Dr. Shadman:
Welcome to “CLL Treatment Sequencing, Where Do Next-Generation BTK Inhibitors Fit?” an ASCO Post Roundtable. I'm Dr. Mazyar Shadman. I'm a Professor at Fred Hutch Cancer Center and University of Washington in Seattle. Joining me today are two of my colleagues.
Dr. Ahn:
I'm Inhye Ahn. I'm an Assistant Professor at Dana-Farber Cancer Institute and Harvard Medical School.
Dr. Stephens:
I'm Deborah Stephens. I'm an Associate Professor at University of North Carolina Cancer Center.
Dr. Shadman:
Great. So we start with our case and I’ll just give a brief presentation of the case and then we'll discuss and go through some of the clinical questions that come.
So SP is a 72-year-old woman with CLL that was diagnosed 6 years ago. She was initially managed with active surveillance for approximately 1 year before she developed progressive lymphadenopathy and had indication for treatment. At that point, the molecular testing showed high-risk disease with del(17p) also p53 mutation. Patient also had del(13q), and the IGHV status was unmutated.
She was treated with first-line acalabrutinib and obinutuzumab, achieved an excellent clinical response, and disease was under control for almost 5 years. Now she presents with progressive lymphadenopathy and increased lymphocyte count. A molecular test is done looking for basically repeat of the CLL markers as well as potentially resistance mutation. So there is still evidence of del(17p) and p53 mutation, and now there is evidence of BTK C481S resistance mutation.
She reports increasing fatigue and early satiety. Her ECOG performance status is 1. On physical exam, there's evidence of bilateral cervical and axillary lymphadenopathy up to 4 cm. Also, there's evidence of inguinal lymphadenopathy. Spleen is palpable.
On labs, lymphocyte count is elevated up to 45,000, but there is otherwise mild to moderate cytopenias with anemia and a platelet count of 88,000. A CT scan is done, which confirms progressive lymphadenopathy with the largest lymph node measured in scan being 5.5 cm and the spleen is measured at 17 cm.
Otherwise, metabolic panel, I would just highlight the creatinine 1.1 with an EGFR of 55 mL/min. In terms of past medical history and other comorbidities, she has well-controlled hypertension. She has controlled type 2 diabetes. She is on chronic antiplatelet therapy due to her history of cardiovascular disease. And she lives 2 hours from the cancer center and really values quality of life and independence.
So, with this case, we'll start and we'll go through our panel of experts here. In a patient who has progressive disease on a covalent BTK inhibitor or second-generation BTK inhibitor like acalabrutinib, let's start with Dr. Stephens, what are the treatment options? And how do you think about those options focusing on the standard of care treatments?
Dr. Stephens:
Great question. With the recent approval of pirtobrutinib in this space, this space became a little bit more complicated for decision-making for these patients because we have a few really good options. And the top contending options would be a venetoclax-based strategy. And I would typically go for venetoclax plus obinutuzumab in this setting vs pirtobrutinib.
And I still have a preference for a venetoclax-based regimen, but you can really look at a patient's medical comorbidities. There are other molecular risk factors like presence of del(17p), and the logistical part of it. So of course, venetoclax and obinutuzumab comes with infusions and a ramp-up. And you just mentioned that this patient lives 2 hours away from the treating center, so I think I foremost try to make the recommendation I think is best for the patient. In this case, both are good recommendations, but I would probably sway towards venetoclax-based treatment.
This patient really has high-risk disease, so you need to think about how you're going to sequence treatments over the course of time. And at least at the current moment, this is probably someone who eventually is going to need CAR T-cell therapy. And right now the label for CAR-T says you have to have both a covalent BTK inhibitor and a BCL2 inhibitor treatment previously. So I typically will switch class of drugs and use that BCL2 inhibitor, but I’m definitely interested to hear, Inhye, how you would approach this patient.
Dr. Ahn:
Yeah, thanks, Debbie. I agree with everything you said. High-risk disease and this patient may eventually need all of the treatment options that you discussed, including pirtobrutinib, venetoclax, and eventually CAR-T. I think the difficulty in decision-making is the lack of head-to-head comparison of venetoclax and pirtobrutinib in this exact scenario.
So I'll just cite a couple of cross-sectional data and retrospective analysis here. In the BRUIN CLL-321 study that tested pirtobrutinib against the investigator's choice of therapy, the median time to next treatment or death on the BTK inhibitor–exposed patient on pirtobrutinib was about 30 months. So it doesn't last forever, but it did have a decent disease control for a couple of years basically.
How about venetoclax? We have a few retrospective data on this topic. I think the biggest one was the one from Mayo Clinic that was presented at the ASH meeting a couple of years ago, that also showed 30-month median time to next treatment with the venetoclax given in the BTK inhibitor–resistant population. So, fairly similar.
