The TRANSCEND CLL 004 study is a study of liso-cel CAR T-cells in relapsed/refractory CLL patients. We know that CLL is an incurable disease, or an incurable type of low-grade lymphoma, but we’ve come a long way in treatments in terms of finding non-chemo targeted therapies, for the most part, in these patients. Patients have been doing very well on these new medications for a long time, however, we’re starting to see a particular group of patients who have progressed on BTK inhibitors as well as venetoclax now. So there’s an urgent unmet medical need to find new treatment options for these particular subgroups of patients. That’s why we designed this liso-cel CAR T-cell study in relapsed/refractory CLL patients, especially who had progressed after BTK inhibitor therapy and most of them had also progressed after venetoclax therapy.
We enrolled 137 relapsed/refractory CLL patients on this study. They were all leukapheresed; we had 96% manufacturing success rate. There were about 20 patients who were not able to get their manufactured CAR T-cells for various reasons and so 117 patients were actually treated with liso-cel CAR T-cells. Out of those, 87 or so were efficacy evaluable subsequently. Our primary endpoint, actually, was complete remission rate in a subgroup of patients who had progressed on both BTK inhibitor and venetoclax therapy, so they were about 49 of those at dose level 2. Dose level 2 is the dose that was expanded, that’s the recommended phase II dose. So all these patients that I’m going to be talking about are pretty much treated at dose level 2, which is 100 million CAR T-cells.
So in that special sub-population of 49 patients, our primary endpoint was met; 18% was the complete remission rate in these patients. Our null hypothesis had been less than or equal to 5% in this very refractory patient population, so we had many more complete responders. Our overall response rate in this group was about 43%. This was not statistically significant compared to our null hypothesis of less than equal to 40%, but we had a whole lot of undetectable minimal residual disease patients, so up to 63% in the marrow and 59% in the blood were uMRD down to a level of less than or equal to 10-4.
Definitely we saw a lot of deep responses, and pretty much all of these undetectable MRD responses happened by the first timepoint of disease assessment after CAR T-cells which is day 30, so there were rapid and deep remissions. What we also found was that the complete remission patients did not reach their median duration of response, their median progression-free survival, or their median overall survival, so those responses are very durable so far. The median follow-up is about two years or just under two years, but I’ve certainly had patients who have gone even up to five years now without relapsing. So we’re still following a lot of patients over time and durability we’ll see over time how that plays out.
In the whole population of patients the median duration of response was about 31 months and the median progression free survival was about 20 months. It was very promising to see such deep and durable responses in such a refractory patient population.
So those were the bulk of the results; we found that pretty much there were very few if any major toxicities. Most of the cytokine release syndromes were grade 1 or grade 2, there were no grade 4 or 5 events. In neurotoxicity, again most of those were grade 1 or 2, there was just one grade 4 neurotoxicity and no grade 5 events. So fairly safely given, this particular CAR T-cell. There were probably 15-16% of patients who were treated on the outpatient basis as well, so we’re certainly learning more and more about that.
How will these results impact treatment?
That’s a very important question because in the new, novel targeted therapy era we’re trying to find ways to get to a cure for this particular disease. I’m not saying we’ve reached it but CAR T-cells might play a big role in trying to get there. Especially for patients who progressed after BTK inhibitor therapy and venetoclax and have poor-risk features of their CLL, for me it’s a no brainer; a one-shot treatment with CAR T-cells will give them a long treatment-free interval afterwards. If we can try to bring this treatment modality a little bit earlier in the lines of therapy because median lines of therapy for this particular trial was five, so patients had gone through a lot of treatments before they came to CAR T-cells. But if we can actually do it after two lines of therapy, or who knows in the future maybe even after one line of therapy, if we can do it earlier in lines of therapy the results might be deeper and more durable. So we have a lot to learn and improve upon, but it’s a very, very good first step in CAR T-cells to treating these very refractory CLL patients. So I think it certainly will fit in, I hope the FDA will approve it at some point in the near future. That way we can have it commercially available.
What is your take home message for medical professionals and patients?
I would suggest that they seek referral or consultation with a CAR T person at a transplant centre kind of situation, like City of Hope, early, if they’ve just started failing the newer drugs like BTK inhibitors. Don’t wait until they’ve failed two, three, four lines of therapy, just come and see us sooner and see if they’ll be eligible for CAR T cells sooner rather than later. That will benefit patients a lot more down the line. So just to be aware of that.