Braunstein: I am Marc Braunstein, and I am the associate professor of medicine at Perlmutter Cancer Center, NYU Grossman School of Medicine, and I treat patients with lymphoma and multiple myeloma. And I am joined by my co-host, John Burke, who can go ahead and introduce himself. Burke: Thanks, Marc. I'm John Burke. I practice at Rocky Mountain Cancer Centers in the Denver, Colorado metro area. I focus in my practice on lymphoma, multiple myeloma, and CLL. Braunstein: So this should be a good discussion. It's been a refinement here for lymphoma, where we have all these new therapies, bispecific antibodies, CAR T-cell therapies, targeted therapies, and next-generation BTK inhibitors. But I think there's still some debate on what the optimal sequences in CLL. So maybe we should start the discussion about continuous vs fixed-duration therapy. Because when we see a new patient who needs treatment, I think this is one of the main considerations. So, looking at the SEQUOIA study, which we had a recent update of the 5-year follow up of phase 3 study of zanubrutinib [Brukinsa] vs bendamustine and rituximab [Rituxan] in patients with treatment naive CLL or SLL. I think for young, fit patients, how do you decide, John, about whether you're going to give the patient a continuous covalent BTK inhibitor or maybe a time-defined therapy? Because there is that that chance that they will relapse on the BTK inhibitor and maybe that breeds certain degree of resistance. Do you think we've moved away from immunotherapy? How do you make that decision? Burke: So, it's a good question. And to even make the question more complicated, I think one could also now consider MRD-driven duration of therapy. I think of it as 3 different options now: continuous BTK, fixed durationÑwhich we've been doing both of those for years nowÑand now we have this MRD-driven option from the FLAIR trial that that makes it even even more challenging for me. So how do I decide? My answer is I really don't. It's more the patient who decides more than me. I will tell you that pretty much all patients in my practice hear about all these options and are involved in a shared the process of decision making where we talk about the pros and cons of these different approaches, and usually they make the call. I will say that most patients with treatment-naive CLL who are going to embark on therapy choose a fixed-duration option and not an indefinite BTK inhibitor option. So, that's what my practice tends to be. But I do give folks the option of doing both things. I think, to direct the conversation to ASH and the CLL-17 trial, which, directly compared those options, with the 3 arms of the trial being ibrutinib [Imbruvica] until progression, fixed-duration ibrutinib-venetoclax [Venclexta] for a year, or fixed duration obinutuzumab [Gazvya]-venetoclax for a year. What that trial showed us at ASH was that the rate of progression-free survival at 3 years was the same in all groups. And the overall survival, statistically at 3 years, was the same in all groups with a slight increase in infectious deaths in the venetoclax-obinutuzumab group, due to COVID-19, mostly. But it sort of confirmed to me that what we've been doing for a long time, which is giving patients all of the options, because we weren't sure which is better, is a still a reasonable thing to do because there's not, to me, a clear winner. And so I take from the CLL-17 study that we heard about that all 3 options are reasonable, and they all lead to good outcomes for most patients. Braunstein": And that study which was published in The New England Journal of Medicine and with the primary outcome being noninferiority between the three groups of venetoclax-obinutuzumab, venetocla-ibrutinib, or indefinite ibrutinib, it's interesting that you do have options, but I think that we've clearly moved away from giving chemoimmunotherapy for patients when we have our options of targeted therapy, some of which could be time limited. And at ASH we also saw the BRUIN CLL-314 study that looked at ibrutinib vs rituximab-bendamustine as first-line treatment, and that was also superior. So, I think that for for newly diagnosed patients, we can have a discussion about time-limited therapy vs indefinite BTK inhibitor. But I think those have become the standard-of-care options now as opposed to using chemoimmunotherap. Are there any patients in your practice where you're using chemoimmunotherapy for your typical CLL or SLL patients who don't have any signs of transformation or anything like that? Burke: Zero. I have not done that in years. Braunstein: I would agree. The the other study that I think is worth mentioning was the AMPLIFY study that was published this year that looked at also fixed-duration combination of a BTK inhibitor with a BCL2 inhibitor, with or without, a monoclonal antibody against CD20. And it's interesting that we're now in a time where we can combine these agents for a fixed duration and still get pretty substantial progression-free survival. But in several of these studies, including AMPLIFY, they excluded patients with TP53 mutations, which, as we know, are higher risk. So, for these patients, not just the ones with the unmutated status, which seems to be sensitive to many of these BTK/BCL3 regimens, for the patients with TP53 mutations, do approach those differently? Or, do you consider fixed-duration or continuous therapy differently in that subset? Burke: I think I might have a different perspective than some, so I'll give you a long-winded answer, maybe trying to touch on some of the trials you mentioned. I think in the last few years, the expert opinion has been that because patients that are high risk, defined by deletion 17p or TP53 mutation, have a appear to have a longer progression-free survival with continuous BTK inhibition as compared with fixed duration. Say they should receive that therapy. And that's been the the expert opinion. And I think that's reasonable, although logic does have the limitation that you alluded to earlier, which is that, well, we don't really know that that improves overall survival, which is what's most important to the patients. And when those patients do relapse from their BTK inhibitor, they have lost that line of therapy. Whereas if you treat somebody with venetoclax-obinutuzumab and they relapse at a relatively short interval of, say, 2 or 3 years, they might still be sensitive to it. And you haven't yet lost that line of therapy, so the net overall survival could be the same. So, prior to recently, I think my approach has been to offer, again, the same options we talked about to all patients, with the caveat that I steer them towards continuous BTK inhibitor therapy for the purposes of that PFS. But I acknowledge that I don't really