We started very many years ago, I think about fifteen, in a protocol for elderly patients or the worst category of patients. Just to remind ourselves that in the past Philadelphia positive ALL was the worst condition you could get in haematology and maybe even in cancer. So we designed a protocol many years ago for elderly, so that’s even worse because to treat a 70 year old, 80 year old with a Philadelphia ALL was palliative treatment very often. So we decided to do a protocol for the over 60s with no upper age limit which was based on only imatinib, so the first generation TKI, plus steroids in induction. The surprise was that literally all the patients went into haematological remission. I’m not saying they were cured, I’m saying they went into remission which in those days was an exceptional result. We had no losses in induction, there were no deaths in induction.

But that was the starting point of a long story. It went into second generation, dasatinib, then we tested nilotinib, then we tested ponatinib, but keeping the same philosophy – an induction treatment without systemic chemo. We had seen less prophylaxis, we had steroids, but if chemo was given it was given after induction.

So this has built up and the data have been rewarding because we kept on seeing haematological remission in virtually, let’s say, between 95-100% of patients and we’ve never lost patients at induction so it’s non-toxic. Obviously you have to consolidate after that so there’s an open question.

The protocol we are talking about now is a further step forward because over the years things change, more drugs come on the scene and one in particular was of particular interest to us in ALL, not only in Philadelphia positive. This is blinatumomab, this bispecific monoclonal antibody which is a form of immunotherapy because it’s bispecific in the sense that it targets an antigen present on all B lineage ALLs, which is CD19. Then the anti-tumour effect is mediated by the host, by the patient’s CD3 T-lymphocyte. So it’s a form of immunotherapy triggered by this antibody and directed against B-cells which are targeted by CD19.

So this monoclonal antibody is of interest and there have been data over the years. It has developed and it has led to the approval first for relapsed/refractory ALL, B-lineage ALL obviously, and more recently even for MRD. So we designed a protocol which was based again on dasatinib. We kept the second generation because we thought it was adequate and we had long data with dasatinib alone. So the induction hasn’t changed, dasatinib and steroids, then as consolidation we included blinatumomab for a minimum of two cycles. The primary endpoint of the study was the rate of patients becoming completely negative at a molecular determination, MRD negativity by molecular monitoring. After two cycles, that’s when we did the testing, we could extend it up to even five cycles and then after that it was open, the centres could do what they wanted and we would get the data in the SIRIUS study and that is what we are doing.

So the study was closed recently and we’re presenting for the first time here the data. It’s the first presentation, first ever presentation, as I said, on Sunday morning. The data are very rewarding because what has happened is that with dasatinib alone we’ve obtained about 25% of complete haemo responses which is in line with what we’d seen in the past with our previous study. Then after blinatumomab we’ve seen a progressive increase in the rate of patients becoming molecularly negative, reaching about 65-70% of patients which is an exceptionally high rate of complete molecular response without any chemotherapy apart from the CNS prophylaxis. So that obviously is extremely important because, again, this study was for all adult patients, 18 up to 70. I think the oldest was 79 but I’m guessing, close to 80 anyhow, and they virtually all responded.

So that opens many important points – a) that you can without chemo get very high rates of continuous response and I remind all of us that in an acute leukaemia we need to become MRD negative. If not, if you have residual disease the patient will eventually relapse. So I’m not saying that if you’re negative you don’t relapse but the likelihood that you don’t is much higher. That’s a key point. Second is that we saw an interesting phenomenon that is very new that even after the second cycle of blinatumomab we kept on seeing an increase in MRD negativity. This is very different from what is in the literature seen before with full-blown relapse with a maximum response after one or two cycles. So this opens an interesting question on the mechanism – is this maybe leukaemic stem cells? So we need more research.

The second point, that we had some patients who had developed in the last days of dasatinib treatment a mutation, a 315 mutation, which may confer resistance to dasatinib. This, all patients responded to blinatumomab so we got rid of the mutation too. That’s a very important piece of information.

So we’re very excited on this and obviously it’s not the end of the story but it’s a major step forward. So the next protocol we’re working on is what do we do after that and we are probably going to use a further third generation inhibitor trial to obtain that. So it’s very good news because particularly to remind ourselves that the incidence of the Philadelphia positive ALL increases with age so if you’re over 50-60 it could be one out of two of the B lineage ALL carrying this genetic abnormality. So managing to obtain a molecular response in most of these patients without chemo, which is difficult to give in an elderly patient, is obviously a major step forward. So the next study we hope to prove this and probably even reduce the number of patients going to transplant which would be good news. So I shouldn’t say but we are obviously very happy with the data and I think it’s a major step forward.