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 who will introduce themselves.
Dr. Ahn:
Hi, I'm Inhye Ahn. I'm an Assistant Professor at Dana-Farber Cancer Institute and Harvard Medical School.
Dr. Stephens:
H, I'm Debbie Stephens. I'm an Associate Professor at University of North Carolina.
Dr. Shadman:
Excellent. For our next case, we'll discuss the management of a patient with multiply relapsed high-risk CLL with prior exposure to chemoimmunotherapy, venetoclax, and equivalent BTK inhibitor.
So TM is a 67-year-old man with CLL diagnosed 7 years ago. The first-line treatment included bendamustine and rituximab. The patient had remission for only 12 months. At first relapse, he was found to have del(11q) and also had an unmutated IGHV; the molecular markers were tested after the first relapse. The second-line therapy included venetoclax and rituximab for 2 years based on the MURANO schedule. Patient achieved a partial response, had detectable measurable residual disease in peripheral blood, and had the progressive disease after less than 2 years.
And for the third line of therapy, he started on zanubrutinib, a second-generation covalent BTK inhibitor. He had a great response initially and remained in remission for 18 months, but then presented with signs of disease progression with worsening lymphadenopathy. At that point, molecular tests were repeated and the FISH data analysis was done and patient now has evidence of del(17p) clone appearing. In terms of lymphadenopathy, patient has cervical and axillary lymphadenopathy up to 4 cm on the exam. Spleen is palpable.
Performance status is reasonable with an ECOG of 1. The patient has mild fatigue and otherwise is active with no major comorbidity or past medical history except for history of multiple squamous cell carcinomas of the skin that have been treated in the past. On the blood test, there's evidence of lymphocytosis, mild to moderate thrombocytopenia, and mild anemia. He is not neutropenic. On CT scan, there's a confirmation of lymphadenopathy and splenomegaly. The metabolic panel shows no surprises, and patient has a creatinine of 1.0 and normal liver function tests and transaminases. Past medical history is notable for well-controlled hypertension, type 2 diabetes, as mentioned, skin cancer history, but otherwise very functional and active.
So going to our panel, let's talk about double exposed and double refractory for a second because I think that's an important definition for CLL these days. And after that, let's talk about what's considered to be the standard of care. For all of these cases, we always prioritize clinical trials. So when we talk about the standard of care options, let's not forget that if there's a clinical trial available, we always prefer that. And then after the definition of its double-exposed versus double failed classes, we'll talk about the standard of care options.
Maybe we start with Dr. Ahn?
Dr. Ahn:
Yes. So in terms of the definition of double exposed and double refractory status, I think the most important piece to look at is why the patients stop the targeted agents. The stringent definition of double-refractory disease is the patient who developed disease progression during active therapy to both BTK and BCL2 inhibitors given sequentially or concurrently. For the double-exposed patients, they could have stopped one or both of the agents due to reasons other than progression. So it could be due to toxicity or completion of plan therapy like this patient who finished then rituximab after 2 years.
I think this specific scenario doesn't tell us how long the remission duration was after the time-limited venetoclax and rituximab, but it sounds like the patient went through rapidly through each line of therapy and the disease control lasted for less than two years consistently. So I would assume that the remission duration was short in this patient. So I would treat this patient as if the patient had double refractory disease.
Dr. Shadman:
Excellent. Going to Dr. Stephens: for a patient with double-refractory disease, what would you consider in your practice today?
Dr. Stephens:
For the majority of these patients, my first go-to drug would be pirtobrutinib, outside of a clinical trial. Clinical trials, as you mentioned, are really important for these patients, but outside of that, or if they have disease that's progressing too quickly to get them on a clinical trial, pirtobrutinib is usually my first go-to. But I don't usually think of it as an either or because this is clearly a high-risk patient and we have to think about how we're going to sequence these patients, and CAR-T or cellular therapy is going to be the next step after pirtobrutinib for these patients. And so, I'm starting them on pirtobrutinib, but also referring them early to consider allogeneic stem cell transplant in a case like this, a younger patient with controlled comorbidities vs a CAR-T therapy because that's the likely next step this patient is headed towards.
