ASH 2013 - New Orleans, LA, USA

FLT3-ITD positive acute myeloid leukaemia

Dr Mark Levis - Johns Hopkins Medicine, Baltimore, USA

This is a tyrosine kinase that’s constitutively activated, it drives the growth of these leukaemia cells so the disease is very proliferative, extraordinarily aggressive. These are the patients that come in with extraordinarily high white counts, are often very difficult to manage clinically initially. We can get them into remission but their relapse rate is much higher than the typical AML patient and we’re still at relapse, they’re almost impossible to cure at that point.

Does that proliferation present hazards but also therapeutic opportunities?

The cancer cells are essentially addicted to that particular oncogene so that represents the target. What’s interesting is the disease evolves from diagnosis to relapse so we start with a disease that’s not fully FLT3 addicted and a FLT3 inhibitor doesn’t work well, necessarily, on the newly diagnosed setting. You give chemotherapy and when it relapses, and we’ve seen this from the genomic studies, it’s clonal almost, thoroughly FLT3 addicted, it behaves clinically aggressively, is impervious to any of our standard therapies but is sensitive to FLT3 inhibition at that point.

Can you explain the skill involved in combining therapies?

We’ve been testing the FLT3 inhibitors in the relapsed setting, that’s the FLT3 addicted clone that’s easy to kill. Clearly it’s showing clinically beneficial responses and we’re able to get the patients back into some semblance of remission and transplant them, salvage and have long-term survivals with this. But you don’t want to wait for relapse, you’re only going to salvage some of those. If you want to move the drug up front, and I’ve just said at diagnosis the cells aren’t necessarily FLT3 addicted, the sub-population that’s going to emerge at relapse is present at diagnosis. Sometimes patients will actually present with a larger burden of these cells at diagnosis, if we can spot those what we would favour doing is giving conventional induction overlapped with a FLT3 inhibitor at induction in the newly diagnosed setting. That’s going to improve our remission rate, bring all those patients to an allogeneic transplant and give them the drug maintenance afterwards.

At what point during treatment is it the right time to use FLT3 inhibitors?

I would advocate doing it very early on when they’re approved. In fact, we do have trials right now testing this so tomorrow afternoon three separate abstracts are being presented orally testing crizotinib, for example, in combination with induction chemotherapy for newly diagnosed patients – one a paediatric and two adults. Those are safety tolerability studies as a jump-off for doing larger phase III randomised trials. All they’re saying is that we’re able to do it tolerably. Yes you have an increased remission rate, in all likelihood, with the addition of this drug but in order to effect improved survival you have to complete the treatment. You’ve got to take the patient to an allogeneic transplant and likely give them the drug post-transplant. So likewise there is a protocol phase I of post-transplant crizotinib. And having done both of those sets of studies now we can merge and do the planned large trial which is going to be done with the groups.

Are there other characteristics in patients with this disease?

It tends to occur in the normal cytogenetic younger patient population, the patient population that can go to allogeneic transplant. You don’t typically see it in the 80 year old, you see in the 64 year old who is still transplant eligible, capable of receiving intensive therapy so it’s a pretty well-defined population.

What advice would you give to practitioners?

At the present time my recommendations are all patients with newly diagnosed AML should be screened for the presence of this mutation and if the FLT3-ITD mutation is present, allogeneic transplant remains our best option for consolidation, for giving that patient their best chance of long-term survival. That’s the single most important thing that I can say out of my presentation.