Episode 51: Treating Relapsed/Refractory CLL

Dr. Matt Davids of the Dana Farber Cancer Institute joins Healthcare Unfiltered EXPRESS to share his data-solidified insights on navigating the treatment of relapsed/refractory (R/R) CLL, considering the welcome advances the field has witnessed in treating front-line disease. Check it out, subscribe, rate, and join the conversation.

Transcript

SPEAKER_00 0:02

Matt, welcome to the show. I really appreciate taking time uh to come on healthcare on Filtered Express. Thanks, Shadi.

SPEAKER_01 0:08

It's a pleasure to be here.

SPEAKER_00 0:09

And congrats on uh uh beautiful paper you wrote, you and and Mazer uh in blood. Really very good. Uh advise everybody who's watching and listening to to take a look at the paper in blood. So congrats on that.

SPEAKER_01 0:21

Thanks so much.

SPEAKER_00 0:22

I know it's hard sometimes to cover a complex topic in a short period of time, but but I know you had to do it many times when you teach fellows, residents, and even patients and families. So our task today is try to talk about treating relapsed and or refractory CLL. Um so I don't know. I mean, how do you how do you approach this? What's what goes through your mind when you see a patient being referred to you with this kind of disease?

SPEAKER_01 0:49

So I guess one of the first thoughts that crosses my mind is what what's the prior treatment and what's been the course of this patient? You know, is this patient maybe who had a sprinkle of Rituximab a few years ago and that's it, and now they need treatment? That's a patient where I'm treating them kind of like a frontline patient. Is this a patient who's had multiple rounds of chemoimmunotherapy in the past? No, there I am not seeing as many of those patients, but there's still some. And I think about all the different targeted therapies that we have. But I would say increasingly in my practice, what I'm seeing is patients progressing on the covalent BTK inhibitors, the abrupt nib, a calbrut nibs, an abrupt nibs, or I'm seeing patients who had a vaneticlax time-limited regimen, and now it's a few years later and they're relapsing. And then increasingly, like the subject of the paper you mentioned, I'm seeing more and more patients who've had both. They've already had a covalent BTK inhibitor and progressed, and they've had venetoclax and progressed, and this is sort of the double refractory group.

SPEAKER_00 1:40

So before you, before you uh before you decide how you're gonna approach this, um, do you still risk stratify these patients? Uh, does this play a role in making the decision, or is it less important you focus more on the type of therapies they receive?

SPEAKER_01 1:57

I do think it's still important, particularly checking TP53 status, because we know there's patients who can start out with CLL and not have that mutation or deletion, uh, but over time they can acquire that with the addition of therapy. And that's, I think, particularly relevant for younger fit patients, where we may be thinking about more aggressive interventions, even down the line, things like allogenaic transplant or CART-based therapy. You know, for your typical CLL patient who's older and frailer, it's maybe a little bit less relevant therapeutically, but it does still have prognostic value.

SPEAKER_00 2:27

So let's take the first example you mentioned. Somebody, the few patients that may have still received prior chemoimmunotherapy in the past. And as you mentioned, they're becoming fewer and fewer. For these patients, um, what do you do?

SPEAKER_01 2:42

So, you know, certainly it's a conversation around BTK inhibitors given continuously versus a time-limited venetoclax-based regimen. In the relapse setting, sort of the purest view would be to use venetoclax with rituximab. This is based on the Murano trial, where that was the experimental arm and showed excellent results as a two-year time-limited therapy. It's challenging though in CLL because we have randomized data in the frontline setting that shows that obinetuzimab is superior to Rituximab with regard to efficacy in that population. And so I would say I if I'm using Venetaclax now in the relapse setting, even in that post-chemo population, I would typically use Venetaclax with Obinatuzimab. Now, there's not a lot of data to support that, but it is in the NCCN guidelines. So we usually do get it paid for. And we do typically still do the two-year course of Venetaclax. So that's sort of weighing those pros and cons. Continuous BTKI, very convenient, easy approach, well tolerated by most patients, but does require continuous treatment versus that two-year Venetaclax time-limited therapy, which is also well tolerated, uh, involves a little more logistical complexity to start. Uh, but then you get that long break, hopefully, off of treatment.

SPEAKER_00 3:49

Is there any reason to I've I've heard sometimes that folks say I will use if it's 17p deletion, I'm going to use a BTKI. Do you do you feel that this is a must or I wouldn't say it's a must.

SPEAKER_01 4:04

I would say it's it's typically still my preference also to use a continuous treatment with a covalent BTKI, particularly in the frontline setting, but I think it also applies here in the relapse setting because we do have the longest-term data with that approach. And it seems like we're getting the longest progression-free survival. With venetoclax-based treatment, we can also get a good progression-free survival. It's just a bit shorter than for patients who don't have TP53 aberration. Um, on the other hand, that opens up the possibility of retreatment strategies with venetoclax. So, in terms of getting to that next PFS, sort of PFS2, we actually don't know yet what's better, sort of intermittent venetoclax therapy or continuous covalent BDKI. And a lot of that's going to hinge on the efficacy of retreatment data with venetoclax. And uh, and that'll give me an opportunity to plug a study that I presented at the EHA and ICML meetings, the so-called revenge study or revenge. So this is retreatment with Vengi, Venetaclax Obentitusimab for patients who previously had Venetaclax in the frontline setting. And we did allow patients with TP53 aberration as well. Very early presentation. We only have data on the first 25 patients so far, but we are seeing responses in all the patients who have reached the first spot response evaluation and very good tolerability. So I think as we accumulate more of this retreatment data with veneticlax, it's going to open up the possibility of using it more in that high-risk population.

SPEAKER_00 5:21

Does it matter how long they've maintained the response, like the duration of or the treatment-free interval to decide on retreatment?

