Dr. Nicole Lamanna:
Welcome to The ASCO Post Roundtable Series on Treatment Approaches to Relapsed/Refractory CLL. I'm Dr. Nicole Lamanna, a Professor of Medicine and CLL specialist at Columbia University Medical Center in New York. I am joined by two of my esteemed colleagues, and if you don't mind introducing yourself, Inhye, we'll start with you.
Inhye Ahn:
Hi, I'm Inhye Ahn. I'm an Assistant Professor and CLL specialist at Dana-Farber Cancer Institute in Boston.
Dr. Nicole Lamanna:
John.
John Allan:
Hi, I'm John Allan, and I'm Associate Professor of Clinical Medicine at Weill Cornell, also in New York City with Dr. Lamanna.
Dr. Nicole Lamanna:
So today we'll be discussing the treatment and management of relapsed/refractory chronic lymphocytic leukemia with three patient cases. And hopefully, this will be informative about, because we have so many now potential options for CLL, it can get a little confusing, and hopefully some of the details of the case. We can bring out a robust discussion about how we look at and approach patients with different features, and age, and comorbidities, and so on and so forth. Given all our treatment options.
So our final installment will focus on third-line treatment of a patient with deletion 13q, trisomy 12, and unmutated IGHV. This is LS, who originally presented with a white count of 13, normal hemoglobin and platelets. The flow is consistent with CLL, and she was observed for 4 years. She then developed progressive disease; some weight loss, splenomegaly and lymphadenopathy. Her white count was much higher now, 220. She was now anemic, with a hemoglobin of 9.4. Platelets were about 102. She is unmutated IGHV, TP53 wild-type, but had a 13q deletion in trisomy 12.
She was initially treated with acalabrutinib for 4 years, but developed progressive disease, and then received venetoclax and rituximab for 2 years. She was monitored, but developed progressive disease approximately 30 months off therapy.
So now she's a little older, of course. She's in her mid-70s, about 74. And so let's, I think we can have a really robust discussion about what treatment options are now that she's had several lines of therapy. So for consideration in your discussion, hopefully we could talk about re-treatment. So is venetoclax-based therapy an option for her now? And also maybe we could talk a little bit about the response duration, whether or not that's a consideration, depending upon the timing of how long she's been off of the venetoclax/rituximab. And then I really want to have you guys talk to us about CAR-T and clinical trials, so we can have a focus on that. So maybe, Inhye, you want to start with this one?
Inhye Ahn:
Yeah. So as you alluded to, we're talking about a third-line therapy for this patient who had been progressive on acalabrutinib and developed a relapsing disease after venetoclax and rituximab. And that's after 30 months. I think 30 months is a substantial gap from the last dose of venetoclax. So this could still be a venetoclax-sensitive disease. And there is some data from the MURANO study that the re-treatment with venetoclax and rituximab, or other monoclonal antibody, is feasible, although, may not be as long-lasting in this covalent BTKi refractory patient.
The other option is non-covalent BTK inhibitor pirtobrutinib, which works in the post-covalent BTKi refractory disease setting. And the expectation from the BRUIN CLL-321 study is that the time to next treatment or death was about 20 months for both BCL-2 and BTK inhibitor exposed patient population.
And lastly, liso-cel, which is a CD19 CAR T-cell product is approved, but there has been some reservations, about 20% of the patients achieved complete responses. And these are really the patients who benefit the most from the CAR T-cell product. The remainder of the patients who achieved either partial responses, stable diseases, or even progressive diseases, did not benefit at all in terms of the durability of response after the CAR T-cell procedure.
Also, there is increased costs; definitely a hospitalization and the need for a really close care provider at the time of the CAR T-cell infusion. So a lot to consider when thinking about cellular therapy in this patient population.
Dr. Nicole Lamanna:
John, you want to add to that a little bit?
John Allan:
Yeah. I think this is where we have a lot of options for the patients. Obviously, having progressed on a covalent BTK inhibitor and now progressing about close to 2 1/2, 3 years after a venetoclax/rituximab, I probably wouldn't reach for a covalent again. Though you could argue maybe that clonal architecture has changed. Maybe a BTK mutation clone is gone, and maybe there can. Before we had reversible BTK inhibitors, we did do this, in fact. And we could eke out some, in fact, benefit and efficacy, given the fact that we have good drugs that were designed specifically for this space. I don't typically do that nowadays, because we do have these reversible non-covalent BTK inhibitors like pirtobrutinib. But I agree with Dr. Ahn, this 2 ½ (years) to 30 months remission is probably enough. They used rituximab as this second-line treatment. This is a scenario. If we do go back there, I definitely would put in obinutuzumab, and maybe we can eke out some similar benefit in another 30 month plus remission with that. So I think it's reasonable.
