that patients got 2 cycles of acalabrutinib, and then the venetoclax was added in the third cycle. And so I think that there's going to be 2 things that happen here. You might have a patient [with whom] you talk about the AMPLIFY study, and you start them on the acalabrutinib, and it's time to start the venetoclax. In general, my patients, when you are about to start therapy, they are always super, super nervous. It doesn't matter how long I've known the patient for; it doesn't matter how long the patient had CLL before we had to start treatment, and how long I've been coaching them about it. They're always super nervous, but when they start taking the BTK inhibitor, they always feel so much better. They realize that the drug is not so toxic. And I imagine that there are some patients who, when it's time to start the venetoclax, might just say, “You know what, I'm doing great on the acalabrutinib. I'm just going to continue.” So I do see that as being a thing that happens. I did have a patient already [to] who[m] that had happened.

You also might have the other patient that you're alluding to, who is a new treatment start, [to whom you say], “Let's just give you acalabrutinib. We'll see how it goes, and at some point, maybe 2, 3, 4, 5, 6 cycles in, we'll start the venetoclax when your disease is better controlled to decrease your risk of TLS as much as possible.” I think that's also a possibility. The question is, when does that lag time end? Do we feel comfortable putting somebody on venetoclax for a year with acalabrutinib, or zanubrutinib [Brukinsa], or ibrutinib, for that matter, who've been on it for 5 years, right? I'm not sure when that lag time ends.

I did have 2 other scenarios. When the original GLOW study came out, I had 2 patients on acalabrutinib, and 1 patient was on acalabrutinib for 6 years, and they told me they just don't want to be on medication anymore. And they said, “Can I stop, or can I add on the venetoclax?”, because they were very well informed. And so what I did was I made a deal with them… that if they were MRD-negative by our flow assay, that we can stop the acalabrutinib and not worry about it. And they were, so we stopped. And I unfortunately left Ohio State University at that point to see how well that patient did in the long term, but for about a year after the acalabrutinib was stopped, she was still in remission. And the other patient, we were considering adding on the venetoclax, but when he heard about the end of toxicity, he decided just to stay on the acalabrutinib indefinitely. So I do think that these questions remain. Can we add on venetoclax as a way to get patients off BTK inhibitors? That's a great question. I know that some people are currently looking at this question, but it's something that the AMPLIFY data do bring up, and especially now that we have the approval for both agents.

Braunstein: You mentioned MRD, and maybe we can take a brief pivot to that. There was the FLAIR study that looked at MRD guidance using venetoclax-ibrutinib, and this is increasingly being used in clinical trials. How are you testing for MRD and which patients were you checking it on?

Kittai: So, the FLAIR study is a randomized phase 3 study that basically has been updated with various different arms over the years. The study that [Dr Braunstein] is referring to is combination ibrutinib plus venetoclax vs ibrutinib as continuous therapy. Now the ibrutinib-venetoclax in this arm of the study had to meet very stringent MRD criteria in order to stop. What [investigators] did was test MRD starting at 1 year into therapy. If somebody was MRD-negative, meaning that their disease was undetectable, they had to continue for the time it took to get to MRD negativity. So the minimum amount of time that anyone could have stopped the ibrutinib-venetoclax was 2 years on this study, but the majority actually stopped at 4 years. So we have to remember that even though this was “time-limited” therapy, this was MRD-directed, and the majority got many, many years of therapy. Additionally, these patients also tended to be younger and fitter, because there was a previous arm to this study that enrolled onto FCR. So this was a young, fit patient who could tolerate combination ibrutinib and venetoclax for about 4 years. And this study showed that there was an OS benefit of ibrutinib plus venetoclax given in this manner vs ibrutinib. And one would think that when you show an OS benefit that this would be the new standard of care. However, this is pretty difficult to give in reality, right—giving ibrutinib plus venetoclax, having this kind of complicated MRD testing, and so it hasn't been widely adopted.

