What Advanced Practitioners Need to Know About CLL With a Focus on BTK Inhibition

Amber Koehler:
Welcome back to the third and final piece of our Roundtable discussion on BTK inhibition and CLL. Welcome back to my colleagues Josie and Becca. Thank you so much for being here and really looking forward to having Josie lead our discussion on BTKi sequencing in the relapsed/refractory setting.

Josie Montegaard:
Thanks for having me, Amber. I'm going to go over how to sequence the BTK inhibitors in the relapsed/refractory setting. But before we get to how to sequence these drugs, I think the first question we always need to answer is why is the patient discontinuing their current BTK inhibitor? And in my practice I tend to see the reason fall into two buckets. Number one being discontinuation due to intolerable side effects, and then number two being discontinuation due to disease progression.

And it's this differentiation that we definitely need to get to the root cause of in order to properly treat these patients moving forward. That being said, I do want to highlight some other factors that you'd want to weigh in consideration of any additional treatment you offer the patient, which would include the patient's prior line of therapies, the patient's current comorbidities, the current available treatments, both FDA-approved treatments and clinical trial options, as well as logistical factors: Does the patient have access to treatment, feasibility of the treatment, and certainly the cost.

When we look a little bit more into discontinuation of BTK inhibitors due to intolerable side effects, you may ask yourself why do BTK inhibitors have any side effects if they're novel targeted therapies targeted to CLL cells? The reason being is that while they are targeted to BTK, they do have off-target side effects, which we briefly touched upon in our prior presentations.

And because they have off-target activity, we do see side effects occur in the patients. Fortunately, over the past few years, we have developed newer generations of BTK inhibitors that are more selective for BTK and thus less off-target activity and subsequently less side effects. And you can see that illustrated in the kinome map on this slide where on the left we have ibrutinib and on the right we have our second generation BTK inhibitors, acalabrutinib, and zanubrutinib.

Those red dots on the kinome maps indicate off-target activity. So, you can see that for ibrutinib there's quite a bit of off-target activity. And while we see some off-target activity in acalabrutinib and zanubrutinib, there is a bit less and that translate to less significant side effects and less frequent side effects. The side effect profiles in general are still the same, but we can see changes in the severity and in the frequency.

So when you're looking to change treatment for a patient who's discontinuing their current covalent BTK inhibitor due to intolerable side effects, one option is you could consider an alternative covalent BTK inhibitor. Another option is you could switch to a non-covalent BTK inhibitor such as pirtobrutinib, or you could switch drug classes entirely to a venetoclax-based regimen.

So conversely, looking at patients who discontinue a covalent BTK inhibitor due to disease progression, these patients no longer have the option to switch therapies to an alternative covalent BTK inhibitor. And the reason being is that most often disease progression while on a covalent BTK inhibitor is due to patients acquiring a BTK resistance mutation. Most commonly this mutation is a C481 mutation, though there are a variety of other mutations that we can detect.

When these mutations occur, covalent BTK inhibitors cannot bind properly to BTK and inhibit the enzyme therefore leading to ineffectively treating the CLL. Fortunately, we now have non-covalent BTK inhibitors available. Both pirtobrutinib, which as Amber had mentioned in our prior presentation, is newly FDA-approved for CLL, as well as others in clinical trials such as nemtabrutinib. Non-covalent BTK inhibitors do not require binding at the C481 site on BTK and therefore it can still be effective even if a mutation has occurred.

If you have someone that is discontinuing a covalent BTK inhibitor due to disease progression, your options would be either to switch them to a non-covalent BTK inhibitor such as pirtobrutinib or switch them to a venetoclax-based regimen.

To jump into our case study, we have Nick. He's a 67-year-old male, he was diagnosed with CLL in 2017. You can see his prognostic workup here is a bit mixed, somewhat unfavorable.

He has unmutated IGHV and a deletion 11q. Fortunately he does not have any of the more high-risk features such as a 17p deletion or mutated TP53. He was on active surveillance until 2020, at which time he needed treatment and started on ibrutinib. And you can see here he has a pretty benign past medical history and current medication list.

He comes to your clinic for a routine follow-up visit. He's feeling well, you can't palpate any lymph nodes on exam, and his blood counts are normal. So he's responding to treatment really well. The caveat though is that he reports that over the past year his primary care doctor has really struggled to manage his hypertension. He's now on high doses of two different anti-hypertensives and his blood pressure is still uncontrolled, so they're considering starting a third agent. So at this point I'm curious, Becca and Amber, would you recommend changing his CLL treatment or continuing on course?