But again, you have to consider, the patient is now 74. That was almost 5 years prior that they got venetoclax/rituximab. Are these same comorbidities the same? Are the patient preferences, where they are in their life stage? Again, a shared decision making process, you constantly have to reevaluate these things. And a reversible BTK inhibitor is very easy to go.
And given the toxicity, and the less than, I guess, hopeful responses, where we see only 20% of patients having these deep remissions, I'm probably reaching for either re-treatment or a reversible non-covalent BTK inhibitor. And maybe in this scenario, where they are in their life stage, probably a non-covalent like pirtobrutinib to get us maybe another 2 years down the line, at which point we can maybe talk about venetoclax. But again, lots of options. No real absolute standard here. Again, reevaluating disease state, disease biologic features, and patient preferences, and your physician comfortability to provide for these therapies.
Dr. Nicole Lamanna:
So it sounds like, and I think we're all in agreement, that this particular patient, I'm going to change it up. But this particular patient would be an option either for venetoclax re-treatment, plus or minus an antibody, right, given what we know from the data, that they've gone a long time. Obviously, we didn't discuss, although Inhye alluded to this, and there's obviously the trial that your group is doing, Inhye, with the ReVenG study, looking at the timing of re-treatment for somebody who's been off of venetoclax. I think many of us would feel uncomfortable if the patient relapsed within a short period of time after the venetoclax/rituximab. So if they relapse, maybe within less than a year, I think many of us would be like, "Oh, re-treatment may not be such a good option." But hopefully we'll have the data from a prospective study to help us clarify the timing of re-treatment for venetoclax.
But also the other option would be pirtobrutinib. And so it sounds like for this particular patient, before we talk about other things, it sounds like then re-treatment and pirtobrutinib would both be potential acceptable options for this patient currently.
Now, what if this patient was, we talked a little bit, you guys alluded to a little bit with the CAR T-cell data, because that is another available FDA approved option that... liso-cel got approved, what, it was March of 2024. So if this person was younger, knowing that they are now a covalent BTK failure, a venetoclax relapsed patient, so let's say they get venetoclax again, or get pirtobrutinib again, knowing that the response duration, as Inhye had alluded to, and they're younger, is going to run out. Before we talk about clinical trials, what do you think about, would you offer then a CAR T-cell if this patient was, let's say a little bit younger? Maybe now after those, knowing that they may only, the durability of their subsequent lines of therapy might only be less than 2 years. John, what do you think about CAR T-cell now, now that we have it available?
John Allan:
And these kind of double exposed, and you can question, let's say it was a shorter remission off venetoclax, maybe double refractory type of patients, I do think CAR T, from what we've learned, if you are in that fortunate 20% can have durable remissions, and we are actually throwing out the term cure with some of these patients. And so, it has great potential high risk, high reward though. And in these scenarios with these younger patients, it might be the one window of opportunity to actually offer it. Because if they start to get into their mid-70s or 80s, many opt not to, many of us don't think they're fit enough for it. Even though we're using liso-cel, which might have a little less toxicity, it's still got a lot of issues along with it to administer that therapeutic strategy.
And so, you do have these windows of opportunity that you also have to think about, and yes, in a younger patient double exposed and absolutely double refractory, if they're in their late 60s and pretty fit otherwise. While we have good research going on and some things in the pipeline, they're not readily available, and may not be so for another 5 years possibly. And when we're talking about pirtobrutinib, we're really looking maybe at a 2-year timeline or even shorter. So that window could close absolutely in their 60s, I think in these double exposed, maybe refractory patients, on moving towards that, because we may not get that opportunity later on.
Dr. Nicole Lamanna:
And then maybe, Inhye, you want to highlight our shameless plug then for clinical trials.
Inhye Ahn:
I think too.
Dr. Nicole Lamanna:
I think this is a good opportunity to talk about, since we've kind of talked about the potential for this patient who is covalent then and now, maybe even a non-covalent exposed, what some of the more exciting BTK degraders, bispecifics. Maybe we could just highlight a few in a summary of this patient who's gotten sort of everything that's maybe currently standard of care or potentially available.
Inhye Ahn:
Sure. I think this is an area where there's a lot of hope for our patients. And Nicole, you already highlighted the important classes, upcoming classes of therapeutic approaches.
I would add, first of all, the combination of a BTK inhibitor and the CAR T-cell therapy. There was an abstract at the last year's ASH meeting presented by Dr. Wierda at MD Anderson. There was an arm in the TRANSCEND CLL 004 study that combined a BTK inhibitor ibrutinib with liso-cel, and that did improve the rate of complete response to almost 50% of the patients. So I think that's a very smart approach. And the toxicity was not too bad. So I would definitely do that if this patient were to pursue CAR T-cell. Maybe even use pirtobrutinib as long as possible throughout the collection and after the CAR T-cell infusion, if insurance allows.