So how I'm currently doing MRD—and this has recently changed—is I use it in 2 ways to inform practice, and the only way I use it to inform practice is really in the frontline setting, sometimes in the second line. Let's talk about it. For patients who I've relegated to acalabrutinib and venetoclax or venetoclax plus obinutuzumab, I simply give it for 12 to 14 cycles and I test MRD at the end—not as a way to determine if I should continue therapy, but to see how deep of a remission they are in and give them some guidance about how well I can predict when they might need their next therapy. The reason why I stopped in everybody who I give those 2 regimens to is because we kind of made a handshake at the beginning of therapy that this therapy is going to be a time-limited therapy, and that the reason why we picked that time-limited therapy is to give that patient a treatment-free interval as much as we can. So it is very rare that I would continue time-limited therapy after giving that 1 year, because it's sort of like this pathway that you sent down the patient. And also we don't have data to say that intermittent therapy with timely with therapy is any worse than continuous therapy either, right? So I'm really trying to optimize that treatment-free interval for that patient.

Braunstein: And how are you testing for the MRD?

Kittai: I always use clonoSEQ these days because clonoSEQ is the FDA approved method. And the reason why I also use clonoSEQ is that not only does it give you the MRD, but it also gives you the IGHV sequence and status. So it gives you the mutated, unmutated status, so you kind of get a twofer. I test the IGHV at diagnosis, and with that clonoSEQ test, you also get the ID, so you can test MRD down the line whenever you choose to test it. So it's a really nice test to have.

Braunstein: So you’re testing it on the bone marrow sample?

Kittai: No, just peripheral blood.

Braunstein: Peripheral blood, got it.

Kittai: Let's take a minute for that, and then I will talk about the other way I use MRD testing that's new. So in all of the studies that looked at concordance between peripheral blood and bone marrow, it was concordant in 90% of the cases, meaning that if you were MRD-negative in the peripheral blood, there was a 90% chance—although I'm probably using “chance” in the wrong terminology here—that they were also bone marrow MRD-negative, so it was only 10% discordant. And additionally, it looks like if you get to the 10^-5 threshold with clonoSEQ on peripheral blood, that was pretty much 100% concordant with being MRD-negative in the bone marrow. So keep a look out; more data on that coming.

In terms of using MRD to direct therapy, there's this new NCCN guideline on MRD-directed therapy in the front line. One was the ibrutinib plus venetoclax FLAIR data that we just talked about. That's actually not a preferred regimen; I think it's recommended under NCCN. One of the preferred methods is for high-risk patients receiving combination triplet acalabrutinib-venetoclax-obinutuzumab or zanubrutinib plus venetoclax. So [about] these 2 studies, one was based on [Dr] Matt Davids’ [of Dana-Farber Cancer Institute] acalabrutinib-venetoclax-obinutuzumab [phase 2 study; NCT03580928] for high-risk patients with TP53 aberrations. And the other one was the SEQUOIA [NCT03336333] arm 4, which was deletion 17p and TP53 patients receiving zanubrutinib-venetoclax. Now, SEQUOIA arm 4 also had very rigid MRD stopping rules. The majority of patients actually got continuous zanubrutinib-venetoclax, whereas [for the] acalabrutinib-venetoclax-obinutuzumab combination, they gave it for, I believe, 16 cycles, if I'm recalling correctly. And if you had MRD 10^-4, you can stop. If you did not, you continued with 9 more cycles and then you can stop. And if you had MRD positivity, after 9 more cycles, you just continued on therapy forever. And this is where I think, although I haven't gotten a chance to use it yet, [for] high-risk patients with TP53 aberrations who are younger who can tolerate that triplet, I think I will likely do [Dr] Matt Davids’ acalabrutinib-venetoclax-obinutuzumab MRD-directed therapy. So that's where I would use MRD to really guide treatments in the current era of treatment-naive CLL.

Braunstein: Yeah, so more and more incorporating MRD testing into practice—that's an interesting approach.

With the time we have remaining, I'm curious; with all the pipeline agents—BTK degraders, new BCL-2 inhibitors—what are some of the things you're excited about, or you're keeping track of in the pipeline?

