It was of interest to me, many years ago when I was beginning this work, to try to understand why there were differences in outcome of the same disease, acute lymphoblastic leukaemia, in children versus young adults versus older adults. One of the things that we thought to do with a paediatric colleague of mine at the University of Chicago using the co-operative group mechanism was to compare outcomes of a similarly treated group of patients by both paediatricians and adult clinicians, and that’s the group between ages 16 and 21 years.

Can you actually define a group like that as being totally different from the older adults?

We can now, it wasn’t so clear back then. But that was the one group that was overlapping and the treatment approaches were slightly different by the adult groups compared to the paediatricians, even though many of the adult regimens, including the ones that we had used, were developed from paediatric regimens but they diverged over the years. So the one thing we thought to do was let’s look to see if outcomes in a similar age group of patients were identical if a paediatric regimen was used for those patients, given by paediatricians, versus an adult group regimen given by adult haematologist oncologists.

Could you say what you did, what the protocol was for this study?

It was a retrospective analysis of about a decade and a half of clinical trials performed by the Cancer and Leukaemia Group B, which is the adult co-operative group with which I’m affiliated, compared to the Children’s Oncology Group, or CCG, combination group at that time which is the children’s co-operative group in the United States. So there were a series of trials performed by each of those groups and we looked at the outcomes of 16 to 21 year olds.

Now you would have had a more intense regimen as compared with adult regimens, wouldn’t you perhaps? And also more consolidation perhaps?

The differences are actually… we call them intensive paediatric regimens, our adult regimens were also very intensive but they were intensive in different ways. The drugs that the paediatricians have always intensified were different from the ones that we’ve intensified. So therein lies part of the treatment, the major part of the treatment difference.

I want to ask you about the benefits, but first I do want to ask you about toxicity, because the big risk is you could end up with too much toxicity.

Yes, so part of the reason that these regimens evolved in the adult co-operative group away from the paediatricians was in part just because of the fact that we believed that dose intensification of drugs that cause bone marrow suppression, called myelosuppressive drugs, would be important for both ALL as well as in AML. Because we use that approach in AML we decided to use that approach in ALL as well whereas the paediatricians have focussed on another series of drugs that are an important component of ALL regimens and those are drugs that include glucocorticoids, vincristine and asparaginase. These are not such myelosuppressive drugs but they’re very intensive drugs for the treatment of ALL.

In your group of young adults and adolescents did you get a high toxicity?

Are you talking now about the retrospective?

The retrospective study, yes.

Yes, the toxicity profiles are very different and there was quite a bit of toxicity in both but the treatment related toxicities were different but not dramatically so for that same age range of patients. But the outcomes were dramatically different and so dramatic that it caused a big uproar when I first found those data. I didn’t actually believe them myself when I first saw them, this was a long time ago now, but there was a 30% difference, more than 30% difference, in survival, event free survival, if you were a 16 to 20 year old treated on a children’s regimen versus an adult regimen. And that’s why we’ve moved forward.

So what were the outcomes of… you’ve been looking, then, at 318 patients of whom…

Now, that’s a different story. Now we took that…

OK, so tell me about this study.

OK, so the study is a prospective study of actually 296 eligible patients treated by the United States co-operative groups. They were between ages 16 up to the age of 40 and with both precursor B and precursor T ALL. We took the paediatric regimen that was most recently used for high risk paediatric ALL by our colleagues in the children’s oncology group and we applied that identical regimen to this population of patients.

Primary endpoint was what?

The primary endpoint was actually feasibility, tolerability and event free survival.

What did you get?

We got the fact that we showed that it was feasible, it was tolerable, that our treatment related mortality was not different than a similarly aged population treated on the children’s oncology group trials. There were some subtle differences in toxicity, particularly during the first month of treatment, that we still need to tease out but the important point is that we were able to accomplish this regimen, that we had low treatment related mortality and that our event free survival at two years, which is still quite early, has improved from our historical control which was longer follow-up, admittedly, of 34% to now 66% with 79% overall survival with nearly three years of follow-up now.

Sounds quite good, what do you conclude from this?

What we conclude is that we’re not the only ones to have shown this, we’re the largest study to have shown this. Other smaller studies have been done both in Europe and in the United States that have demonstrated that the use of a paediatric regimen is possible by adult haematologists for young adult patients with acute lymphoblastic leukaemia, that it seems to improve outcome and our conclusion is that we’re going to use this regimen or a very similar regimen as the foundation for building future studies.

But you’ve been saying that not all patients are the same, there may be a worse prognosis group among these and you can molecularly identify them.

That’s correct and we can identify them in a number of ways. Two of the ways we’ve looked at is that recently a number of groups in the world have described a BCR-ABL like signature which basically is a gene expression profiling signature demonstrating up-regulation of multiple kinases, many of which are targetable therapeutically. The other way to monitor these patients is by detection using molecular methods of minimal residual disease. What we have found is that there are patients with this BCR-ABL like signature who comprise almost a third of these patients who do poorly. Some of them have, and others don’t have, but another important prognostic marker is this minimal residual disease after induction therapy. So using both of those features we are able to identify high risk groups that we may be able to specifically target with particular therapies.

So what should doctors get out of all of this, then? It sounds interesting.

It’s a very promising result. The most important message that I would like to convey is that I feel it’s critically important for this age group of patients to be enrolled on clinical trials. In the United States we’re not as good in the adult groups at getting referrals for these patients to enrol on clinical trials, unlike the paediatricians who are generally all enrolled on clinical trials in the United States. That’s the only way to make significant progress in survival. So, as we move forward now, we have multiple very exciting new agents that we can incorporate into the front-line treatment of young adults with ALL but that we need to do this in a prospective clinically trial driven fashion.

You have some experience, though, so what would you pass on to the doctor with a young patient with ALL in this category, young adult or adolescent? 

I think that this approach is reasonable. ALL is a difficult disease to treat, it needs to be treated by an experienced medical centre group that has a lot of experience treating this disease. That’s one of the main reasons that ALL has improved so significantly in children in the United States and perhaps one of the reasons that we’ve lagged behind. We’re very pleased and proud of our results that show that the United States co-operative group mechanism can work for improving outcome of young adults with ALL but we need to do better and one of the ways we’ll do better more quickly is by enrolling more patients on new and important clinical trials.