Dr. Nicole Lamanna:
Welcome to The ASCO Post Roundtable Series on Treatment Approaches to Relapsed/Refractory CLL. I'm Dr. Nicole Lamanna, Professor of Medicine and CLL specialist at Columbia University Medical Center in New York. Joining me today are two of my esteemed colleagues, and if you wouldn't mind to introduce yourself. John, you want to start?
John Allan:
Yeah. Hi, everyone. I'm John Allan. I am also New York City at Weill Cornell as an Associate Professor of Clinical Medicine.
Dr. Nicole Lamanna:
Inhye?
Inhye Ahn:
Hi, everyone. I'm Inhye Ahn. I'm an Assistant Professor and CLL specialist at Dana-Farber Cancer Institute in Boston.
Dr. Nicole Lamanna:
Again, thank you guys really for joining me today. We're going to be discussing treatment and management of relapse refractory chronic lymphocytic leukemia with three patient case studies. Hopefully these case studies will really go over in a more detailed fashion the different options that we have for our CLL patients given that we have so many options now, which can sometimes get confusing. And so hopefully these cases will help highlight certain differences and nuances. Our second installment with focus on the second-line treatment of a CLL patient with deletion 11q and unmutated IGHV.
This is a 71-year-old gentleman who presented in 2014 with symptomatic CLL after he was monitored for a period of about 4 years. He then developed progressive fatigue and weight loss and organomegaly and bulky lymph nodes. He had an unmutated IGHV and deletion 11q. He initially was treated with ibrutinib at 420 mg daily. He then developed progressive disease after 5 years.
Let's talk about in second-line treatment options what are the considerations for treatments because I know there are many. And then I want to throw out some different to incorporate in your discussion of what you would offer this type of patient. Do we test for BTK resistance? What is the standard? What are the options for that, and what does that mean potentially for the patient? Would you retest their cytogenetics, their 17p, TP53, and their mutational status? How do you choose between the best option now that he has progressive disease that's been confirmed? Do you incorporate the discussion of resistant mutations to the patient in your discussion?
Maybe we'll start this case. John, you want to start first?
John Allan:
Yeah, so this is a patient progressing 5 years later, which is not an uncommon scenario. We can see this happening. I've had many patients start to progress 7, 8 years out, so there are some high-risk features here. This is not an unexpected thing and you have to be ready for it. Even in chemo-naive patients, they've never seen chemotherapy, they can still become resistant to these drugs like ibrutinib and other BTK inhibitors.
Regarding the second choice of therapy, it really comes down to what you used first, frankly. If you were on a covalent BTK inhibitor as this patient, typically the standard approach is to use a venetoclax-based approach. That's based on some of the MURANO data or venetoclax/rituximab. The guidelines actually now are recommending just to substitute rituximab with obinutuzumab because we have multiple clinical trials showing that obinutuzumab is a superior antibody in the CLL space. We can manage the toxicity slightly increased there.
In general, we tend to reach for venetoclax. I typically reach for venetoclax in my patient population if they are venetoclax-naive, but we are now having a new class of drugs, non-covalent BTK inhibitors like pirtobrutinib, start to become available. Right now currently approved after double exposure, but presumably that will be a little bit broader in that we can reach for a venetoclax-based approach or a reversible BTK inhibitor like pirtobrutinib. And so this will continue to evolve over time.
I tend to use a venetoclax-based approach if they are still naive. I do think with the antibody it can probably allow finally for the first time after many years a potential fixed duration. This doesn't need to be continual therapy, but obviously with venetoclax you come down to the logistics and the renal function that you need and, again, age. All these things start to come into play, whereas they may have been a younger patient when they started out and now they're in their mid-70s, maybe venetoclax isn't the best approach. That's where we might reach for some of these other agents.
It comes down to a little bit of imperfect data to really tell us what is the best sequence to use. Right now we can use various sequences depending on what we started with essentially, and I think though in my practice I typically reach for that venetoclax or obinutuzumab-based approach, whether it's 1 or 2 years depends on somewhat response, and again some nuance. The standard would be a 2-year approach in that setting.
Dr. Nicole Lamanna:
Inhye, you want to comment about what you would do in this scenario as well?
Inhye Ahn:
Sure. I totally agree with Dr. Allan's recommendations on using venetoclax-based approach while non-covalent BTK inhibitor pirtobrutinib is also allowed per the NCCN guidelines.
