iwCLL 2023 | The use of anti-CD19 CAR-T therapy for Richter’s transformation

This is a really big pet project of mine, I’ve been working on this for quite some time, and so I was excited that I got to present it here at iwCLL. So this is a multicenter, international retrospective study that looks at the use of standard of care anti-CD19 directed CAR T-cell therapy for Richter’s transformation.

So this study was based off of a previous study that myself and Dr. David Bond, a colleague of mine at OSU, performed of nine patients who received axi-cel for Richter’s transformation. And in that study, those nine patients did remarkably well with close to a 100% response rate, with one patient dying of AE, but he did actually respond if you looked at CT scans that were performed around the time. So ultimately, this led to a multicenter initiative because it is very difficult to do a Richter’s transformation study, number one, and it’s even more difficult when you’re using anti-CD19 CAR T-cell therapy, which wasn’t really approved for Richter’s transformation until recently. And so this was…basically most of these patients probably got off-label CAR T-cell therapy, but now liso-cel is actually approved for Richter’s transformation because in the label you can give it to patients who have transformed indolent lymphoma, which Richter’s transformation is.

So we had seven centers and we had 55 patients and they either received axi-cel, liso-cel, brexu-cel, or tisa-cell. And it looked like the overall response rate for these 55 patients was around 61%, and the PFS and the OS were not as high as I’d hoped – the PFS was around four months and the OS was around eight months. Now, when you look at these numbers, you might say, well, CAR T-cell therapy probably doesn’t work for Richter’s transformation, but I would argue that these patients who were included in this particular analysis were very heavily pretreated. They got around two lines of therapy for their Richter’s transformation, and they also got around two prior lines of therapy for their CLL. In addition, the majority had either got in a BTKi or venetoclax or both at some point during their treatment. So this group of patients were heavily pretreated, really had all of the bad prognostic signs for Richter’s and they still responded pretty well to this therapy.

So I think there’s still room to improve around using CAR T-cell therapy for patients with Richter’s transformation, I think there are a lot of new trials that are coming out that combine CAR T-cells with BTKI’s and various other alternative ways of boosting T-cell effects, and I think that we still should pursue the use of CAR T-cell for Richter’s transformation, especially when there’s really no other option for these patients, especially after they’ve already been through two lines for their Richter’s transformation. In addition, we did a multivariable analysis to look at what predicted outcomes and increasing lactate dehydrogenase (LDH), increasing Ki-67, as well as increasing number of lines of prior therapy were all independent prognostic factors for survival for this group of patients. And so what this tells me is that we should maybe even be considering using CAR T-cell therapy as an earlier line of therapy than having already received two prior lines.

So I think more work needs to be done, but I still think that CAR T-cell therapy is a worthwhile endeavor to pursue for patients with Richter’s transformation, and I’m excited to see the results of a few different prospective clinical trials that are currently underway. One is my trial, which is zanubrutinib plus liso-cel for Richter’s transformation. There’s another study of ibrutinib plus liso-cel plus nivolumab for Richter’s transformation. And there’s another study that is currently ongoing that brexu-cel for Richter’s transformation.