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?
Dr. Ahn:
I'm Inhye Ahn. I'm an Assistant Professor at Dana-Farber Cancer Institute and Harvard Medical School.
Dr. Stephens:
I'm Debbie Stephens. I'm an Associate Professor at the University of North Carolina.
Dr. Shadman:
Excellent. So, for our third and final case today, we'll discuss a patient with Richter transformation refractory to first-line chemoimmunotherapy. Let's start.
M.R. is a 56-year-old man diagnosed with CLL at an early age, at the age of 52. After a period of being on active surveillance, he started treatment on acalabrutinib and venetoclax, finished the 14 cycles, achieved a partial response, but had detectable disease both in the marrow and blood. But because he finished the fixed-duration therapy, he was observed off-therapy.
Two years later, he presented with rapidly enlarging cervical lymph node, night sweats, and highly elevated LDH on the blood test. On exam and on imaging, lymphadenopathy was confirmed. In fact, on PET scan, which is a test that we always do whenever there's a question about histologic transformation, the PET scan showed FDG-avid lymphadenopathy with SUV of 18 specifically in the cervical area.
Excisional biopsy was done. Again, that is preferred over core or other forms of biopsy. So, a total lymph node was taken out and did show large B-cell lymphoma. The physician was able to test for clonal relatedness, and that's something that's important to consider in a case of Richter transformation, and the large B-cell was related clonally to the underlying CLL.
So, for this patient, for the the first line of therapy, chemotherapy was used. Basically treatment that we use for de novo large B-cell lymphoma are commonly used in the absence of clinical trials, and this patient received polatuzumab vedotin plus R-CHP. The physician took a look after two cycles and basically there was no response. So, the disease did not change in terms of the size and disease burden was the same.
A blood test indicated some general mild to moderate cytopenias expected after chemotherapy, and otherwise no significant findings or abnormalities in the metabolic panel, including the renal and hepatic function. So, if we wanted to summarize this patient, a 56-year-old man who received one line of therapy for CLL, acalabrutinib and venetoclax for fixed duration, and a couple years after stopping that developed Richter transformation with no response to chemotherapy.
Dr. Stephens, what do we have available today outside of a clinical trial? And we'll get to the clinical trial options, but what would you use in your practice today based on what's available?
Dr. Stephens:
Yeah, this is really an all-hands-on-deck situation because this patient is in big trouble. The median overall survival for these patients is still 6 to 9 months, and especially somebody who's refractory to that initial chemoimmunotherapy. And keeping in mind that there are actually no approved therapies in the U.S. specifically for Richter transformation, and that's often because these patients are sick, and sometimes difficult to enroll on trials quickly enough, and they're excluded from a lot of the de novo diffuse large B-cell lymphoma studies.
And so, you have a few main classes that have shown activity, and you have combinations of BTK inhibitors and BCL2 inhibitors, and there's a lot of data on different combinations. Even ibrutinib/venetoclax, pirtobrutinib/venetoclax, and obinutuzumab are some combinations that could be attempted as an off-label option. Another class of drugs that's shown some activity here is just single-agent pirtobrutinib.
And the important data to know about that is from the original phase I BRUIN study, there was a whole cohort of patients, about 80 patients, which is quite a large study for patients with Richter transformation that received single-agent pirtobrutinib, and they had an overall response rate of about 50%. Only about 10% of those were complete remissions, but still that's a very good remission rate for patients with Richter.
The problem is that the median PFS was only about 4 months, so it's quite short. And in those patients who did respond, the median duration of response is only about 6 months. And so, there's clearly activity there, but that shows us that you can't sit around and watch these patients. Even if you get them on pirtobrutinib, you might want to consider combining them with something else. Another class of drugs that's approved for diffuse large B-cell lymphoma are the bispecific CD3 x CD20 antibodies, which have shown some activity in Richter transformation.
And so, you have these combinations of BTK inhibitors with BCL2 inhibitors, maybe bringing in even PD-1 inhibitors. So, activating the immune system. There's a lot of scattered data on combinations, but no clear choice in these patients.
In my clinical practice, number one, I'm going to aim to put them on a clinical trial. Number two, I'm going to start them on pirtobrutinib and then be lining up my next lines of options and potentially combining pirtobrutinib with another one of the agents I mentioned.
Dr. Shadman:
Excellent. Dr. Ahn, what's your goal of therapy? And I know you have clinical trials at your institution, but if a patient achieves, let's say a complete remission or close to that, what's your next step?