In terms of the addition of monoclonal antibody, I prefer obinutuzumab given the more favorable progression-free survival that is shown in the treatment-naive setting, not the relapsed/refractory. But still that's a reasonable choice. And then in terms of the duration, I follow the MURANO study which used venetoclax plus monoclonal antibody for 2 years in total.
That said, the MURANO study did not include patients who were exposed to the BTK inhibitor. We do have very little data on that. I think the closest data that we have is the VENICE trial, which used single agent venetoclax. I think half of the patients had a prior BTK inhibitor, not the refractoriness like this patient, but exposure. In those small population, the progression-free survival seemed to be a little bit shorter than a BTK inhibitor–naive patients. I'll be very upfront to this patient that venetoclax plus monoclonal antibody may last about 2 years for this patient based on the best existing data.
Dr. Nicole Lamanna:
It's interesting because the way that some of these drugs have obviously been approved has obviously been the way we've formulated our treatment sequencing. But John, as you alluded to very eloquently that we don't know now that as we get newer agents that get approved, so we do have pirtobrutinib, but typically the way the sequence has been we've been using it after, although you can use it. The question is how the data as pirtobrutinib is moving up in clinical trials in less heavily pretreated patients, how that will influence the sequencing of these therapies.
Do any of you think that there's that notion of, well, if we stick in the same, should we exhaust the BTK pathway? Is that an important thing before going to venetoclax? Or maybe do we need to have more of these types of trials where we can see if we go from the covalent to then to then a non-covalent that the progression-free survival or are there times that their subsequent treatment might be different depending upon the way we sequence these drugs? How do we get to that kind of data?
John Allan:
Like I said, I tend to favor venetoclax. Obviously progressing on a BTK inhibitor, particularly in this case where there are chemo-naive, is saying something about the clone. It is clearly deriving resistance to B-cell receptor inhibition, and so that's why this is a high-risk clone that's progressing. We don't know anything about the BTK mutations, et cetera, but I would probably look for those even though it's not necessarily recommended to do because we don't really act on that information. But we do know that patients who have BTK mutations that are not of the C481 most common seem to have that clone grow out. While they respond equally to pirtobrutinib, if that clone is there at a subclonal level, I do fear that those patients will have an inferior outcome if we were to be able to go to from a covalent straight to a drug like pirtobrutinib. They probably will develop resistance quickly.
That's one reason to look for it and to potentially avoid it if you're seeing one of these non-C481 mutations there. Now, not a lot of data to say that that's the appropriate thing to do. But anecdotally that's what we see. That's one reason to look for the resistance. Though with that said, not necessarily a recommended thing. I do it in my practice.
I guess this is something that we did see in the BRUIN studies where the 321 looked at pirtobrutinib vs idelalisib or BR is that those patients who were venetoclax-naive basically and not double-exposed actually did pretty well and better. Now, it's hard to interpret that data because those patients who were double-exposed also had chemotherapy and were really, really high risk, and so they might break through. But it showed that you can technically go from a covalent to a reversible and have a meaningful outcome in these patients and actually can do pretty well if you are in fact sequencing in that order.
Again, it makes sense for some older patients who aren't going to be able to do the venetoclax ramp up and maybe not tolerate the antibody, or whatever it might be. There are going to be situations where we do that, although my opinion without a lot of data just treating a lot of these patients, seeing the type of MRD negativity and the responses we can get with venetoclax-based treatments, I do think that with that approach we'll probably eke out a benefit over just staying within and expending that BTK class and keeping that reversible back in the back pocket for when we need it a little bit later down the line.
Dr. Nicole Lamanna:
Inhye, knowing again what John said about the fact that we don't have a lot of data just yet but we're trying to get more of this data in all the clinical trials that are currently ongoing, do you think BTK resistant mutation testing will become more standard of care practice? How do you incorporate that into your practice currently?
Inhye Ahn:
Yeah, I think so because the tests are available in the commercial platforms and the sensitivity is pretty good. Usually 1%, but in some platforms less than 0.1%. I think we can very sensitively pick out the resistance mutations associated with covalent as well as non-covalent BTK inhibitors. As we see more and more clinical trials using non-covalent BTK inhibitors in the second or first line settings, we may have to understand what kind of genetic architecture patient has before the sequencing question is addressed. In my practice I always test for BTK mutation.
Another argument for this is that the non-covalent BTK inhibitors associated with mutations outside the C481 residue. However, the covalent BTK inhibitors like ibrutinib, acalabrutinib, and zanubrutinib can also create these mutations. When they have these non-C481 mutation, their likelihood of responding to ibrutinib theoretically is lower. I think having this information before treating them with a BTK-directed therapy would be useful in the future.
