Richter's Transformation & CAR T Therapy in CLL | Adam Kittai, MD | ASH 2023

Hi, my name is Adam Gattay and I'm an assistant professor at the Ohio State University where I treat patients with CLL and Richter's transformation along with related illnesses. At ASH 2023, I had the honor of presenting two oral presentations regarding Richter's transformation. Richter's transformation is when CLL transforms into an aggressive lymphoma and is one of the areas of unmet need for patients with CLL because we've done so well with our treatments with CLL over the last 10 years that we still have this rare occurrence that can occur that leads to poor outcomes for our patients. About one to five percent of patients will experience a Richter's transformation at some point during their disease course, so luckily it's rare. But in recent evaluations, the overall survival for patients with Richter's transformation continues to remain poor. So in the last 10 years, we've revolutionized the treatment of CLL with the development of BTK inhibitors and BCL2 inhibitors, also known as Abrutinib, A-calabrutinib, Xanabrutinib, Venetoclax, and the recently approved Pyrto-Abrutinib. And all of our prior studies that evaluated Richter's transformation was for patients who developed Richter's transformation after receiving chemotherapy and maybe one of those new therapies. So we decided to do a study looking at patients who developed Richter's transformation who only received our new therapies because typically we only give these new therapies anymore and we no longer give chemotherapy. So this was an international multi-center retrospective study involving 11 academic centers and we identified 240 patients who had developed Richter's transformation who had not received prior chemotherapy. Excuse me. And of these 240 patients, 80 of those patients had received one of our new therapies. The other 160 patients had developed Richter's transformation without receiving any prior therapy. So we decided to compare these groups to see if there was any difference in their overall survival and also to see if there's any treatments that work better for patients who had received our new therapies for CLL versus our old therapies for CLL. And so what we found was that patients who had received small molecule inhibitors and then developed Richter's transformation did much worse than those patients who did, who had received no therapy and then developed Richter's transformation. The main overall survival, meaning how long do these patients live after a diagnosis of Richter's transformation for patients who had received prior therapy was only around eight months, whereas patients who had received no prior therapy had an overall survival that ranged from 40 to 70 months. When we looked at how these patients did in terms of their first line treatment, we also noticed that patients who had received prior therapy really didn't do well with any of our currently available treatments. Really identifying this group of patients who have received small molecule inhibitors, our new therapies, and then developed Richter's transformation really as a continued area of unmet need. So what do I tell my patients? I tell my patients now that if they develop Richter's transformation without receiving prior therapy, that they'll probably do pretty well, very similar to how a normal patient would do with Diffusal ARGP Cellulophoma, and we should continue using the therapies that we currently have. However, if they develop Richter's transformation after receiving treatment with some of our new therapies for CLL, I usually will try to get them onto a clinical trial or try to treat them with something that we haven't treated with them with before, because we know our prior treatments that we have don't really work so well in this group of patients population. So moving on to my second abstract, this really highlights a new therapy for patients with Richter's transformation. So CAR T-cell therapy has revolutionized the treatment for large B-cell aggressive lymphomas. But unfortunately, CAR T-cell therapy and the trials that led to their approval didn't include patients with Richter's transformation. So this specific abstract looked at patients who received CAR T-cell therapy for their Richter's transformation as the largest published data to date. So this was once again an international multi-center retrospective study of 12 academic centers, and we found 69 patients who had received anti-CD19 chimeric antigen receptor T-cell therapy for their Richter's transformation. This was one of four FDA approved products for CAR T, and that include Axa-cell, Lysa-cell, Tissa-cell, and one patient with Brexa-cell. This was a very heavily pre-treated group of patients. They had received four prior lines of therapy total, including CLL and Richter's, and two prior lines of therapy for their Richter's alone. So really, we don't have any therapies available for this group of patients that we looked at. And these patients didn't do as well as we had hoped, but there were a certain subset of patients that did remarkably well. So the progression-free survival, meaning how long did these patients take to progress after receiving CAR T, was about five months. And the overall survival, once again, how long did these patients live after receiving CAR T-cell therapy was around nine months. However, about 47% of patients attained a complete response, meaning that we could not detect their disease after receiving CAR T. And of those patients who attained a complete response, the duration response, meaning how long did they have a response after receiving CAR T was 27 months, which is quite remarkable. So we now know that CAR T works for a subset of patients. We're working on identifying what these subset of patients are and how to implement CAR T into the future. And one of the things that we found in the study was that for patients who had received less lines of therapy, they tended to do better, meaning that we need to implement CAR T sooner in the treatment algorithm for patients with Richter's transformation. So I'm excited to present this data because it really concreates that CAR T does work for a subset of patients with Richter's transformation and really encourages the continued use of CAR T for Richter's transformation. So now we need to figure out how to boost the effects of CAR T for Richters. And there's multiple clinical trials that are currently looking at this. One's at the Ohio State University that combines Zanabrutinib, a BTK inhibitor, with CAR T. And another one's at City of Hope, which combines Ibrutinib, a BTK inhibitor, plus CAR T, plus that PD-1 inhibitor, nivolumab, that's currently accruing. So this is all exciting data for our patients, excited to continue to offer CAR T for our patients with Richter's. And I encourage our patients with Richter's to seek out a clinical trial and an expert opinion. Thanks for listening to my talk.