SPEAKER_01 5:28

It does. So in the trial, we used a minimum of one year of remission from initial veneticlax to even be eligible. And that's actually more of an experimental cohort of the study, one to two years. Really, the main cohort of the study was two years or longer of initial remission, would qualify you for that main cohort. Because if you're relapsing shorter than a year or two after venetic lax, it's unlikely you're going to have durable benefit from venetoclax again.

SPEAKER_00 5:51

So now you get a patient who has is progressing on BTKIs. What do you do?

SPEAKER_01 5:57

So one really important distinction, I want to get this message out there, is that you have to know that they're really progressing well on the BTKI before you would want to switch mechanisms or switch to a different class even within BTKI. And the reason I mentioned that is I do sometimes see patients who have intolerance to a covalent BTKI, even xanabrut nib, acalibrut nib occasionally. And so the drug is held and then they progress. But that's not really progressing on the drug. And these are actually patients you can sometimes rotate within the class, particularly if it was a brut nib that led to intolerance. You can give the patient a break and then put them on acalibrut nib or xanabrut nib. In contrast, if you have a patient who's actually progressing well on a covalent BTK inhibitor, you don't want to switch to a different covalent BTK inhibitor. And that's because these covalent inhibitors all have common resistance mechanisms, usually this BTK C481 type of mutation, but there are others. So if the patient's really progressing on covalent BTKI, there's kind of two main options now. I'd say most of the time I'm switching patients to Venetaclax if they haven't had it before, and we expect a very good response there. But the other option to consider is actually switching to the non-covalent BTK inhibitor pertebruten nib, which has a totally different spectrum of resistance mutations and is very likely to work in patients who are progressing on a covalent BTKI. And so we have good data now supporting both approaches. Uh, and I think a lot of it comes down to some of the same conversations we have in the frontline setting around convenience, familiarity with class, uh, and uh and also sort of whether the logistics of the Venetaclax ramp up are feasible for patients and for the physicians.

SPEAKER_00 7:25

Makes a lot of sense. Let's flip it now. You have somebody who progressed on Ben or Bintuzumab um in the frontline setting. Um I know you mentioned the retreatment is an option, uh but uh if you're not gonna retreat, uh do you just do go to BTKIs?

SPEAKER_01 7:43

Yeah, so typically then I would go to a covalent BTKI. Um I'm a little bit less confident about that approach, mainly just because we don't have a lot of prospective data there, really very little, actually. We have some retrospective studies that do suggest that a BTK inhibitor will be very effective post-pheneticlox. Uh, but it'd be nice to have a little more prospective trial data there. Um, but nonetheless, the retrospective data suggest about 85 to 90% response rate and PFS in the sort of three three-year range or so. And that's pretty consistent with what I've seen in my clinical practice. So I think you can probably go in either order, Venn to BTKI or BTKI to Venn.

SPEAKER_00 8:18

You are gonna see these patients come in your way who have progressed on both. Um, what are you doing there?

SPEAKER_01 8:25

Yeah, so this was really the focus of the article that I wrote with Mausier and Blood. This is a very challenging population. There was an initial series from a group in Australia that looked at their double refractory patients and showed a median overall survival of only about five to six months. Um, even if it was CLL or Richters, it didn't matter. Uh, we actually recently did a retrospective study uh in our population from Dana Farber and showed actually more like two years median PFS in that double refractory group, suggesting that we do have better options now for these patients. And one of them is certainly pertabrutnib. You know, that would sort of be my go-to for the typical patient who's double refractory, expected probably about an 80 to 85% overall response rate and a median PFS in the range of about a year to a year and a half. Uh, so it's much better than it was a few years ago now that we have pertabrutnib. We do also have lysocel uh approved for CLL in that double refractory population. Uh, it's got about a 20% CR rate. And so it's not as high as what we expect in other lymphomas. For those patients who do get to a CR with lysocel, they can have very durable response. Actually, none of them had progressed with a couple years of follow-up. So the challenge is really identifying who are gonna be those patients who are gonna respond well to lysocell or not, and we're still kind of struggling with figuring that out. Um, there's a lot of promising stuff on the horizon. We mentioned this in the article as well. Uh, things like bi-specific antibodies are being explored now in CLL. We also have BTK degraders that are coming along nicely. So I think we're gonna have more options, but I'd say right now in clinical practice, usually perdebrutinib should be the go-to for that double refractory population.

SPEAKER_00 9:53

I guess my last question to you, Matt, is uh are you integrating any MRD in the decision making for treatment of relapse disease outside of trials? I know a lot of trials are looking at this in your real-world practice.

SPEAKER_01 10:07

In my practice, I would say if I'm using a vaneticlax-based regimen, I am typically checking MRD along the way to have some extra information. Why is that useful? So, one example might be a patient who you're planning on a two-year course of veneticlax for relapse CLL, but you're running into issues with toxicity. Maybe it's neutropenia and infections, you're dose reducing, you're giving growth factor support. If you have that MRD that you've been tracking along and it's become undetectable, maybe you don't push it for those last six, eight months, whatever it is. You know that they've already had a good response and you can stop therapy early. Uh, so that's a sort of a real world scenario of how I find MRD to be useful. On the flip side, I'm not someone who's using MRD detectability at the end of treatment to extend therapy longer. That's really not been proven to be effective. I do worry theoretically, if you're extending therapy for longer, you're increasing the risk of resistance, for example. And so I'm sticking to the trial data in terms of the length of therapy, with the exception of occasionally shortening therapy for patients with toxicity.

unknown 11:03

Dr.

SPEAKER_00 11:03

Matt Davids, thank you so much for coming on Healthcare on Filtered Express. This was really very helpful.

SPEAKER_01 11:08

My pleasure. Thanks, Shadi.