Developments in the treatment of acute myeloid leukaemia (AML)

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Published: 20 Jul 2010
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Professor Alan Burnett - Cardiff University, UK
Prof Burnett speaks about research into the treatment of AML presented at the 2010 EHA congress. The topics include developments with immunoconjugates, clofarabine and the hopes for the FLT3 inhibitor AC220. Prof Burnett discusses how his group decides which drugs should be evaluated in clinical trials and explains how this differs according to the targeted group of patients.

15th Congress of the European Hematology Association (EHA), 10—13 June, 2010, Barcelona

Interview with Professor Alan Burnett (Cardiff University, UK)

Developments in the treatment of acute myeloid leukaemia (AML)

I’m Alan Burnett, Professor of Haematology at Cardiff University and I co-ordinate the national trials in the UK in acute myeloid leukaemia.  These trials also run in Denmark, Sweden, Norway, Australia and New Zealand and we recruit around about 1,000 patients a year to the trials.

Okay.  We’re here in Barcelona for this year’s EHA meeting.  I wonder if you could give your views on what’s exciting in particular in AML this year?

Well, at  these sorts of conferences we always hear about new drugs, usually rather preliminary results  and not randomised information. There is no shortage of new agents to look at and to study further.  Many of them, of course, are not approved drugs and are still going through the process of getting  approval.  So in that category, although not a new drug, there are still data emerging about mylotarg  , which might augment chemotherapy to the benefit of survival.  Clofarabine is a novel nuclear side analogue, again not that new, but this coming year we would expect the randomised data to begin to emerge and that will be rather key to whether this becomes a new standard of care in one or other of the AML situations.  There are a number of inhibitors of Flit-3, Flit-3 being a common mutation in AML that’s associated with a high relapse risk and therefore a target for therapy as well as a prognostic factor. There are two or three major international randomised studies, including one of our own, which are about 70% complete, using first generation agents, but there are new agents and I think of particular interest is the compound called AC220. The reason that that’s interesting is that in the pre-clinical models the benefit in the pre-clinical in vivo models persists even although the drug is not being administered which is unusual for the Flit-3 inhibitors.  Secondly, going into the early stage trials, the first generation did not generally achieve complete remissions but we are seeing complete remissions with this agent in these dose-finding studies.  So there will be randomised trials; there’ll be a fairly large Phase II trial conducted internationally and there’ll be randomised trials incorporating it with chemotherapy as well.

There seems to be quite a lot of interest in Clofarabine.  Historically, of course, it was developed as a paediatric  leukaemia drug and now it seems to be finding a niche within the adult AML population.  Do you see it being used predominantly as a combination therapy?

Well, it may well get a niche as monotherapy in the elderly where it’s definitely practical and indeed we can give this as a day case treatment which is convenient, and it certainly produces rather encouraging remission rates.  What we don’t know is whether the survival benefit is there because, just because patients  get remissions doesn’t necessarily mean they’re going to survive longer although we think that is a very good surrogate for survival in the elderly.  When a drug is that interesting then the obvious way to deal with it is to bring it into other circumstances, perhaps in younger patients, perhaps in combination and of course the MD Anderson has pioneered combination studies with Ara-C.  We have just completed an 800 patient trial combining it with Daunorubicin, against Daunorubicin plus  Ara-C  plus or minus Mylotarg and we are looking at it in high risk patients in combination in young patients with a view to getting more of them through to transplantation.  I think it’s going to be fairly crucial that it shows some benefits in the rather limited number of randomised trials that are coming to conclusion this year.

Is it an issue that there are so many interesting molecules coming through in terms of selection?

Well it is and, you know, the pressure is also on in the AML scene to devise new forms of trial design.  The traditional trial design that we’ve used in the UK has been large numbers looking for small differences and we’ve been rather dominated by that concept.  Well, that works in young patients because survival in the young is improving, but in the elderly we’re not seeing the same improvement, so it really questions that strategy and our attitude has been to develop what we call a “pick a winner” approach, which is sequential randomised comparisons where you’re looking for big differences and therefore small numbers.  So why look for big differences?  Well, the drugs are going to be expensive and there’s no point in spending many thousands of pounds on a drug with a 3% or 4% survival benefit, so it’s reasonable to look for substantial improvement in remission rate which we hope will convert into a survival advantage.  So that sort of trial design has allowed us to go through four   trial combinations in three years which would otherwise have each taken us about four years.  So there needs to be more of this sort of approach and I think it is statistically, supported now.