Double-Class Refractory CLL in Community Practice: Current and Future Management

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Welcome to CE on ReachMD. This activity, titled “Double-Class Refractory CLL in Community Practice: Current and Future Management” is provided by Total CME.

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Dr. Mencia: 
Hello and welcome. Today we will be discussing current and future management of double-class refractory chronic lymphocytic leukemia in community practice. I'm Dr. William Mencia, and here with me today is Dr. John Byrd.

Dr. Byrd, let's get right to it. For patients with CLL who have relapsed on both a BCL2 inhibitor and a covalent BTK inhibitor, how do we differentiate if it was intolerance or if it was resistance? And how does that set us up for selecting next-line treatment options?

Dr. Byrd:
That's a great question. And with BTK inhibitors, a big dichotomy are patients who, for one reason or another, don't tolerate them and are taking them on and off, which can give the findings of progression, versus somebody who just flat is being very compliant, not having problems with symptoms. And you see either lymph nodes increasing or the lymphocyte count persistently going up. And in this setting, on a BTK inhibitor, one can differentiate by a good history and also molecular tests that often, in the setting of progression on a BTK inhibitor will show one of the—either the BTK mutations, the most common for covalent inhibitor progression is the BTK Cys41S, although gatekeeper and the 474I and the 528 and 428Ds can also show up as can PLC-gamma 2 mutations. When you see these and you see counts going up, you pretty much know you have progression, as in and the neck there becomes, say, particularly if somebody is on a BTK inhibitor, say, not stopping that without having a plan in place. Because often when people stop BTK inhibitors cold, even if it appears they're progressing, they will develop hyperprogression symptoms. They can even look like Richter's transformation with worsening cytopenias, rapidly increasing LDH. So it's really important in that setting to be ready for your next line of therapy.

Dr. Mencia:
Well, that's great information, Dr. Byrd, thank you. And as we focus on sequencing approaches in these patients with double-class refractory CLL, what information do you feel is important for community-based providers to know about applying, for example, BRUIN trial data on non-covalent BTK inhibitors into practice?

Dr. Byrd:
One of the key things when somebody is progressing on a BTK inhibitor, or has had a BTK inhibitor and then received venetoclax and is then progressing on venetoclax, is really knowing what the molecular characteristics of the CLL is at that time. And so doing a genomic study at minimum that includes, say, the coding-region of BTK and PLC-gamma 2, is important.

In the setting of having a Cys41S mutation, which is the most common mutation, or no mutations in either of those genes, my approach is to stay in the same class of drugs. So if they're on a BTK inhibitor, which often they are, I will leave them on a BTK inhibitor and transition to pirtobrutinib, which the BRUIN study showed in this population had a 70+% response. It was superior to other traditional therapies that are given in this setting, idelalisib and rituximab or bendamustine and rituximab.

The challenging part when people are coming off a covalent inhibitor is when one of the less common mutations, the PLC-gamma 2 mutation, or one of the BTK silent or kinase-dead mutations, the L528D, F528, or the A428D or the gatekeeper, the 474I, shows up, then we know from molecular studies that pirtobrutinib is not going to work. And in that setting outside of a clinical trial, first, I still wouldn’t take the patient off the covalent BTK inhibitor if they're on it. So that's going to be a patient that, if I'm in the community, I'm going to want to refer potentially for CAR T-cells or a clinical trial, or consider a doublet, and potentially adding venetoclax to the BTK inhibitor that I'm using as I'm referring the patient for CAR T-cells.

I think an important point for physicians to recognize in the community that these double-refractory patients and how we work with the molecular medicine testing to assess is pirtobrutinib an appropriate therapy, or should we be going in another direction? It is complicated, and the next step often is going to be a CAR T-cell. So having an expert, where you have access to CAR T-cells, to clinical trials at this point, is going to be important. And in the community, this is often where I encourage people to involve a CLL center to co-manage the patient.

Dr. Mencia:
That's really helpful advice, Dr. Byrd, and a great transition to my next question. And before we move on to some of those emerging agents in this setting, I want us to spend a moment on collaboration. What should optimal collaboration look like between the clinician and the patient, as well as community clinicians and specialized referral centers, in particular when dealing with these double-refractory patients?

