Hematologic Oncology Update, Issue 3, 2016 (Video Program) - Video 5Case discussion: A 62-year-old man with chemotherapy-refractory diffuse large B-cell lymphoma whose disease is controlled with R2 achieves a complete response with chimeric antigen receptor T-cell (CAR-T) therapy
5:49 minutes.
TRANSCRIPTION:
DR NASTOUPIL: I had a 62-year-old male who was essentially primary refractory. He was advanced stage at presentation with bulky disease, with a greater than 10-cm intra-abdominal node. It was a nongerminal center. And in the midst of R-CHOP, he had an interim scan that looked like he was responding, but at the completion of 6 cycles of R-CHOP, he still had refractory disease. And we could critique what was done at that point, but he essentially underwent consolidative radiation therapy. And within the time period of completing his radiation, he had progression outside of the radiation field. At that time, he went on to receive R-GDP, which is based on a publication that’s come out in the last few years primarily from the Canadians, looking at R-GDP versus R-DHAP, which appears to be equivalent in terms of efficacy but slightly better tolerated. And it might be more appealing as an outpatient regimen. Unfortunately, he was still refractory to his first-line salvage therapy. At that point, he was initiated on R-ICE. And there is data that is coming out of the CORAL study looking at folks who fail their first salvage and what is the response to second salvage. And generally speaking, when patients are primary refractory, their outcomes are quite poor. So in general, their overall survival is expected to be, at best, 20%. Of those who fail second line, again, very, very poor outcomes. But if you look at that paper closely, you might be able to salvage as many as 40% of patients who still fail their first salvage therapy and not necessarily the primary refractory. So I don’t think it’s unreasonable to try a third-line chemotherapy, but our optimism at that point of it working was quite low. He was then initiated on lenalidomide and rituximab. This is a gentleman that was not close to Houston. So he lived approximately 8 hours away. And participating on a clinical trial was not entirely feasible. So we treated him with lenalidomide and rituximab and actually had a quite good outcome. He did not achieve a partial response, but he did have reduction in tumor volume. But what was so striking is that he had been rapidly progressing in the setting of chemotherapy, but in the setting of lenalidomide, we actually gained disease control and actually had some improvement in tumor volume, though again, not more than 50% to classify him as a partial response. At that point, we then were successfully able to enroll him on a clinical trial, which it’s amazing what patients will do whenever they are faced with essentially refractory disease. But we were actually successfully able to treat him with a CAR T cell on protocol, achieving his first complete response and also which has been durable. But what I wanted to highlight in this case is that there are clearly targets in the nongerminal center large cell lymphoma which appear quite appealing, particularly for patients who are not chemosensitive and not your candidate for high-dose therapy/autologous stem cell transplant. It also suggests that if you can identify a subset of patients that respond to immune therapy, a more intensive or specific immune therapy approach might be quite appealing. So I generally think of lenalidomide as having 2 aspects. One, you’re targeting the nongerminal — the B-cell receptor signaling pathway. And you’re also augmenting the innate immune system by enhancing NK and T cells. So I generally will use this approach particularly in my nongerminal center large cell lymphomas who are not trial candidates or are not candidates for high-dose therapy and autologous stem cell transplant. DR LOVE: With or without rituximab? DR NASTOUPIL: That’s a great question. So if you look at the studies without rituximab, the response was only about 20%. When you add rituximab, particularly in Phase II studies, you get higher response, but it’s much more durable as well. So there are clearly subsets of patients that respond well. At least that’s what we’ve learned from our Phase II studies. But about 30% of patients will respond and do so for more than 6 months. DR LOVE: So how long has it been since this patient got the CAR T therapy, and is he — DR NASTOUPIL: So he underwent CAR T-cell therapy in December of 2015. DR LOVE: So that’s like 9 or 10 months. DR NASTOUPIL: Correct. DR LOVE: He’s in CR? DR NASTOUPIL: Correct. DR LOVE: Wow! What a story. I want to ask you about that, but just to pick up on a couple of the other things first. First, do you think that — it’s interesting that he benefited from the lenalidomide and then afterwards benefited from CAR T therapy. Do you think there potentially could be any connection or even something related to sequencing? DR NASTOUPIL: Yes. I think you highlight some really good questions that we don’t currently know the answer to. We generally do like to see some sense of response before I will take patients to CAR T. And what I mean by that, if I can debulk them some, I generally think that they will have a better outcome. Now, this has not been described in prospective studies, but we do know that the CAR Ts are currently associated with pretty high toxicity. And so if we can have some idea that they’re going to respond to an immune therapy approach with something such as lenalidomide, and if I can reduce the proliferative rate prior to proceeding with CAR T, I’m much more optimistic about the outcomes in those patients. Now, generally speaking, we’ve seen only small case series that have been presented at meetings in terms of the CAR T efficacy, but it does appear to be quite high. But there are some patients that do fail. And we’re trying to tease out who those are. And does it have to do with the conditioning regimens? Does it have to do with the loss of CD19 expression? Does it have to do with just the limited efficacy with the CAR Ts themselves? So there are many questions that are still being teased out with the CAR T. But, we do know that the toxicity is not something that should be minimized, and it should be managed with, again, a multidisciplinary approach in centers where you have access to ICU care, because these patients can get quite sick in a very short period of time. So my general opinion is that it’s more toxic than an autotransplant, but it might be applicable in a patient who has chemorefractory disease who’s not a candidate for auto and you’re not going to get the patient to an allotransplant. DR LOVE: And you’re kind of talking about the cytokine release syndrome that’s seen with CAR T therapy? DR NASTOUPIL: Correct. |