Chemo-free approach using IDH2 inhibitor shows positive response in acute myeloid leukaemia

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Published: 7 Dec 2014
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Dr Eytan Stein - Memorial Sloan Kettering Cancer Center, New York, USA

Dr Stein talks to ecancertv at ASH 2014 about an ongoing Phase I study evaluating the safety and maximum tolerated dose of the IDH2 inhibitor AG-221 in the treatment of acute myeloid leukaemia.

Watch the press conference or read the news story for more.

ecancer's filming at ASH 2014 has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

 

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ASH 2014

Chemo-free approach using IDH2 inhibitor shows positive response in acute myeloid leukaemia

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


What IDH is is normal IDH, or normal isocitrate dehydrogenase, what that is, as everyone who is a physician knows, is a part of the Krebs cycle which helps produce energy for cells. When you have a mutation in IDH1 or IDH2, and today we discussed IDH2, what happens is that those cells, the cells with the mutation, are unable to turn into healthy adult neutrophils or infection fighting cells. So what happens is that you get these immature blood cells crowding your bone marrow and that’s what leukaemia is, leukaemia is when you have immaturity of the blood cells, they crowd the bone marrow and they are unable to differentiate into normal, healthy adult cells.

Now what is AG-221?

AG-221 is used to block this mutant enzyme. And you think that if you block this mutant enzyme what we can do is we can cause those immature cells to be reprogrammed and to mature into healthy adult neutrophils. This is a very different way of thinking about treating cancer. Traditionally treating cancer was killing cells, now what we’re doing is we’re trying to transform cancer cells into healthy adult cells.

So it’s a form of differentiation therapy?

Correct, a form of differentiation therapy, that is correct.

And what did you do in the study then? How many patients have you looked at? What happened?

So there have been 73 patients enrolled in the study as of October 1st 2014. There are 45 patients who we can evaluate for efficacy, meaning that they had a bone marrow biopsy at day 28. Of those, 25 of the 45 patients had some sort of response – either a complete remission or a partial remission. Actually, 15 had a complete remission or a complete remission with incomplete blood count recovery and 10 had a partial remission for an overall response rate of 56%.

It sounds good. Now how does that compare with historical controls for this particular group of patients?

It’s much, much better. Unfortunately patients that relapse or are refractory AML, their survival is usually measured in weeks to months. We have many patients on this trial who’ve been on this treatment for over six months with minimal to no toxicity at all. So we’re very, very excited about the treatment.

It sounds almost too good to be true.

It is an interim analysis of a phase I trial so I try to be a little cautious in what I say. But I would think that if this data holds up it will be a real revolution in the way we treat AML in patients with IDH2 mutations.

The thing about differentiation therapy is you avoid chemotherapy.

Correct.

Are there advantages in that?

Absolutely. The chemotherapy that we give now lands people in the hospital, it causes them to have low blood counts, which they already have but it causes those low blood counts to persist for a longer period of time. They’re susceptible to infections. When you have a treatment that can cause differentiation and the blood counts beautifully come up, it’s amazing.

But it’s a powerful drug, so were there toxicities?

The toxicities were minimal. The toxicities that we’ve seen are really common toxicities that we see in all patients with AML. So the most common were fatigue, a little bit of nausea and some fevers, nothing that has been directly related to the drug itself.

What do you think doctors should be making of the results right now?

I think the doctors should be very excited because I think that we should wait to see how the completion of the phase I trial turns out but if this pans out this may be… not only would it be a treatment for IDH2 mutant haematological malignancies but one has to think about whether we can find other agents that can cause differentiation in other sub-types of AML.

And there are other IDH mutations too, aren’t there? So you could apply the principle?

Correct, there’s a mutation in IDH1 and there’s actually an on-going trial of an IDH1 inhibitor that started a number of months ago. Those results were presented actually at the EORTC conference showing, at least in the very, very early phases of the trial, there were only about ten patients presented, it showed similar effects.

Meanwhile your oral differentiation agent has proved quite interesting, to say the least. If your hopes are fulfilled, what could potentially be the clinical applications?

It’s very early so it’s hard to… I don’t want to lay down my nickel too early but I would say that if this pans out and if the trial keeps going the way it is now, what I’d like to see is that we could potentially cure AML with IDH2 mutations with an oral treatment in and of itself or in combination with a little bit of chemotherapy. So we’ll have to see how it pans out.

The take home message in just a couple of words for doctors?

The take home message is this is an extremely exciting new therapy, it’s a wonderful differentiation therapy. It seems to have enormous activity that appears to be durable, responses have been up to eight and a half months, and stay tuned, we’ll see what happens at the end of the trial.