Dr. Byrd:
So this is a great question. I would say the best partnership for patients with CLL is to receive care as close to home as possible, which can generally be done with CLL, but also involve a CLL specialist optimally at time of diagnosis to get all the information about the disease and really get comfortable with the disease at the time of first treatment. And at the point where either a BTK inhibitor or covalent BTK inhibitor or venetoclax stops working, that's probably where it's important to have a CLL specialist more involved with your community doctor at home, because there's very unlikely to have a very durable remission with therapy beyond first-line treatment. And for sure, when you get to the double-refractory setting, the interpretation of molecular tests for picking the best drug and the sequencing is very important. And at that point, that's a place where most community oncologists have very limited experience. They're great doctors at managing CLL, but they have limited experience in managing this. And having a team approach, where you're getting therapy hopefully as close as possible to home but at the same time have an expert looking at your information, is really important, and it's going to assure the best outcome.

Dr. Mencia:
Those are really great insights, thank you. Let's turn our attention now to the future. We have a lot of new and exciting data for patients with double-class refractory CLL, including potential combinations. What's on the horizon, Dr. Byrd?

Dr. Byrd:
It’s a real exciting time for patients with CLL because we continue to see a number of therapies, both in the BTK inhibitor space that enable us to stay in class as well as combinations and targeted immune therapy. Well, let's start with the approach with double-refractory that if I can stay in the same class, that I’d like to stay in the same class of drugs, similar to what we do with CML. And the BTK degraders, and there are two of them, BGB-16673 and NX-5948, that really in clinical trials thus far look identical in that they work virtually against all of the mutations in BTK, because they degrade BTK, and they also work against PLC-gamma 2 mutations. So this gives us the opportunity, on a trial, to stay in class, even if patients have developed virtually all of the mutations, with the exception of one, say, that are seen as part of covalent BTK inhibitor resistance.

So in addition to pirtobrutinib, there are other covalent and/or covalent/non-covalent BTK inhibitors. The one most furthest along is nemtabrutinib, a broad kinase inhibitor that hits BTK and has activity in this double-refractory population and also in Richter’s transformation. And it's being looked at together with venetoclax and also is being examined in the up-front setting. The rocbrutinib is the covalent/non-covalent BTK inhibitor that's in clinical trials and has activity in gatekeeper and Cys41S-mutant CLL as well. We have a number of agents, covalent and/or covalent/non-covalent, in the space that pirtobrutinib is approved that offer the potential for efficacy in this area.

The introduction of CAR T-cells initially was disappointing, but the TRANSCEND CLL 004 had a cohort of patients that received liso-cel with ibrutinib. And there, we saw the durability of remission significantly increase with much higher CR, and this was predicted by preclinical data. And I think it highlights that when you go through CAR therapy, you're biting off a potential risk of significant toxicity, even a small chance of dying. You want there to be a durable remission at the end. And the addition of ibrutinib with this really showed this.

The other exciting therapy that has been updated at ASH this year is the use of epcoritamab or the CD20 bispecific antibody that is currently approved for a number of lymphoma indications. And what's real encouraging about this is in double-refractory patients, approximately 50% of people attain complete remissions. That is complete remissions, which is truly amazing. These therapies, by themselves, are not easy therapies to administer. And the company right now is doing combination studies where we'd expect the results either giving them with BTK inhibitors or BCL2 inhibitors, we would expect them to be better.

So all in all, a lot of exciting new things coming forward for CLL in this double-refractory space. And it again highlights that partnership with the community doctor and a CLL specialist at this point can offer opportunities for the patients that the community doctors might not have and still produce durable remissions with people going many years without needing therapy, particularly with CAR T-cells or even what we're seeing with the bispecifics right now.

Dr. Mencia:
Well, we're just about wrapping up, but before we do, Dr. Byrd, if you could leave the audience with one take-home message from today's discussion, what would that be?

Dr. Byrd:
The options for CLL patients at all points of care, whether you're talking about initial therapy, second-line therapy, or even for double-refractory patients have expanded. And for patients, even in this most advanced setting, there are lots of options, and picking the right option can lead to a durable remission, with patients having exceptional quality of life. So we're really at a great place for CLL. It's going to be exciting to see some of these newer therapies that we're talking about, complete responses in double-refractory patients, moving to earlier lines of therapy, where I believe we'll see even more benefit and perhaps at some place a cure of CLL.

Dr. Mencia:
Unfortunately, that's all of the time that we have. So I want to genuinely thank our audience for their participation and a big thank you to you, Dr. John Byrd, for your time and for sharing all of your valuable insights. It was great speaking with you today.

Dr. Byrd:
Thank you very much.

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