Pirtobrutinib is a really good option for this patient and most of our patients just because the toxicity profile is outstanding. Usually people feel really good when they're on this drug and have minimal side effects outside of the bleeding and bruising that comes along as an on target side effect of all BTK inhibitors. But the critical data to know is from the original BRUIN study; the PFS is pretty short in this population, pretty short in terms of CLL studies. So we're looking at only about 15 to 18 months, which might sound like a lot, but really when you take into consideration that you're going to have to do some prep work to get these patients prepared for either CAR-T or stem cell transplant, that's a pretty short time period and this is a great time to type them to see if they have any matches and interviewing for family members that might be matches for an allogeneic stem cell transplant.
And then just getting insurance authorizations for things like CAR-T because one of the important data that's come out recently at ASH this year was some real-world data with using liso-cel. And one important piece of that data, the data looked better than the original clinical trials in terms of the response rates are higher. We actually see in the real-world data and there were a lot of patients that actually were on pirtobrutinib as they were collected for CAR-T and maybe were treated throughout. And while there's no prospective data yet, it looks like pirtobrutinib is a really great treatment for that holding therapy before you collect their T cells and bridging therapy for patients. And so again, I think pirtobrutinib would be my first go-to for most patients here, but I'm already thinking about what are next steps and how can we bridge these patients to more definitive therapy.
Dr. Shadman:
Great summary. And maybe for Dr. Ahn, so I think this is an important message to our colleagues about the timing of referral for CAR-T., So in a patient like this, I believe outside of the clinical trial, we all agree that pirtobrutinib is the drug to start with. And I want this message to be specifically and clearly relayed from us. So, do we wait until pirtobrutinib stops working? Do you make that referral for CAR T when you start pirtobrutinib? Tell us about your process in your practice in terms of the timing of referral for cell therapy, if that's something that you consider in this patient.
Dr. Ahn:
I totally agree with Dr. Stephens that this is the perfect timing to refer the patients and consider cellular therapy, including CAR-T and allogeneic stem cell transplant. When the patients go through two targeted agents and have a disease progression to both, this is the perfect timing. And while responding to pirtobrutinib, I would refer them. I just want to take home the point of Dr. Chapman's group's data that was presented at ASH, keeping pirtobrutinib on and giving cellular therapy improve the complete response rate to CAR T. So that's what I currently do. I continue pirtobrutinib during cell collection and continue through conditioning and sometimes over 30 to 90 days after cell infusion to make sure the patient's disease is well controlled. And that seems to actually help the immune system because if the disease burden is lower, the immunotherapies tend to work better.
Dr. Shadman:
Great point. And what I always tell patients is that there are so many drugs for CLL, but at the end we have maybe three or four real classes. We have covalent BTKis, noncovalent BTKis, currently pirtobrutinib is the only member, CAR T-cell therapy and BCL2 inhibitor therapy. And knowing that results and outcomes after CAR-T are not perfect. We can make them better by sending patients in with better disease control and maybe with fewer prior lines of therapy. But at the end of the day, we know that most of the patient, more than half, will still need something else. And it's nice to have a drug that works, pirtobrutinib. So if you make a referral while pirtobrutinib is working, and even if CAR T cell fails the a patient, you can still go back to pirtobrutinib, and it's a drug that could easily be utilized.
Excellent. So basically, to summarize this patient case, we know that we talked about distinction between prior double-exposed vs double-refractory CLL. Whenever we decide that covalent BTK inhibitors and BCL2 inhibitors are not an option for this patient, then I would call that patient double-refractory and Dr. Ahn provided the official definition. So pirtobrutinib would be the choice. Of course, CAR T-cell therapy, lisocabtagene maraleucel is also improved in that space, but logistically pirtobrutinib initiation makes more sense. It's an oral drug, can be started as soon as possible.
However, we all talked about the importance of thinking about CAR-T and making that referral as soon as possible and not waiting until failure of pirtobrutinib because unfortunately as good as this drug is —and it works—the median time to progression or progression-free survival or time to next treatment, however we look at it, that timeline is limited in the range of somewhere between 2 or 3 years. And so early referral makes sense because CAR-T works best when disease is under control, disease is less bulky and we don't have to use medications or treatments that could impact the CAR T or the T-cell quality around the CAR T-cell therapy.
We talked about allogeneic transplant, which is something we should not forget. In some patients that still remains an option. And of course, a number of novel agents are in the pipeline, BTK degraders, some of the T-cell engagers and hopefully more cell therapy options are becoming available for us to use in the clinical practice in future and always consider and prioritize clinical trials for patients for every patient including and specifically for patients with double refractory disease. Excellent. So this brings us to the end of this case. Please see our other segments for further discussion about the latest research in CLL or visit ascopost.com. Thank you.