know that that for sure is the best treatment that's going to lead to the longest survival, and that it's very reasonable if they prefer to do a fixed duration. I certainly allow that. So that has been my practice. Where I think you alluded to AMPLIFY with the the doublet of acalabrutinib [Calquence] and venetoclax being, in theory, the winner there with less progression-free survival but better overall survival than the other two options of FCR and the triplet in that trial. For me, interpretation of AMPLIFY, the triplet makes me nervous. I realize that the PFS looks good, especially in the unmutated IGHV patients with the triplet. But because the toxicities, which admittedly were largely COVID-related, so maybe that problem goes away. But I'm not totally sure of that. And so the added infectious risks with the triplet makes me nervous. So for me personally, I don't see incorporating those triplet regimens into my practice, routinely, even for unmutated IGHV. Which brings me to, well, what what do we do for those higher-risk IGHV mutation patients? And I think the FLAIR data are very strong, demonstrating not only improved progression-free survival with MRD-driven ibrutinib plus venetoclax, but a significant improvement in overall survival in the IGHV-unmutated patients with that MRD-driven doublet. So that is sure something I'm giving thought to. And they presented some interesting, not definitive data at ASH, but interesting data that, going back, they sequenced everyone even though they didn't allow the deletion 17p patients on the trial. But they found, I think it was 11 or so patients that had TP53 mutations, which none of them had relapsed with the with the MRD-driven duration. And they also had not developed BTK mutations. So unlike the patients treated on the other arm with the ibrutinib continuous, who did develop BTK mutations, the doublets might be preventing development of BTK resistance mutations, perhaps by causing these deep remissions that don't allow such mutations to develop, at least to the level of clinical significance that we can detect. So I found the FLAIR data to be really interesting at ASH this year, and it has me thinking seriously about using those oral BTK plus BCL2 inhibitor doublets, arguably for a longer period of time than I have been doing until now. Braunstein: You make a good point. I don't check MRD on all my CLL patients. I think that it is becoming clearer that it's an important factor to consider, especially in patients with high-risk mutations, to have that discussion about whether it's safe to discontinue therapy. So that might be my future strategy for those folks, especially as you asked about the TP53 aberrant patients, maybe maybe go longer-term with the with the all-oral doublet, maybe track that MRD. I don't know that we know what to do once they achieve MRD negativity. Do you keep it going? Or do you stop both, as they did with all the patients on the FLAIR trial? I don't know. So that's an interesting question. And that that algorithm was what Peter Hillman, one of the FLAIR co-investigators or lead investigators proposed for those folks. So now we have our patient on BTK inhibitor and they've progressed. Do you reach for a noncovalent inhibitor like pirtobrutinib, or do you tend to switch mechanisms? Or does it come down to certain comorbidities or patient-related factors or prior exposure? What are some of your considerations for that next line of therapy? Burke: Just to link that question to the to the BRUIN CLL-321 trial, which took patients post BTK inhibitor and randomly assigned them to pirtobrutinib vs control arm, which was idelalisib-rituximab or rituximab. Half the patients on that trial had received prior venetoclax, and the other half had not and demonstrated activity in all the patients. That has led to the recent full FDA approval of pirtobrutinib for second line and beyond. So I think when you have a patient who gets frontline BTK inhibitor, as you ask, and now is progressing, what do you do? You have 2 obvious choices. There is pirtobrutinib and it now has an approval for that based on CLL-321 or the venetoclax-rituximab combination. This is a scenario that has less data, or we don't have a direct head-to-head trial here to answer that question. IÕm not sure we ever will. So I think that's the scenario where I'm just going to discuss with my patients. I don't have a strong opinion that one way is better than another. And I think it's going to come down to patient preference with theoretical pros and cons more than anything else. So that's my my take on it. I don't know about yours, but it's hard to be dogmatic about what to do with that patient. Braunstein: I think to your previous point about the time-defined therapy, that does give you a gap between their first-line therapy and their next line. And you may even be able to rechallenge patients if they've had a gap of a certain period of time, whether it's 1, 2, or more years. But someone directly progresses on it, I agree, it comes down to a conversation. I think also in the future will probably be routinely checking BTK mutations and seeing if they have a mutation that's sensitive to a drug. So 2026 is here. Tell us what what you're looking forward to. Burke: I think in CLL, I know we're going to get more data on the MRD-driven doublet duration in TP53. The FLAIR investigators talked about how they added a cohort of those patients. So we're going to get more information on on those folks, so that'll be interesting to see. I'm going to predict that they saw good things with that combination. But we'll see. I have no insight as to the actual data, so that'll be interesting to guide frontline therapy a little bit better for those folks. Other things in CLL that are of interest, of course, the BTK degraders, to my eye, looked extremely effective in heavily pretreated patients with response rates in the 80 and 90% range and reasonable tolerability. Early days, but we know those are now moving into label-enabling trials. And so I don't know if they'll be available in 2026 commercially, but certainly 2027, 2028, those should be on the market for CLL would be my prediction. And they look good to me. So, thinking longer term, they may be good enough where we're moving them forward to the earlier lines of therapy would be would be my guess. So I would say that's my highlight and the modality I would be most enthusiastic about here in the short term. Braunstein: I completely agree. I'm not sure how much to add other than maybe we'll be seeing more use of time-defined therapy in the first line and then have have even more options at our disposal in something like therapy and kind of really prolonging, duration of remission in these patients, which is pretty remarkable.