EHA 2010 Annual Meeting, 10-13th June 2010, Barcelona
Professor Tony Goldstone (University College London Hospital, UK)
Treatment of adolescent and adult acute lymphoblastic leukaemia
We, in what used to be called the MRC in the UK, have been doing a joint study with ECOG, the Eastern Co-operative Oncology Group from the US, because this is a rare disease actually in adults, since 1993 and closed it in 2005-6 and reported the data in 2008, two years ago. That accrued 2000 patients which gives a very considerable number for a proper statistical analysis.
One of the problems with this rare disease has been that there haven’t been enough patients in any individual study to make clear-cut conclusions before. Now we’ve analysed that data, in the UK that was called UKALL12 and because, superstitious though we are, we called the next one UKALL14. Some people didn’t want to use UKALL13, I think it’s childish nonsense, but anyway the next study is just starting, UKALL14. Basically what we did with these adult patients is as soon as they were diagnosed and treatment began to see if they had a sibling or very closely related family member who was an identical donor. And if they had, and they went into remission, the plan was to allogeneically transplant them, do an allograft. And for the rest of the patients who didn’t have a sibling donor, we randomised them between extensive long-lasting chemotherapy and a much shorter treatment that included an autologous transplant at the end.
So the autograft arm would be complete in about six months or a bit longer, whereas those in the chemotherapy arm would have treatment for two and a half years, and the rationale was that if the autotransplant was just as good, if not better, it might be a better bet for some patients to have the shorter treatment. So the only way to study this properly was in a randomised fashion and that’s what we did.
What were the results of this trial?
There are two main conclusions, and the first one is if you have a sibling donor it’s the right way to go to have that treatment. That’s on assessment by what’s called a donor versus no-donor analysis, which means all those that had a donor are compared in outcome against all those that didn’t have a donor. However some of those that had a donor didn’t actually have the transplant although they’re still in the donor group. And that is superior for all age groups. This was a study which started at 15 years and finished at 60 years. And that’s the best treatment of all, seemingly.
Now, if you didn’t have a donor and you were randomised between chemotherapy and the autotransplant, surprisingly or not, and perhaps disappointingly to some of us, the chemotherapy arm came out with a better survival of around 7% or 8% superiority.
Now, for all these three groups, chemo, auto and allograft, the survival was not that great, although it was 10% better clearly and significant for the allograft. But this is a disease which, compared with paediatrics, doesn’t have a great outcome, so you know the best group are having a 40-50% survival at five years.
What possible explanations are there for these negative results?
One of the contentious issues that has emerged is that it looks possible to give what is called paediatric-style chemotherapy to a much higher age group, certainly through the teens and into the early twenties and perhaps beyond. And it looks as though the data shows that this will produce a better result than trying to transplant any young patient under the age of 25 or 30 with either an allogeneic transplant or an autograft. Because people are concerned, of course, about losing the patient with the treatment and of course of the toxicities of the transplant, even when it succeeds in terms of GBH etc.
How is risk defined in this disease?
You define risk in this disease at two different points when you see the patient. The first is what are the features when you diagnose them? How old is the patient? What is the blast-cell, the white cell count when they first present? Because the higher it is the worse it is in terms of prognosis; and have they got any of the chromosome abnormalities in the bone marrow which we know are going to produce a bad result on conventional chemotherapy? So you define high and standard risk pre-treatment. Now, what’s happened in the last five years in the adult scene is that the value of measuring MRD, or Minimal Residual Disease, has been learnt from the paediatricians who have been using it for over ten years, and showing to know when everything looks well, whether there is still a refractory disease in small amounts, or indeed whether it reappears in a patient you thought of as in remission. So you can factor in now this MRD analysis in addition to all the pre-treatment characteristics. So it gives you a whole extra dimension in terms of the rationale for considering a transplant or not.
Does this allow you to monitor the dynamics of MRD during therapy?
Yes, and it’s exactly what you should do, particularly in the first few weeks or the first two to three months of therapy. Whether that Minimal Residual Disease disappears entirely or not is going to be very important, both to the patient’s general outcome and to what kind of treatment you may select later.
Has the range of transplant options increased in recent years?
Yes, when that UKALL12 MRC study started 17 years ago in 1993, I think the only serious kind of transplant considered was a sibling transplant. We did make one caveat for the Philadelphia positive group, which was that if you had an unrelated donor, the results were so bad on conventional therapy they could take the risk of that in a patient who had the Philadelphia chromosome. Now there’s more evidence about two other kinds of transplant. And the evidence is that unrelated donors in general, if they are well-matched with the patient, produce just as good a result as sibling donors. So if you wish to, and it was appropriate, you could widen the constituency of eligibility for transplantation. The second important thing is this so-called Reduced Intensity Conditioning, or RIC transplant, or mini-transplant. The rationale for that is as follows: that in this disease the conventional therapy for the over-40s produces very poor results indeed, and strangely enough, unlike in many situations, you might consider a transplant for them because, although risky, it might still produce a clear-cut more superior outcome. What the Reduced Intensity Transplant does is actually very clever in rationale, I can say that because I didn’t devise it, which is to reduce the ablative toxicity of the transplant so that there is less chance of losing the patient from treatment, yet continuing to harness the allogeneic effect so that, if you like, the graft eats away slowly at the residual disease and you don’t try to give it one walloping at the beginning. And there’s a lot of evidence that this makes the whole procedure less toxic, and that the older patient can survive it and benefit from it in a reasonable fashion, unlike a so-called myeloablative transplant which is very difficult over the age of 40 or 45.
