Case Study: Approaches for Double-Refractory Patients

Amber Koehler

Hi Josie! In past discussions, we followed the course of CLL therapy with our patient, “Jim.” He was 60 years old when we started seeing him. Now he's in his mid-seventies. He has been treated with venetoclax plus obinutuzumab in the frontline setting, followed by zanubrutinib as second-line therapy. But now, unfortunately, he’s starting to develop progressive disease again, and this is in the setting of somebody who initially had some pretty benign prognostic markers. He had mutated IGHV, no abnormalities on FISH. But then in the second-line setting, restaging showed he had developed clonal evolution, with a new TP53 mutation. So, talk to me a little bit about how you would approach this? This gets tough, right, these “double-refractory” patients?

Josie Montegaard

Yes. These are tough ones, and unfortunately, we are seeing them come out of the woodwork more and more. I mean, that's the great thing and the downfall of the novel agents, is that we are using them more and more, but then patients are becoming resistant after they've gone through multiple lines of treatment with them. And we're trying to figure out what to do with those patients. So first and foremost, for someone like Jim, as we did when he started to show signs of progression or needing a new line of therapy after venetoclax and obinutuzumab, I would repeat his prognostic workup. This is really helpful before starting any new line of treatment, but in particular in his case, because we really need to know if he has developed any Bruton’s tyrosine kinase (BTK) resistance mutations.

If he hasn't, you can still consider some sort of covalent BTKi-based therapy. But if he has, then the covalent BTK inhibitors are off the table, and we'd have to look at the non-covalent BTK inhibitor class or another drug class altogether. What are the considerations that you typically take into account for a patient like this? 

Amber Koehler

There are a couple of points that I’d consider. One, in these folks, I’d think about getting a lymphoid next-generation sequencing panel to see if there are any targetable mutations. At this point, off-trial, your options are limited. Oftentimes, what we're using is pirtobrutinib, which was approved for mantle cell lymphoma. It is on the NCCN guidelines in terms of recommended therapy for these double-refractory CLL patients, meaning those who have either progressed or not tolerated BCL-2 inhibitors such as venetoclax-based therapy as well as a BTK inhibitor. 

We’ve had some success getting pirtobrutinib off-label, outside the context of a clinical trial. But I really think oftentimes the best bet for these folks is to do a referral to either a large academic medical center or a cancer center where there are clinical trials available. Some of the main things I think about are certainly the pirtobrutinib-based trials. I think about CAR T-cell therapy. There's always a lot of buzz around that, right? And then BTK degraders are kind of the new kid on the block. Have you used a lot of pirtobrutinib?

Josie Montegaard

Yes, we've used quite a bit of pirtobrutinib, and I’m a big fan. It really is a new lifeline for these double-refractory patients. Whereas before pirtobrutinib, we'd maybe put them on a clinical trial and they'd get a few months out of that, with pirtobrutinib we're seeing really durable responses and people are tolerating it really well. We still counsel them on the same sort of side-effect profile that we would with any BTK inhibitor. And I see similar side effects in my own clinical practice, but it is quite well-tolerated and works for those BTK-resistant patients. Is that similar to your clinic? 

Amber Koehler

I think it's still early, but I do think it's similar. We're still pretty early on in our understanding regarding the length of remission with pirtobrutinib. In a recent phase 1/2 study led by Dr. Mato, the median progression-free survival (PFS) for all comers with relapsed/refractory CLL was about 19.6 months with a median follow-up of about 19.5 months.¹ And that drops a little bit, to about 16.8 months in the folks who are double refractory, meaning again, they've received both venetoclax and a BTK inhibitor. 

So, in general, I agree. I think pirtobrutinib is a great option in this group. It's generally pretty well-tolerated. And with CLL, so often the name of the game, especially in these really-high-risk patients, is buying time as more and more treatments are coming down the pipeline. So I think it's a great option. 

Josie Montegaard

I agree. I always tell my patients that we're trying to kick the can down the road. In general, for CLL patients, a PFS of 16 to 19 months is not very long compared to what we see with a covalent BTK inhibitor in the frontline or relapse setting or with venetoclax. I think for these double-refractory patients, the matter of 1+ years moves mountains in terms of what clinical trials may be available and what FDA approvals will have come around the corner. I think that's something really important to educate patients on. 

