AACR 2014

AG-221 shows clinical activity in acute myeloid leukaemia

Dr Eytan Stein - Memorial Sloan Kettering Cancer Center, New York, USA

Can you tell us a little about the work you’re doing with acute myeloid leukaemia?

What we’re doing is we’re looking for patients who have acute myeloid leukaemia who have a mutation in a gene called IDH2. We think by targeting that mutation in the gene called IDH2 we can lower levels of a substance called 2-hydroxyglutarate or β-hydroxyglutarate. We think elevated levels of that substance are what are leading to the leukaemia and by lowering levels of that substance we can cause the leukaemia to go away.

And is the non-mutant form of IDH2 involved in normal haematopoiesis?

The normal IDH2 actually is involved in the Krebs cycle, the citric acid cycle, and the normal IDH2 enzyme what it does is it converts isocitrate to alpha-ketoglutarate as part of the process of your cells making energy. What this mutant enzyme does is instead of doing the normal thing, converting isocitrate to alpha-ketoglutarate, it converts alpha-ketoglutarate to this substance β-hydroxyglutarate, or 2HG. It’s the elevated levels of the 2HG that accumulate in the patient or in the patient’s leukaemia cells that drives the leukaemia and causes the leukaemia.

Do you have to look for the mutant before you can use your substance?

You do. So all patients, before they come on trial, need to have a confirmed mutation in their IDH2 enzyme. If they don’t have the mutation then we would suspect that they may not respond to the drug.

How many would patients with AML typically have?

The preliminary data suggests that about 10-15% of patients with acute myeloid leukaemia have this mutation. There’s a pre-leukaemia called the myelodysplastic syndrome where about 5% of patients have this mutation.

Had these patients exhausted all other options?

The typical options, it’s sobering, but we’ve been treating acute myeloid leukaemia the same way for forty years. There has been one drug approved for acute myeloid leukaemia over the past forty years and that drug was pulled from the market a number of years ago after a brief stint on the market. So this is very, very different from what we typically do which is chemotherapy. The same chemotherapeutic agents that have a lot of toxicity, that have been given for the past forty years.

Could any of these patients have undergone an allotransplant?

Some of these patients could only go for an allotransplant if they were able to get back into a complete remission. So doing an allotransplant with patients who have active acute leukaemia typically doesn’t work. So they really need to get back into a remission to go for an allogeneic bone marrow transplant.

So what happened in the study?

In the study we saw there were ten patients we were reporting on. Unfortunately three of the patients were not evaluable because they passed away from disease related infections before we were able to evaluate them. Of the seven patients who were evaluable, five of the patients had a complete remission or a complete remission where their leukaemia went away but their platelets had not yet come up to a normal level. Having said that, all of those patients, their neutrophils, their infection fighting cells, did come up to a normal level, such that of those five patients none of them ended up in the hospital with infections or infectious illnesses, which is a dramatic results. These patients with AML are in and out of the hospital all the time. So there are five patients with a complete remission or complete remission with the platelets a little bit low and there’s one patient who had a partial remission.

So these patients would ordinarily have died after a month – how are they now?

Of the patients that we’ve looked at they’re all doing quite well.

At how many months?

So the longest patient who has been out has been on for about 5½ months, the others have been on for about 3 months as of the March 20th cut-off date.

What should oncologists make of this?

These results, as you suggest, are extremely early but I think that if the data holds up in the next groups of patients that we treat this would really be a remarkable result because in these patients who have IDH2 mutations it would substantially alter the natural history of the disease and may provide a real benefit to them in terms of their quality of life and how long they live.

What’s your take-home message?

I would take home the following. Number one, you should check all of your patients for an IDH2 mutation because if they do have an IDH2 mutation and have relapsed or refractory disease this is an agent which really may provide clinical benefit to the patients where other things haven’t worked.