Becca Rezac:
I do think at this point where we're kind of maxing out our doses of the current losartan and amlodipine and even looking to start a third agent at this point, it would be pretty typical in our practice to start looking at switching to a second-generation BTK inhibitor.

Amber Koehler:
I think the other piece that would be part of this conversation for us is I agree, I mean I think at this point he's on two new anti-hypertensives, now talking about starting a third. It’s certainly not atypical to see increases in hypertension over time and our patients on ibrutinib. The other thing we would actually think about would be simply discontinuing ibrutinib and going into observation.

And that would be based on some of the E1912 follow-up data. It was ibrutinib and rituximab vs FCR (fludarabine-cyclophosphamide-rituximab). But what they found is that people who stopped ibrutinib for adverse events actually had a median PFS of about two years. A lot can happen in two years. And so, in general I would have a strong interest in considering simply discontinuing treatment and going into observation and then reserving perhaps a second-generation BTKi or maybe a venetoclax-based regimen for later on down the line. But I think either is reasonable.

Josie Montegaard:
Yes, I completely agree with both of you. I think given that he doesn't have any signs of disease and he is been on treatment for a while, Amber, you make an excellent point that you probably could just stop treatment and monitor him until he shows signs of disease progression and requires treatment again. I think for the sake of our sequencing discussion, if you were to need to initiate new treatment for him, do you have an idea of what you would choose for him?

Amber Koehler:
That's tricky, right? Rebecca, what do you think? I mean, it's hard to do cross-trial comparisons with respect to hypertension. I think in my mind the picture is much more gray in terms of hypertension with acalabrutinib vs zanubrutinib. But what do you think from a pharmacist perspective?

Becca Rezac:
I'm going to be honest; I could see us going either way. They do tend to have really comparable numbers for the adverse effect profile specific to cardiac adverse effects. So I don't know that we would necessarily pick one over the other. In this case, it may also just be based on patient preference if they're willing to do daily dosing vs twice daily dosing. Those might be more of the factors that we might consider. But really probably either of the second-generation BTK inhibitors.

Josie Montegaard:
I completely agree and in my practice I find that sometimes it is clinician-dependent. Some people really favor acalabrutinib, some people favor zanubrutinib. So I think that there doesn't seem to be a clear winner with regards to the cardiovascular effects. When we think about the treatment choices in general for him, one option would be to switch to another BTK inhibitor and we discussed the two covalent BTK inhibitors that would be available, acalabrutinib vs zanubrutinib.

There's also the non-covalent BTK inhibitor, pirtobrutinib, that's FDA-approved. Though that being said, it is FDA-approved after two lines of prior treatment. So if you were considering that for this patient, it would be considered an off-label use. So I think we would not consider that for him at this time. The other option would be to switch drug classes entirely and consider a venetoclax-based regimen.

I think in my practice we tend to like to exhaust one drug class before we move on to the next, especially if we feel like there's still a lot of life that we could give him on a BTK inhibitor. I think either acalabrutinib or zanubrutinib would be perfectly reasonable for him. And here you can see a table that we've already shown similar versions of highlighting the differences between the BTK inhibitors. Now would this treatment decision change if we were discontinuing for uncontrolled atrial fibrillation or a more life-threatening side effect?

Amber Koehler:
For me, yes, I would just stop and watch.

Becca Rezac:
Yes, I would agree with Amber, either stop and watch or if for the sake of the case we're saying we have to treat, then I would say we would move away from maybe my clinic standard practice of, similar to yours, Josie, remaining on the BTK until we've exhausted it. We would likely then at that point move on to the venetoclax-based regimen if we needed to continue treating.

Josie Montegaard:
Yes, I agree. I think if we could give him some time off treatment, we probably would. But certainly, if he needed treatment again we would switch to venetoclax. So moving along. Nick ended up going on acalabrutinib and fortunately his hypertension remained controlled on only amlodipine, which is great.

So, he comes in now for another clinic visit with us, and now he's not feeling too well. He notes some worsening stamina on his walks. He has no significant lymphadenopathy on exam, but his labs don't look great. His absolute lymphocyte count is rising. He has new anemia and he has some new mild thrombocytopenia. Moving forward, how would your discussion go with Nick at this time?

Becca Rezac:
I would say it’s definitely looking like it's time to switch therapies. In the case of selecting what to do next, I think it'd be important to know if new mutations have occurred to his BTK inhibitor therapy. I will say oftentimes the FDA-labeled indications end up guiding us maybe a little more than we'd want to with regard to selecting a pirtobrutinib vs moving to that venetoclax-based regimen. That's not to say we wouldn't still pursue pirtobrutinib for some patients, but just kind of knowing that barrier might be there if we haven't also used a venetoclax-based regimen prior.