Kittai: Let's start off with the BCL-2 inhibitors. The new kid on the block is sonrotoclax, which is an agent from BeOne, the same makers that make zanubrutinib. The CELESTIAL study [NCT06943872], which combines zanubrutinib plus sonrotoclax vs venetoclax plus obinutuzumab has fully accrued, so hopefully we'll have some data there soon. Now, the questions that remain from sonrotoclax is: A), is it more effective than venetoclax? We don't know yet. B), How will the final ramp-up look? That has also not been determined yet. Will it be easier than venetoclax? That'll be the goal, but we haven't seen it yet. And the data that make me excited about sonrotoclax is that there have been some data that have been presented in the phase 1/2 setting that looks like patients who receive sonrotoclax respond really fast, and so I'm hoping that that really fast response correlates with better outcomes into the future, but a lot of unknowns there, so we'll see how sonrotoclax plays out into the future.

In terms of the degraders, what's interesting about them is that instead of just inhibiting BTK, like the covalent and noncovalent BTK inhibitors do, these degrade the BTK entirely, and so they should be effective in patients who have those resistance mutations that confer resistance to both the covalent and the noncovalent BDK inhibitors. These are being studied in the relapsed setting and have shown some nice responses in patients who have very refractory disease with multiple lines of therapy, and are now being brought forward to the 1 prior line [setting] and also hopefully soon the treatment-naive setting. Now, the one concern with degraders—it's very similar to the concern with noncovalent BTK inhibitors—is that there's now a resistance mutation identified with the BTK degraders called the A428D mutation. This A428D mutation confers resistance to all BTK targeted agents that we have. And so the concern is that if we give degraders continuously, like we have with the covalent BTK inhibitors, they might confer resistance to covalent BTK noncovalent BT caters for second lines of therapy. So, a lot of these degraders are being adopted as time-limited agents, and so we'll see how they do as they are brought into earlier lines of therapy.

Braunstein: Is that mutation—the A428D—something you see with BTK inhibitors as well with covalent or noncovalent?

Kittai: It’s popped up with some of the covalent and noncovalent [BTK inhibitors], but it's super, super rare. So far, we have 2 reports in just 8 patients that this is the resistance mutations, so we can't really make conclusions based on these 8 patients alone. There's also this issue where we are detecting this mutation in patients who have terribly relapsed disease. We don't know what the mutation profile is going to look like when they're used in the frontline setting, when the disease is not so replicable, right? So the disease is not so aggressive in the front line. We'll see how these mutations look like when we're using these agents in the front line, especially as time-limited therapy too.

Braunstein: Right, before patients develop any mutations when they’re most sensitive.

Kittai: Exactly, exactly.

Braunstein: So, [is there] anything you wanted to discuss about things you're working on, or research efforts you're currently involved in?

Kittai: Yeah, I would love to talk about Richter’s transformation. So Richter’s transformation, as we all know, is when CLL transforms into an aggressive lymphoma and is normally associated with terrible outcomes. But there's been some movement recently with multiple clinical trials that have investigated novel combinations and have been added to the NCCN guidelines. So I was hoping that we would maybe talk about some of these combinations and agents, so that way, patients and providers who are not so used to dealing with Richter’s transformation are at least aware of them, because we know that chemoimmunotherapy is not effective against Richter’s transformation.

Braunstein: Yeah, definitely, because this group of patients seems to be very high-risk, and a question that comes up on tumor boards all the time [is], what's the ideal regimen? So maybe you can tell us a little bit about what you're doing.

Kittai: Yeah, of course. So how I think about Richter’s transformation is based on how the CLL was treated prior. We know that patients who have CLL, who get treatment and then develop Richter’s transformation, do much worse than those patients who have CLL [who] do not get treatment and then develop Richter’s transformation. This most likely is a reflection on the disease itself. The CLL that requires treatment is probably more aggressive and then therefore more likely to turn into Richter’s transformation. It's also probably a surrogate for clonal relationship. Clonal relationship is when CLL literally turns into the Richter’s transformation, vs not clonally related, which is CLL and you just so happen to get diffuse large B-cell lymphoma [DLBCL]. And just like we know in cancer in general, whenever cancer turns into another cancer, it's never a good thing, right? And so clonally-related CLL prior treated turning into Richter’s do much worse.