Then there was another paper that was published 2 years ago by Dr. Al-Sawaf. It was a match that just did indirect comparison of pirtobrutinib and venetoclax in this exact setting. And in that study, the progression-free and overall survival seemed similar. So based on that, I think pirtobrutinib and venetoclax as similar options.
My personal preference is to switch class as well just because with the BTK inhibitor continuous therapy, there is a chance of generating more resistance mechanisms. So I tend to switch and hopefully give a little bit of a treatment break that can regain the sensitivity to the treatment.
Dr. Shadman:
Great point. So I think, Inhye, you brought up a very important point. At the 2025 ASH Annual Meeting, there was also a study that they looked at patients who received the covalent BTK inhibitor, and I think they got the data from both the original BRUIN and BRUIN CLL-321. And they basically looked at the cohort of patients who received covalent BTK inhibitor and then moved to pirtobrutinib.
They reported both PFS and time to next treatment or death. So when you compare that to the retrospective data, it's important not to compare the PFS to time to treatment or death because in retrospective analysis, there's no way of really calculating the PFS. So the 30 months that you mentioned is important and looks pretty similar between the two.
Dr. Stephens mentioned the practical points for a patient who lives 2 hours away. How easy is it to get the patient started on the CD20 and venetoclax? Many times it's much more practical to start pirtobrutinib, but I think you both covered all the clinical points about that.
So, we heard on a press release, and maybe in a couple of weeks we'll see some data presented in a more official way of BRUIN CLL-322 study, which is looking at the combination of pirtobrutinib, venetoclax, rituximab vs venetoclax, rituximab in a head-to-head trial.
And maybe this discussion of pirtobrutinib vs venetoclax will be less relevant when we see that if efficacy and safety is acceptable and if the combination receives the regulatory approvals. What do you think of PVR as an option in the patient like this? Again, not knowing the data and not knowing all the details, assume the best case scenario.
Dr. Stephens:
I think this is a great question and I'm excited to see those data. I mentioned already that I typically use obinutuzumab when I'm choosing to use a CD20 antibody. And so when the study comes out, I'm sure there might be a critique that rituximab was used instead of obinutuzumab in this space. But recognizing that that's the way it is at least regulatorily approved in the US, I understand why they chose that combination.
But I think maybe an even more interesting question would be, what about venetoclax and obinutuzumab vs pirtobrutinib and venetoclax? But I do think there are complications with using three-drug therapy. There's no way around it that that's going to increase the toxicity.
And so I think it's important that we look at the toxicity data. And understand is whatever toxicity that's added by doing a three-drug combination, is that really benefit the PFS so much over the two-drug combination of venetoclax and rituximab?
Because I mean, I don't know the data, but I think I would hypothesize that the PVR would lead to a longer PFS. But again, I think that toxicity data is going to be important to understand if it really is clinically meaningful PFS.
Dr. Ahn:
I agree with Dr. Stephens that the toxicity is a key piece, especially for our older patients who have gone through multiple lines of therapy. Personally, I'm excited about this study though because the press release indicated that there was a PFS benefit, which was the primary endpoint, and the trend toward overall survival benefit, which was a key secondary endpoint.
I think the other part that is relevant to this specific case is that how many of these patients in the BRUIN CLL-322 study had a prior covalent BTK inhibitor. The study randomized and stratified by the covalent BTK inhibitor exposure status, but we don't exactly know what the proportion of patients who have been refractory to BTK inhibitor. So I think that piece has to be fleshed out and analyzed separately.
Dr. Shadman:
Excellent point. So we'll wait for that data hopefully soon.
Some of the clinical takeaways from this case, so just a quick summary that after progression on a covalent BTK inhibitors, we now have two options. We have venetoclax-based therapy with either obinutuzumab if we can have access to it, or rituximab. Or pirtobrutinib and that's based on the results of the BRUIN CLL-321 trial, and the recent update in the label of pirtobrutinib that made it now available after at least one prior line of therapy that is covalent BTK inhibitor.
We talked about some of the decision-making factors that we think about with pirtobrutinib. It's an oral drug. It can be started rapidly and there's no need for ramp-up. With venetoclax-based therapy, you have a CD20 antibody and you have a venetoclax that requires some ramp-up, and logistically is more challenging.
We talked about the fact that there's more sequencing data of using pirtobrutinib after venetoclax at the current time. And also thinking about down the road and options including CAR T-cell therapy, that's only an option for patients who are exposed to both BTK inhibitor and BCL-2 inhibitor.
And also we are weighing the upcoming results of the BRUIN CLL-322 trial, which actually combines the two drugs or the two options of pirtobrutinib plus venetoclax plus rituximab. It's important to look at the safety profile and details of efficacy and maybe that would be an option for some patients. And so important study to look for.
In conclusion, this brings us to the end of this case and please see our other segment for further discussion about the latest research in CLL. Or visit ascopost.com. Thank you.
