In ALL we use a drug called dexamethasone in the induction therapy at the beginning to try to get the kids and young adults into remission. Dexamethasone has been studied and compared in a lot of studies compared to the steroid we used to use called prednisolone and it is definitely better at reducing relapse rate. The problem is that it’s also toxic and all the studies that have shown that it improves relapse risk also show that it ultimately ends up killing some children primarily through infectious mortality in that induction. So that was the background – we’ve got a drug that’s more effective but more toxic and how do we move on from there?
Some study groups have chosen to not use dexamethasone or not use it in certain groups. We took a view that we’d try to use dexamethasone in a different way to try to avoid that toxicity. The way that we chose to do that was you standardly give dexamethasone over 28 days at a fairly standard dose; we looked at a regime that used it at a slightly higher dose but just for 10 days, trying to see if that would reduce the toxicity. The logic and the theory behind that is if you look at the toxicity from dexamethasone quite a lot of it happens in the second half of induction so we reasoned that maybe it’s a time of exposure as opposed to just a dose effect. The regimen that we used has been shown to be safe in other studies where they’ve used that short dexamethasone, that’s what we call it. So that was the rationale for what we studied.
How many patients were involved?
We were looking originally for about 2,500 patients, in the end we studied just over 1,900 patients. We stopped the study early because we saw an excess of induction deaths in one of the regimens that we were studying. So about half the patients get three drugs in induction and the other half get four drugs and we saw an increased induction death rate in the patients with the three drugs. Now, we didn’t know the results of the randomised part of the study but we saw that so we asked the data monitoring committee to have a look at this. They looked at it and they decided it’s time to stop. They basically said we’ve done a futility analysis which looks at whether you’re going to answer your question, they said, ‘You’re not going to answer your question so you should stop now.’ So we ended up with 1,900 rather than the planned 2,500.
Can you give me a bit more detail on what you found?
We then looked at the data a few months after the data monitoring committee had said stop when we’d got all the data. What that essentially showed was that there was fundamentally no difference between the short dex course and the standard one, that it didn’t make anything any worse but it did not make things better. When we delved into that we were looking at three different things – we were looking at induction deaths, which is a very clear marker of how things are, that’s very obvious, but also looking at a thing called serious adverse events and if they were steroid related whether there was any difference in the number of those that happened between the arms. So we looked at all that and essentially there was no statistical difference between the two.
When we delved into it a little bit more there were numerically more deaths with the short dex than with the standard dex and that was surprising. So we then looked at that even further and we looked at that when we used the short dex with the three drugs or we used it with the four drugs and we saw that those numerically increased deaths were actually with the three drug induction. So this is the safest and the simplest arm to deliver, not with the more complicated one. That was odd. So we’ve looked at that.
Now, overall on our study the actual induction death rate is lower than our previous study, it’s about 0.85% and that’s quite a low figure of induction death rate; that’s very good. Indeed, in our four drug arm we’ve got a markedly low induction death rate, it’s about 0.5% with the standard dex and it’s even less than that with the short dex. So that’s really very good and that shows that we can do that very safely. But it’s slightly confusing – we’ve got more induction deaths just with three drugs and short dex and that’s quite a high figure compared to international norms. That’s what we’ve seen, none of that is statistically significant and it may simply be a small numbers effect. We don’t know absolutely but we’re looking at that. But on the face of it short dex hasn’t improved things but things have improved generally compared to our previous trial. That might be because we’ve just got better at looking after patients, we’ve got more used to using dexamethasone. It may be a little bit to do with how we allocate Down’s Syndrome patients to treatment, they’re doing better in terms of toxicity than before. So those are the main findings.
We did also look at a side effect called osteonecrosis which is where your bones get damaged and that’s primarily driven by the steroids you get. There didn’t seem to be any major difference between the short dex and the standard dex there. There might be, there’s a signal towards the short dex being a little bit better in the patients who are over 16 but that’s not significant and the numbers aren’t there to say that that’s going to hold with longer follow-up.
Finally, we did look at whether there was any effect on relapse rates. That wasn’t the question we were asking, there shouldn’t have been and reassuringly there isn’t. There’s no difference in relapse rates between the two arms so they seem to both be equally effective but at the end of the day the short dex is not less toxic than what we’ve previously done.
Can you give us a bit more info on the implications and the next steps?
We haven’t found out that short dex is any better than our standard way of doing it. So in that sense it’s a negative finding but the positive out of this is that it seems that the way we use standard dex has got much safer. We have really reduced the induction death rate. It may sound trivial, we’re talking about the odd percentage here or there but this is a disease that we can cure 90% of children and so losing any children at all to induction death is a really bad thing. So it’s really reassuring that we’ve got such a good induction death rate, such a low induction death rate, just with the standard way of doing this which really reassures us that we can keep using dexamethasone throughout our studies going forward. That’s what we’re going to do in our next trial that we’re developing at the moment, dex will be in there for all patients in induction.
Can you give me some more details on the next trial?
We’re just forming it together. It’s a collaboration, it’s a cross-European collaboration, it’s called ALL-Together. Fourteen countries, 1,400 patients a year. The UK is a big contributor to that but we’re joining a lot of our European colleagues in developing the next trial. As things get better and the cure rates get ever better in paediatric leukaemia we need bigger and bigger numbers to answer questions because if you’re looking for small differences you need lots of numbers to answer those questions. So we’ve had to come together; it’s been great coming together. We’ve almost finished off developing our backbone and we know what the questions are we’re going to ask and we’re just finishing that off and hoping to get running in the next year or so.