Amber Koehler

Yes, I couldn't agree more. Another thing patients ask about, even before they enter into this double-refractory space, and well, even newly diagnosed CLL patients ask me about this, is CAR T-cell therapy. I think there are probably a lot of reasons for that. As of right now, CAR T-cell therapy for CLL is only available in clinical trials. Is that something that you've had some experience with? 

Josie Montegaard

Yes. It’s been limited because the spots on the clinical trials are quite competitive. Often they're shared among many academic centers, so you're waiting for a spot to open up that's allocated for your site. We have had a handful of patients go on to receive CAR-T cells for CLL, and I would say that the response has been mixed. I don't know that it’s a home run in our eyes quite yet in terms of seeing some of the consistent durable remissions we see for the more aggressive lymphomas that they're using CAR-T cells pretty regularly for. That being said, there's still a lot of research to be done in the more indolent lymphoma space. 

Amber Koehler

Absolutely. I think the word “mixed” is perfect. That's been my experience too. In fact, the other day I was just looking at the updated data from the TRANSCEND 004 trial, which looked at CAR T-cell therapy in CLL.² There were about 117 patients. All of them had previously been treated with a BTK inhibitor. I think about a little bit more than half of them had also experienced venetoclax failure. So you're looking at a complete remission rate of about 18%. I think that's important because my general impression is that in patients with CLL for whom CAR T-cell therapy works, it works fabulously. But it's important to remember that, to your point, it's not a home run for the majority of patients yet. 

There was an article published in Nature titled “Decade-long leukaemia remissions with persistence of CD4+ CAR T cells." ³ And I know there was just a story recently on the Mayo Clinic News blog about a gentleman who was treated with CAR-T and is doing wonderfully.⁴ But we need to remember not to oversell things to our patients. That said, I'm excited about a lot of the work that's being done in CAR T-cell therapy, so I'm hopeful that this will become a better and better option for patients over time. 

Josie Montegaard

I agree. And the other thing is that patients sometimes can get attracted to the flashy headlines of remission for decades and things like that, but CAR-T cells don't come without risks. You have the cytokine release syndrome risk,  the neurotoxicity risk, and the infection risk that comes with giving anyone high-dose chemo prior to receiving their CAR-T cells. These are all things we need to talk to patients about because I don't think they’re quite aware of what the process is, and how safe some of our other therapies can be that we would recommend first. 

Amber Koehler

Yes, I agree completely. Tell me, I haven’t had as much experience with the newest kids on the block, BTK degraders, in terms of potential treatments for double-refractory folks with CLL. Have you seen much of them, or can you speak a little bit about how they work? 

Josie Montegaard

Regarding a BTK degrader, I believe there are a couple of trials open now that are first-in-human. We have one open at our site. We have not put any patients on yet, but I believe there are patients actively on the trials at other sites. But the way a BTK degrader works is that, whereas BTK inhibitors inhibit BTK among the BCL2 pathway that then prevents CLL cells from proliferating and persisting, BTK degraders completely destroy the enzyme itself, so they can still work for patients that are resistant to BTK inhibitors. Because we're not inhibiting the enzyme anymore, we're just making it non-functional. 

I believe that it should have some effect. It’s still very early, so it remains to be seen. But the big questions I have are, number 1, what the efficacy will be, but also number 2, are we going to see the same side-effect profile as we do with BTK inhibitors? Because many times we associate some of the side effects with BTK inhibitors to be due to off-target effects of BTK inhibition. But if we are specifically just degrading a BTK enzyme, I wonder if we will see the same side-effect profile or if it will be completely different. 

Amber Koehler

That’s a great explanation, thanks Josie. I think ultimately, the bottom line is that there’s more to come. 

Josie Montegaard

Yes, more to come for sure. But in CLL, “more to come” will happen every 6 months to a year or more. I think if we have this same conversation next year, we'll have a lot more to talk about. 

Amber Koehler

Absolutely. It sounds like we’re both in agreement that for double-refractory patients, getting them onto a clinical trial is the best next step. If that’s not possible, pirtobrutinib off-label is probably your only good option, and that is supported by the NCCN guidelines. Hopefully we’ll continue to have more options for this tough-to-treat subset of patients in the years to come.