In terms of other novel agents, BTK degraders are really being heavily studied in this patient population who are either double refractory or double exposed. There are currently two molecules in phase II studies, and both of them showing really amazing response rate. Overall response rate are approaching 80% in one of the molecules. These are oral drugs, so very convenient for the patient. And one of the study has also reached the progression-free survival of almost 1 year. So that was very exciting in this heavily pretreated population.
And then the last class of a molecule is a bispecific antibody. We currently have three FDA approved bispecific antibodies that are indicated for other types of lymphomas, and they're moving on to the CLL population. Again, at the last ASH meeting, there was an abstract from one of the epcoritamab studies that introduced an additional step-up dosing, and mitigated the cytokine release syndrome, which is a toxicity of the bispecific antibody. So we now know that with a different dosing and step-up dosing schedule, we can deliver this class of a drug safely to the CLL population. That really opens the door for our patient population for older and frail.
Dr. Nicole Lamanna:
I think that that was a great summary of summary of the up and coming drugs. I think that we have a lot of excitement and hope for our multiple relapsed/refractory CLL patients. We have lots of clinical trials and combinations available.
John, if they've got nothing available, so they can't get to a clinical trial, and they've been through all these therapies, and I know that we all have done this. Is there a role for sort of, you know, the fact that they've had these therapies, but is there a role then that we could maybe combine some of the therapies they've had together previously to see if we can salvage, or enhance maybe, until one of these newer agents get approved? If there's a strategy for doing that in some of these combination approaches?
John Allan:
So I mean, we recycle these treatments when we don't have a lot of other options, and sometimes the clone has changed and there is some sensitivity that is regained. We can't forget about PI3 kinase inhibitors here. They are still FDA approved in the CLL space. And in fact, there's actually a lot of good data for PI3 kinase inhibitors in more accelerated and transforming type of CLL. Which clearly, when we're talking about this scenario where we've been through all of these therapies, that's probably what is happening here. And so we do have good data that the other inhibitory paths that PI3 kinase inhibitors hit can actually kind of help in terms of these more accelerated CLLs. We're still faced with the toxicities there, but they have been combined with venetoclax and BCL-2 inhibitors, et cetera.
And so recycling these, we can't forget about those other options. High dose methylpred, is it tried and true? It kind of gets you out of hot water. It's not something long-term. Has some issues, but can get some of these patients under control. IMiDs and lenalidomide has some data there in the CLL space. You have to watch for it. There's flares and things like that. But there are drugs that are still out there that might have some ability to get control of the disease, and possibly get the patient in a better state to get to a trial, or whatever it might be.
But yes, I mean, we do think about all of these drugs at our disposal, and we talk about the combinations, and we look for novel approaches to use, because there is a lot of data historically with some of these agents. They've just fallen out of favor many times because of toxicity.
Dr. Nicole Lamanna:
That's a great summary, and thank you for actually reminding us about the PI3 kinase inhibitors. And you're also reminding me how old I am when you bring up the IMiDs and lenalidomide, so I'm very happy that you did that. But it is true. There are these additional agents that people could go to, particularly if you don't have availability to send your patient to be on one of these clinical trials. And remember, for some of this, this might be a bridge until the next agent gets FDA approved. And so you have to consider that. Is that CLL is a journey, not a marathon. It takes a long... These patients are going to be with you, and oftentimes, particularly if they're younger, might need more than one therapy during the course of their journey. And so it's always important to think ahead.
So to conclude, let's some key clinical takeaways for this. So after a patient has progressed on a covalent BTK inhibitor and a venetoclax-based therapy, the options are a little bit more limited. So obviously, if they've had a long time since their venetoclax-based therapy, certainly re-challenging them again with a venetoclax-based combination is potentially an option for them, particularly if it's more than a year or so after they finished their venetoclax-based combination. You now can, obviously, go to a non-covalent BTK inhibitor with pirtobrutinib, and there are others in development. But you know that if they're double refractory, or they're concerned that they've had a covalent and now truly venetoclax refractory as well, that their response duration for any of these therapies is going to be shorter.
And so you do have to think, even if you're starting them on pirtobrutinib, you're going to be thinking, "Okay, what is the next line of therapy that I have to think about for this patient?", because their response duration is only going to be so long. And so now CAR T-cell we've discussed is available potentially, depending upon the comorbidities and the age of your patient with liso-cel. And yes, now they're having some, hopefully we can improve. I think a future goal of many of these CAR T-cell therapies is to try to see if we can improve that response that we saw by adding a BTK or doing some other things that may enhance the response, which we know is really important for CLL after CAR T. So if they get a complete response, that will be more durable than if they don't. And then again, exciting clinical trials that were highlighted with BTK degraders and bispecifics.
So to conclude, lots of hope for your multiple relapsed/refractory patients. This brings us to the end of this case. Please see other segments again for further discussion about the latest research in relapsed/refractory CLL, or visit ascopost.com.
And again, I want to thank my esteemed colleagues, Inhye Ahn and John Allan, for joining us today on all of these cases. Thank you both.
