It’s a real pleasure to talk about our work and also to see a session focussed entirely on CAR T-cells is really exciting to me and represents the value that ASH puts on these new clinical approaches. So this is absolutely an update to a registration trial for what is painfully named tisagenlecleucel, previously called CTL019, and FDA approved as Kymriah. I’m speaking on behalf of an amazing group of international investigators who participated in this trial in 25 centres in 11 countries across the world.
This was the first CAR T-cell trial with a potential registration endpoint, the first global trial, the first trial in which there was a global supply chain from the drug company that was commercialising the product, which was Novartis. This was in patients under 25 years of age and these patients essentially formed the basis for the FDA approval in August 2017. After this we’ll hear about the further approval in lymphoma and this was the same product, just to be clear, these two talks are about the same product. Now this has moved forward to approvals in the EU, the UK, Canada, Switzerland and we’ll see about other countries as we try to approve global access.
These were relapsed and refractory patients, eligibility criteria: ages 3-21 although that was 21 at diagnosis so patients could be a little bit older. They had to have morphologic disease. We didn’t allow isolated extramedullary disease or prior anti-CD19 directed therapy, which included the drug blinatumomab. The overall endpoint was remission rate within three months, either CR or CRI with incomplete count recovery. This update is really eleven months further follow-up in this group of patients.
This and two slides from now are the key take-homes from what we’re presenting here. These curves, the first curve is the duration of remission curve and I want to be clear about the fact that we’re taking patients who have responded to the therapy and asked the question how are they doing over time. Now with more follow-up what we’re seeing is patients who go into remission, which is 82% of the patients, remaining in remission 12 and 18 months about two-thirds of the time, 66%. So that longer term follow-up is very exciting to us and indicates that there are a group of patients for whom this therapy, most of these patients did not go on to transplant and we’ll hear more about this in the future, this is a therapy that has the potential for long-term disease control. Then if you look at all the infused patients, the other curve is the overall survival curve and again we’re seeing excellent overall survival in these patients. So we’re pleased by this long-term follow-up data.
The overall survival numbers at a year 76% and at 18 months 70% so quite consistent with what we’re seeing in the duration of response curves as well. Obviously these are two slightly different analytic populations.
We’re really not seeing anything new in terms of toxicities. We see the significant toxicity of cytokine release syndrome, up to 50% of patients have significant cytokine release syndrome that was controlled by the toxicity management protocol that was developed for this protocol and has been used in a number of treatment protocols and commercial settings since then. Low infection rate. There are some patients who have cytopenias that don’t resolve, so grade 4 cytopenias in 18% of patients at day 28. Very low neurologic events, no grade 4 neurologic events and no cerebral oedema. So this has been consistent throughout the CHOP studies, the Penn studies and the various Novartis studies in terms of the toxicity.
This is the other fascinating new piece of information. The 82% of the patients who went into remission, all but one were negative for the typical approach to MRD, minimal residual disease, testing that we do which is multiparameter flow in the United States. This is another assay, a next generation sequencing assay, that is more sensitive, at least tenfold more sensitive. Here we’re asking the question what’s the impact of being sensitive by this next generation sequencing assay on these patients who are in remission. So you see this really significant curve separation between patients who are positive and negative. So patients who are negative by this assay about 80% of the time remain in remission and if they are positive more like 20% of the time remaining in remission. This is quite striking and this also holds up in the overall survival analysis.
So this is brand new data and that green curve, as we think about the role of transplant, and again you’re going to hear more about this, this is a group of patients that I’m wondering whether they actually need transplant and the vast majority of them did not get one.
So clinical outcomes. The other sense that we’ve gotten is that patients with high degrees of CRS also have higher degrees of neurologic events. We’ve seen more grade 3 neurologic events in patients who have grade 3 and 4 cytokine release syndrome. Again, we didn’t see any grade 4 neurologic events. The relapses, as a transplanter, look like relapses after transplant. So if you’re not relapsing by a year or two the likelihood of that happening is a lot lower, so it happens within the first year. Most of these relapses are immunological escape, CD19 negative, and those patients who have CD19 negative ALL still have CAR T-cells that are still working for the patients but they don’t prevent relapse because the ALL has lost the CD19. Then I already mentioned the MRD analysis.
So we think the efficacy is sustained and excellent – 82% of the patients achieving remission. These are durable CRs, even without further therapy, haven’t reached median duration of response or overall survival. We can manage toxicity and I think this is clearly an opportunity for us to treat our patients both in America and now across the world. Thank you very much.
Could you give more information whether a transplant is needed or not?
The role of transplant after CAR T is one of the areas that produces the most passionate debate. I am actually a bone marrow transplanter by trade and I actually find the idea of not being able to transplant a large number of these patients to be very attractive. The performance of these cells differs very much; the clinical trial setting is also somewhat different. Comparing trials to trials is sometimes a challenge. But the thing that has emboldened us to avoid transplant in 80-90% of our patients is really the issue of persistence. So you saw Shannon’s B-cell aplasia curve which applies to our data and because so many of these patients keep their CAR T-cells, this is the group of patients we’ve really focussed on. We agree very much that patients who lose their B-cell aplasia need more intervention before six months, so I think there’s agreement on that, and all of us are very uncertain about the issue of if you’ve already had a transplant, you relapse after a transplant, then are you going to need another transplant? That really seems like a bridge too far for a lot of our patients.