Dr. Nicole Lamanna:
Yeah, I completely agree with you both on that information.
I think just to specify also for the audience in this case, if a patient is just... We didn't talk about this at all, but certainly if they're having progression on a covalent BTK inhibitor, you are not going to change them to an alternative covalent BTK inhibitor. Just to make that obvious. If you're having a toxicity issue, you certainly can consider switching within another covalent BTK inhibitor if you go from ibrutinib to acalabrutinib or to zanubrutinib or so on and so forth. But if you're really having progression, you need to switch entirely, so not to go from one covalent to another covalent.
As both Inhye and John alluded to I think in this patient, most of us I think are more familiar because we have more data with going to a venetoclax-based regimen that a key takeaway is that many of us would go to a venetoclax antibody combination.
Maybe just to switch this case just a little bit and briefly, now if you're repeating the cytogenetics and now this patient has either a deletion 17p or TP53, how would you alter your recommendations on the treatment options for this person now?
John, you want to briefly comment?
John Allan:
Yeah, so I think you bring up a good point. A patient progressing on any of these drugs. It's been 5 years since we've reevaluated their disease. We talked about sequencing these patients, Dr. Ahn and myself are going to do that. I think it does provide some interesting information. But additionally it is wise to repeat your FISH and your karyotype because you sometimes can see new acquisition events like a deletion 17p, and you might change how you think about that patient.
Now with that said, if you see the acquisition of a new clone or this grew out or acquired this, I don't know if it changes how you think about the patient so much. I think still giving a venetoclax-based approach is still very reasonable. I think giving a reversible BTK or non-covalent BTK like pirtobrutinib is still reasonable, though it probably changes how you think about this patient, how you prognosticate for this patient, how long you might think they respond to that next line of therapy. If you start to see one lymph node maybe not responding and everything else went away, it might make you want to think, "Hey, we should maybe PET scan this patient." Are they transforming?
Because all of a sudden with these new high-risk features, you do have to think about them differently and manage them slightly closer in terms of follow up, et cetera.
Dr. Nicole Lamanna:
Inhye, anything to add to that, or you agree with John?
Inhye Ahn:
I agree with John.
The only addition that I would like to make is that the evidence of clonal evolution would help us understand why this patient progressed on ibrutinib after just 5 years. The median PFS on the BTK inhibitor with the presence of deletion 17p or TP53 aberration about 7 years. Yeah, I think that would help us understand this case better. I totally agree on closer follow up of the patients with TPF3 aberration.
Dr. Nicole Lamanna:
Good.
Just to sum up some key clinical takeaways from this case, it sounds like we're all pretty much in agreement that after a patient has progressed on a covalent BTK I think many of us would test for BTK-resistant mutations. Not yet standard of care, but just to help inform potentially for sequencing of therapies or considerations for sequencing of therapies. Whether you're going to go from a covalent to a non-covalent, that's where it might impact many of our decision-making along those lines, but certainly we need more data with that regard.
I think most of us, we all agreed that we would repeat the cytogenetics and the karyotype. But to inform us even though we still are looking to treat them with targeted therapies that are known to work well for patients with 17p or TP53, it will inform us a little bit about the fact that they are becoming more resistant or have acquired now higher risk features, which may mean that they might have a shorter duration of whichever therapy we're going to embark on in second line. And so I think we'd all want to know that even though we might still recommend a venetoclax-based approach.
I think we would all retest, and I think that's important to note because then you might have closer follow-up as both John and Inhye alluded to. Options as we talked about after BTK, covalent BTK include a venetoclax plus a monoclonal antibody. We've heard a little bit about substitution with rituximab and obinutuzumab. We know obinutuzumab is a more potent CD20 monoclonal antibody, and so many of us are substituting that even in the relapse setting. Although I think there's still some fair consideration if you think somebody is more frail to still use rituximab if you want to so do so because you're concerned. But a lot of us have substituted that in most of our patients.
Of course I think that we didn't even get to discuss this, but certainly you could think about some other combination approaches. We're hopefully going to address new future ages in clinical trials for a patient in this setting, and pirtobrutinib is a potential option moving up in lines of therapy.
With that, we're going to conclude case two. This brings us to the end, and please see our other segments for further discussion about the latest research in relapsed/refractory CLL or visit ascopost.com. Thank you both again for joining me.