About 90% of patients have had prior CLL treatment or have clonally related disease, so the majority don't do great. So my general approach to the treatment of Richter’s is if they, if you think that they will be chemo-responsive, which is a rarity, I use a chemotherapy backbone, and I'll use R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], but I like the combination of the venetoclax–R-CHOP, which is based off of [Dr] Matt Davids’ study that showed high overall response rates when you target both the CLL and the DLBCL. Additionally, I've been involved with a clinical trial that is out of Cornell by Dr John Allan, which is combination of PolaR-EPOCH [polatuzumab vedotin (Polivy)-chemoimmunotherapy] for Richter’s transformation, and those patients we presented at ASH also had a high overall response rate. So my overall approach, if I don't have a clinical trial for first-line Richter’s, is actually going to be now, venetoclax–Pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone]. And the reason why it's Pola-R-CHP is that Richter’s is classically a non-GCB [germinal center B-cell] DLBCL. Now, if I decide I don't want to use chemotherapy as all, I typically will grab for 1 of these 3 options: either pirtobrutinib [Jaypirca]-venetoclax-obinituzumab, which showed great data out of MD Anderson that was recently presented at ASH; I also like the addition of the tislelizumab [Tevimbra] plus standard zanubrutinib data that were added to the NCCN guidelines. Tislelizumab is a PD-1 inhibitor; Richter’s likes to express PD-1. And last but not least is bispecific antibodies, and I'll usually pair that with a BTK inhibitor.

So those are my 4 approaches. I tend to look at whether I think somebody's going to be chemo-responsive based on what they received in the past; if I think so, then I’ll do venetoclax–Pola-R-CHP, and if I want to use something novel, I'll do tislelizumab-zanubrutinib, epcor[itamab; Epkinly]-BTK inhibitor, or pirtobrutinib-venetoclax-obinutuzumab. In general, I just want to encourage everybody to think about Richter’s as being DLBCL plus. Think about not just using chemoimmunotherapy; if that's what you're used to, try to add on something that directly targets the CLL as well. And those patients should always be considered for consolidation either with [chimeric antigen receptor T-cell therapy] or with [allogeneic hematopoietic stem cell transplantation].

Braunstein: Yeah, that's an interesting way to look at it, because essentially, the regimens you're suggesting based on those studies are DLBCL mixed with CLL-based agents. So hopefully, [there’s] more hope on the horizon for those less common patients who have Richter’s transformation.

So to wrap things up, we'll do one rapid fire question about one piece of advice for an oncologist navigating the expanding CLL landscape in 2026 and maybe I'll start and let you close us out. I think that, other than coming to see you for an expert consultation, I think one piece of advice, I would say, is that you have to really tailor the various options to the patient's biology, to their preferences, and to their risk status. And I think that a clinical trial is obviously always a valid option, especially with the incredible results we're seeing in frontline trials. And so, I think that it's really about tailoring the choice of therapy, but we certainly have options for time-defined therapy that we've been discussing and that, I think is something that that patients will certainly appreciate. What's your one piece of advice, [Dr Kittai]?

Kittai: I want to echo what you just said. A lot of our therapies that we currently have work well for most patients, and so I think we're at a time when we can really decide what to treat our patients with based on their preference and what works best for their lifestyle. Ultimately, all of our therapies are quite effective, all of our therapies are quite safe, and we live in an era in CLL where we can take a pill and keep our cancer away and so [it’s a] really exciting time in CLL, hoping that we attain a cure. We're not there yet, and we still need to enroll our patients onto clinical trials, because despite how well our frontline therapies work, they are still not completely safe, and they are still not curable. So, enroll patients to clinical trials, but if we can't, at least our therapies work quite well and are safe.

Braunstein: Excellent point. Well, I really enjoyed talking to you today, [Dr Kittai], about this. I'm really looking forward to you joining us at NYU and hope we have more discussions like this as the treatment landscape evolves.

Kittai: Of course, it's been great.