Amber Koehler:
There’re a few thoughts that I have. So one is, I'm curious, is this a sudden trend? Is this a gradual trend? I often think about CLL kind of like a freight train, right? Most of the time you see it coming. So, let's say you're seeing somebody every six months and you notice some changes, "Gosh, maybe we should see you in three." And you see them at three and you think, "Hm, maybe I ought to see you in six weeks," or "Okay, we got to check this again in a month," or "Gosh, we should see you in two weeks." Normally you kind of have that understanding of where things are heading. So I think if it was sudden I would start to question things like infection, make sure you're not missing something that way. Obviously Richter's is always on your differential, but he doesn't sound like he's sick, he doesn't sound like he's got the typical presentation of somebody with Richter's.

But re-staging would be one thing I would think about pursuing. I know Becca, you, I think mentioned some of the repeating the cytogenetic testing, like FISH testing. I would be thinking about imaging because certainly there are lymph nodes we can't feel on exam and it's not that hard to miss conglomerate adenopathy that's deep in the belly, particularly in people with larger body habitus.

I think the other thing that I would definitely be doing in this patient would be sending off testing for BTK mutation, looking for some of the things like the C481S or the PLC-gamma 2 that Josie had alluded to earlier in this. So I think bottom line, my recommendation would be to pursue re-staging and BTK resistance testing.

Josie Montegaard:
Yes, I totally agree. I think if this patient comes in, it to me looks like he's progressing and I think it's time to start with re-staging assessments. Number one, to look for any new acquired mutations including those BTK resistance mutations. Also repeating imaging to make sure that we know what we're dealing with in terms of nodal volume and spleen size.

And that can be helpful if we do want to consider a venetoclax-based regimen down the road, we need up-to-date imaging to determine tumor lysis risk. And then lastly for Nick, I'm not too worried that he's developing any myelodysplastic disorder given that he hasn't had any prior chemoimmunotherapy. But if someone had and they were coming to my clinic with new cytopenias, I probably would consider getting a new bone marrow biopsy just to make sure that there's no myelodysplasia going on that could be contributing to those counts.

So, for Nick's case, we did repeat all of his re-staging workup and he does now have a new C481 mutation, and he has some modest nodal disease and splenomegaly. I'm curious how both of you would treat this patient moving forward.

Becca Rezac:
I kind of stole my own thunder unintentionally, but I think with the options available with the new mutation needing to move to a non-covalent BTK inhibitor, if that's the route we're choosing to go, vs a venetoclax-based regimen, I know we've done it both ways, but I do tend to see a little bit of resistance and pushback by payers when we try and go the pirtobrutinib route first. So obviously like I said, not to say that we would totally write that off as a treatment option, but certainly if we're worried about the turnaround time for that and we get an initial denial, sometimes that will guide what we do next.

Amber Koehler:
Yes, so I think there's several layers here. In general, I agree that based on the data that's out there in terms of PFS data, we would lean toward venetoclax plus a monoclonal anti-CD20. Actually, for the past several years we use obinutuzumab plus venetoclax in the relapse setting. That's not technically on label and it's not technically on the NCCN guidelines, but there's a lot of data to show that obinutuzumab is more effective than rituximab and CLL.

So if you can mitigate some of those cytopenias and infusion reactions, I actually think it's a really great option for people. Even though he'll likely have a shorter remission with a time-limited venetoclax-based regimen, given his unmutated status of IGHV, I still think based on my interpretation of the data, I still would expect him to have a longer PFS with the venetoclax-based regimen than the pirtobrutinib.

And then again, as we've talked, once you get into this post-covalent BTKi, post-BCL–2 space, it gets a little more tricky. Right? And so I want to maximize our time before he's at that crossroads because there's so much happening in the world of CLL, with lots more to come.

Josie Montegaard:
I agree. The option really for him is going to be a non-covalent BTK inhibitor vs a venetoclax-based regimen. Covalent BTK inhibitors are off the table given that he has that BTK resistance mutation. And in his case, I think I would choose a venetoclax-based regimen as well. We're kicking the can further down the road. Who knows if he gets three, four years maybe out of this. We could be in a totally different space with what treatments are available. And that still includes pirtobrutinib, which would still be an excellent choice for him down the road should he ever need it. And so that concludes our discussion on BTK sequencing and the relapsed/refractory setting. Thanks for joining us.

Amber Koehler:
Wonderful. Well, thank you so much Josie, and thank you Becca, both of you for fabulous several discussions. Clearly we could all talk about CLL for a very long time, so I'm glad that each of you were able to join us. And if our viewers have any questions or want more information, please don't hesitate to check out more CLL-related content at JADPRO's website at JADPRO.com.