AB: Good evening and hello from San Francisco, the 56th annual meeting of the American Society of Haematology. This is the first day and I’m Alan Burnett and I have my colleague and friend, Sergio Amadori, with us. We have listened to some of the presentations in the first day’s session on acute myeloid leukaemia and we thought it would be interesting to discuss one or two of the issues that came up and how we feel this changes, potentially, the treatment of the disease. So, Sergio, what stuck with you?
SA: I think today’s session on AML was quite interesting, in particular two issues pop up as very important for clinical practice. The first issue is the issue of treatment intensification in AML, front line treatment intensification through an increase in the dosing of daunorubicin. Daunorubicin is known to be one of the pillars of the remission induction treatment of AML and the question is whether the dose of daunorubicin which is mostly used in clinical trials is the correct one or whether by increasing the dose you can expect to have more remission, better quality remission and possibly an improvement on long-term outcome in these patients. I think the presentation by the NCRI group concerning the results of the AML17 trial were of great importance because my understanding is that the results of that trial clearly indicated that, at the moment, in a randomised study complex by design but very important in terms of number of patients randomised, clearly demonstrated that increasing the dosing of daunorubicin up to 90mg/m2 versus what can be considered, generally speaking, a sort of standard dosing of 60mg/m2 does not add anything, any extra benefit to the patient, both in terms of complete remission, quality of remission or risk of relapse and overall survival. I think this is very important because this is one of the hot issues which is currently under discussion in the setting of this disease, not only for young adults but also for elderly people. So this information is important because people could concentrate on other issues rather than continue with the old question of whether the dosing of daunorubicin should be changed, modified, intensified as many other trials are doing at this moment, for example.
AB: Yes, the point of doing the trial was that there are studies who have suggested that 90mg dose level as the standard of care but they were compared against 45mg and produced results that were not over-convincing in the control arm. There has never been a study of 90 versus 60 and 60 is widely used so this was the point of doing the study. The survival curves were identical. There was actually an excess mortality in the first 60 days in the 90mg and when every subset was looked at by risk group there was no sub-group that turned out to have a benefit except possibly there might be something happen in the future about FLT3. So the message from it is that if you use 60mg as your dose continue to do so; if you use 45mg then you should be thinking about 60mg or 90mg as the routine dose.
SA: Yes, correct. I think this is the right message which is important in theory but also in the clinical practice because many investigators used to treat patients outside clinical trials at home with regimens including cytarabine and daunorubicin and they listen, they are aware of this discussion about the dosing and it could be important to clarify that at the moment there is no indication that the dosing of daunorubicin compared to the 60mg, which is the most widely used strategy, should be implemented. So it could be too risky for the patient with no substantial benefit. I think this is a very important finding, very important contribution, because it can be applied also in clinical practice.
AB: So maybe the last thing that came up in the session that is worth mentioning is the first studies coming through on looking at dasatinib in the core binding factor leukaemia. Core binding factor leukaemias are those with chromosome and inversion 16 or a t(8;21), it’s about 15% of younger patients. It’s rather like APL, it’s a subgroup that seemed to be getter better anyway over the years. It’s very important these patients receive high dose Ara-C as their consolidation. It may be that they are particularly sensitive to increased doses of anthracycline, we’re not sure, but a proportion of them have a mutation called a KIT mutation and this, although they get a generally favourable response to chemo, if they have that mutation they have a higher risk of relapse. That doesn't always mean that they will have a poorer survival because the other thing about this subgroup is that even if they relapse they’re still very curable.
SA: Yes, they can be salvaged.
AB: Yes, absolutely. But anyway this KIT mutation is theoretically sensitive to the dasatinib which is a tyrosine kinase inhibitor that’s developed for chronic myeloid leukaemia more than anything else. So we heard an unrandomised trial report of an experience of something like 50 patients with KIT mutations given this drug and it was very clear that it’s not randomised data but it produced really very encouraging disease free and survival data, even in older patients. This could be arguably the first or second example of targeted therapy of a molecular nature in acute myeloid leukaemia. There are lots of molecular targets and there are other targeted agents like IDH2 or Dot1 which are in development but are not nearly at the stage of the dasatinib. There is a German study also picking this up for a bigger group of patients. So it does seem that that is a second example of targeted therapy which is quite encouraging.
SA: Yes, very important findings because you have to remember that many investigators at the moment consider patients with core binding factor AML hyper-expressing the c-KIT or especially with c-KIT mutation as candidates for allogeneic stem cell transplantation, because there are data from the literature indicating that these patients have an increased risk of relapse. The fact that in reality by combining chemotherapy with targeted agents like dasatinib or using, as your group has shown in the UK, using a different remission induction regimen, for example the FLA-Ida or the FLA-Dauno, so a combination of fludarabine, Ara-C and anthracyclines. So the possibility of having similar very good results without intervening with allogeneic transplantation first remission would be very important.
