Clofarabine and other novel agents in AML; interview with Alan Burnett at ASH 2012
Professor Alan Burnett- Head of Haematology Department of Medical Genetics, Cardiff, Wales
Can you tell us about clofarabine – the history of the drug and where we are today?
As you know, nucleoside analogues have been, particularly ara-C, has been the backbone of treatment of AML for forty years. The hope is with an alternative like clofarabine, for example, we could make more progress, particularly in difficult areas of the disease. Clofarabine had some attractions to us; it was manufactured to have the best of cladribine and fludarabine, both of which are active but the dose level that they’re active is not really practical. I got interested because there was a prospect of this being oral, which is important for particularly older patients. So we started looking at it for elderly patients who are not fit for conventional chemo where we would normally give low dose ara-C which represented about a 15% chance of remission. When we did that in an unrandomised setting we found that the remission rate was about 40-45%. So we knew that we had a drug here and, of course, we did not develop the drug, it was developed in the MD Anderson, but we thought this could be particularly useful for this older group of patients, that it was well tolerated, the patients didn’t lose their hair. So we felt it had other benefits. Other people were developing it in addition to conventional ara-C and it’s clearly feasible to do that.
Having established it as a runner in the disease, we then embarked on two randomised trials, well actually three randomised trials, in different settings. One was is it better than low dose ara-C in the older patients who are not really fit for intensive treatment; can it displace ara-C in combination with donorubicin as an up-front treatment for older patients and in combination with ara-C does it do any good in younger patients who have high risk disease? So these are the three areas that we looked at it.
Do you think the best combination with clofarabine is still ara-C?
I think it’s beginning to look like it. We found no difficulty in getting it into patients with donorubicin with the nucleoside analogue with the conventional donorubicin although you had to compromise on the clofarabine dose. It’s been difficult to get it in in combination with idarubicin because it requires so much dose reduction but I think it’s fairly robust to get it in combination with reasonably serious doses of ara-C. So I think that may turn out eventually to be the best way to use it. That wasn’t the way we used it because we knew other people were doing that.
Could you touch on some of the other new compounds that have new developments?
We know a lot more now about the molecular characteristics of AML and about a quarter of younger patients will have a mutation called FLT3. That doesn’t prevent the patients going in remission but it predicts that these patients are going to have a much higher relapse risk, so it confers a poor prognosis. Some people believe that that’s an indication in itself for transplanting the patient; I’m not so sure but nevertheless it would be nice to have a drug that targeted the consequences of the FLT3 mutation. There have been a number of them looked at over the years and what they were able to do in relapsed disease, FLT3 positive, the blast cell came down but it never cleared the bone marrow. So there were always reservations about whether that would work. Some of them have gone on to major phase III randomised trials, the results of which we don’t know yet but I don’t think anyone is terribly optimistic that they’ll deliver the goods.
The interesting thing about AC220 is that when you give it to relapsed patients you clear the peripheral blast but you also clear the marrow in a fair proportion of patients, something like 35%. It’s also got some activity in non-mutated patients because some non-mutated patients express, they’re not mutated but they have a high level of FLT3 on the leukemic blast so they may be slightly addicted to it so an inhibitor might work. So there is a rationale in both the mutated and the non-mutated to look at it. So this drug has shown that it can clear the marrow, what is less clear in the patients in the abstract is whether they recover their blood counts fully and that’s a question mark. Whether that means it’s myelotoxic or whether it means that the patients in the study had so much prior treatment that their haemopoiesis was just limited is a bit of an unknown question. So it’s clearly active and the issue is how should it be used in a randomised trial etc.; there is an issue about dose level still to be resolved. So I think the abstract presented does show very encouraging data in quite a large number of patients in an unrandomised phase II so I think we’ll keep an eye on this drug actually.
Are there any other new exciting targets coming through?
There are quite a lot of new drugs around that need to be tested in a randomised setting; there’s no Gleevac in AML yet. But the other interesting area that’s developing is that we’re finding a lot of mutations that are quite useful prognostically but they’re so complicated because they don’t occur on their own, they occur together and it may have a completely different prognostic implication. So that’s going to be extremely difficult to incorporate into clinical decision making and is going to require a lot of patients and considerable lab expertise and I’m not sure that’s going to be that feasible. The other area that’s interesting is the techniques that have developed for minimal residual disease assessment. Again we know there are a number of ways of doing this, there are a number of molecular targets. We know that the leukemic cells have aberrant expression that can be picked up by flow cytometry so you can monitor quite low levels of residual disease. But it begs the question as to whether you’re better off to treat somebody who shows that than let them relapse because patients with low levels don’t always relapse. So how you would apply that clinically is again going to be a bit difficult but at least the technology is there. But the danger is making the assumption that the technology is an indication, say, for transplant in all cases. So it’s prognostic but it may not be predictive of what to do about it. So that, I think, is the clinical challenge there but it’s clear that this technology is available now in AML.
Treating AML in the elderly: are there any particular patient regimens?
Collaborative groups, including ours, have not been very good at catering for this population. Of course the median age of the disease is around 70 and when you get over 70 you collect things like hypertension and bad hearts and diabetes and things so it doesn’t mean that chemotherapy is necessarily safe. So there is a big push on now to cater for this population by finding treatments that may help them and clofarabine was a candidate there, there are other drugs. But nothing has emerged in a randomised context yet to say that it’s really the answer. Demethylation agents are popular, particularly in the US and some patients do very well because it nurses the disease along without necessarily getting in remission and that’s quite useful for some patients. But I think most of us feel that to get a real benefit the patient has to be got into remission. But there are a number of drugs around that are being given a chance to see if they can do that but nothing has done it yet.