What problems can be associated with this treatment?
Well just because it’s reduced intensity or RIC conditioning doesn’t make the whole game easier, because you may not lose these patients from the immediate toxicity but they may have problems in engraftment and they may have more problems with relapse, so re-emergence of disease because the conditioning regimen is less aggressive. And because they are very immuno-suppressed, they may have even more opportunistic infections than the regular transplant, so it’s not easy, no.
Why are you investigating the use of autogous stem cell transplantation?
Well, as I said previously, when we structured the study in 1993 it was on the basis that if autograft was the same or better in terms of survival, it represented a better buy for the patient because it was shorter. Unfortunately it turned out 7% worse, so on a big randomised study published in Blood it got cast into the wilderness. Even at that time I thought some patients may still take the option of having something 7% worse if they finish a year and a half earlier, but the way randomised trials work, they don’t get offered it anymore. But there’s now a new kid on the block in all this which is MRD. What we did not know when we structured the initial study and when we carried it out, is what was the MRD status of those patients who were getting an autograft. And there’s now data, not surprisingly, that shows if you have MRD residual disease and you have an autograft, you’re pretty likely to relapse. In actual fact the data shows that if such patients have an allograft, even with the MRD, the allograft may eliminate it because there’s the immune system from another donor, but the autograft couldn’t. However on the other side, if you are MRD negative and you go into the autograft, that there’s no residual disease at that point, there’s an emerging amount of data which suggests that actually this may indeed be a useful treatment and those patients if autografted might not finish on the worse side of patients with chemotherapy. So there is an argument, strangely, to reconsider the autograft in an MRD negative patient, which to me is actually amusing and really quite positive.
Could autologous stem cell transplantation be more effective than allograft?
That’s an interesting question and as always we don’t have the answer. But if you look at the MRD negative patient getting an autograft, well it just may be that particularly for the MRDs, the unrelated donors or the RICS for the elderly patient, it might turn out to be a better bet, but of course we can speculate as we like; those studies need to be done properly.
Now the MRC ECOG study of seventeen years had its positives and its negatives. Its positives are it’s the biggest number in one single trial so it gives you some clear-cut recommendations. And the negatives are that the world moves on apace and you can be stuck with an approach where there are emerging things happening. And the use of the MRD was not relevant to that study but I think is clearly important. So we have to use it now.
What advice do you have for clinicians treating patients with ALL?
Well the advice is actually very simple, but it may not be available to everybody. I think it’s widely thought, if we look at my own country for instance, that if you are a general paediatrician and you have a kid with ALL, that child goes to a major centre and likely goes into a properly structured study. You may end up with shared care between you and the major university centre, and that’s fine and good for the patient. This is much less likely to happen with the adult patient where the general haematologist is trained well in the management of leukaemia and can treat the patient, but actually, a lot of the adult patients do not get put into formal studies, which is a great shame. In my country we find that they get treated on the same protocol actually, but the centres haven’t gone through the regulatory business to get the study approved, and they haven’t got the data management and they haven’t got enough staff to send every sample for analysis at exactly the right time. So in many ways the patients are not worse off, but actually for the future, with these very complicated selection criteria, for different kinds of transplant or not, my most simple recommendation is that more and more adult patients must go into formally structured trials in major centres in all countries in Europe. In the UKALL12, which is the thing we started in 1993, we had 120 different centres. Some people are only seeing one, two, three patients a year, and it’s too much to put the study through all the regulatory issues. So the simple firm recommendation is, if you’re not going to be a centre yourself, is to liaise with and centralise the treatment of adult disease so that we can harness the value of MRD and other decision making much more scientifically than we have been doing.
Does the addition of TKIs to chemotherapy eliminate the need for transplant?
Whether the addition of the TKI to the chemotherapy eliminates the need for transplant at all in the Philadelphia chromosome may be true in the younger patient. I am certainly not convinced it’s true in many adult patients, I think there’s still a place for transplant.
To summarise the whole picture in fact, you end up with this very strange anomaly, where for thirty years we have been talking about transplant for younger patients in all sorts of diseases and transplant being too toxic for older patients. So in this disease you might have a shift of the age-frame for eligibility for transplant, so that there are fewer younger patients, because they do well on chemo without it, and with the paediatric style chemo and monoclonal antibodies, and actually more transplants in older patients because the chemo results are so bad, but the transplant itself may become more tolerable. So this is a great irony and it’s possibly the first time it’s ever been seen in haematology. So less for the young and more for the old.
Is there an age limit after which it is difficult to treat ALL?
Well I think it’s very difficult to accrue meaningful data over the age of 65 or so, although there are certainly patients in the older age group. They can clearly not tolerate the same level of aggressive therapy as the younger patients, and not tolerate any kind of transplant at all. But you may be able to get them into remission very easily however, and the trick will be some simple treatment to keep them in remission without very aggressive therapy. This is possibly more use of monoclonal antibodies such as Rituximab and Epratuzumab continually through the treatment, and maybe the use of these new BiTE antibodies in addition, and all that remains to be explored in the next few years.
What is your key message for clinicians treating patients with ALL?
This is a very easy disease to get into remission, so you think you’re going to be highly… you are highly successful with your first treatment, but the decision-making thereafter is extremely difficult, and if you really don’t see very many of them, please consult with those that do.