Dr. Ahn:
Definitely allotransplant. This is a young and relatively fit patient, so I would consider allo at the first attainment of complete response, be it after a couple of cycles of chemoimmunotherapy or pirtobrutinib plus additional agents, as Dr. Stephens reviewed.
I also want to bring up that bispecific antibody is an emerging class of a treatment. There has been a recent publication from the phase one study of glofitamab and Richter transformation that showed promising single-agent activity. It's a small study, 11 patients, but 7 achieved responses. So, I think glofitamab can be borrowed from the DLBCL patients and be used in a patient like this.
Dr. Shadman:
Great points. Dr. Stephens, we heard the rumor that on June 26, there will be the first randomized study for Richter transformation activated in the U.S.. Can you tell us about the SWOG study?
Dr. Stephens:
Absolutely. This is a really important study, as you mentioned, the first randomized phase III study in the U.S. for patients with Richter transformation, that looks at what is probably as good as anything as our standard of care, which is R-CHOP vs R-CHOP plus pirtobrutinib. So, trying to leverage that single-agent activity with the benefit of some cytotoxic chemotherapy.
So, patients with newly diagnosed Richters will be randomized one-to-one to either R-CHOP vs R-CHOP plus pirtobrutinib therapy. The endpoint of this study is looking at both PFS and OS, which are really clear and important endpoints for this particular patient population, and I think it's really important to put these patients on trial.
And so, this is a really great and exciting study that's led by Dr. Shadman here. And so, it's important to get this study open and try to recruit patients to this study to answer this important question: can we leverage both the benefit we've seen with R-CHOP and the benefit we've seen with single-agent pirtobrutinib by combining the two?
Dr. Shadman:
Excellent. Dr. Ahn, there are some other ongoing clinical trials with some of the classes of drugs that you already mentioned, including combination of pirtobrutinib plus epcoritamab in Europe, the German group. And I think there's also an ongoing study with immune checkpoint inhibitor plus zanubrutinib and sunrotoclax.
There seems to be more interest in having clinical trials for Richters from sponsors, from academia, and where do you see the next 3 to 5 years for Richters? And hopefully we will make the same progress we have made in other areas of non-Hodgkin lymphomas and Richters. Any final comments on that?
Dr. Ahn:
I think based on the current data, bispecific antibodies seems to be a very promising option. I think in parallel with the U.S. study that compares R-CHOP with or without pirtobrutinib, the German CLL study group has recently launched a randomized trial in Richter comparing R-CHOP to the chemo-free regimen of pirtobrutinib and epcoritamab. So, I think that study is a very interesting, ambitious design looking at the progression-free survival as the primary endpoint.
The other class that is interesting is BTK degrader. It has single-agent activity, currently very early data. But in the ASH poster presented by Dr. Thompson, there was a single-agent activity in 46% of the patients, and six of the patients out of about a dozen patients had more than six months of therapy with a pill drug monotherapy. So, very exciting, maybe well-tolerated in frail patients as well. I hope that there is more combination studies coming up after this.
Dr. Shadman:
Excellent. So, the clinical takeaways: Richter transformation remains an unmet need. So, clinical trials, clinical trials, clinical trials. We need to make progress there for patients who are waiting for the clinical trial or for whom clinical trials are not available. Pirtobrutinib now has published data with solid efficacy of responses around 50% and the complete responses of around 15% to 17%. So, that's an agent that could be used.
We talked about the U.S. intragroup study, SWOG-2504, or "pirAMID" that is a randomized study of using pirtobrutinib plus R-CHOP vs R-CHOP. That study is active as of June 2026 and we are highly encouraging all our colleagues to consider the trial. We talked about some of the other trials that are ongoing within the U.S. and different institutions, and also some randomized trials in Europe combining pirtobrutinib with epcoritamab, as bispecific antibodies are also very active and promising. There are also studies that combine BTK inhibitors, BCL2 inhibitors, and immune checkpoint inhibitors.
We talked about the importance of, the goal today remains to be getting the patient to complete remission, and if patients are eligible, then talk about allogeneic stem cell transplant. That is a process that needs to start early on. It requires a lot of logistical coordination, finding a donor, and really planning. So, early consideration, early discussion about allogeneic transplant is highly recommended and that includes early referral to the specialized center where there's access to all these modalities.
So, with that, this brings us to the end of this case, and please see our other segments for further discussion about the latest research in CLL or visit ascopost.com. Thank you.
