DR CORTES: This is a fascinating path, because if you remember the Krebs cycle from your biochemistry lessons, this is part of this cycle, this respiratory cycle and the mitochondria. And as you know, this IDH is an enzyme that’s part of this cycle.

As it turns out, what happens is that it turns isocitrate to alpha ketoglutarate. But when it’s mutated, it switches that. And the alpha ketoglutarate is switched. It’s converted to hydroxyglutarate. And 2-hydroxyglutarate, we’re starting to understand now, has many proneoplastic properties, perhaps through epigenetic modifications. So only the mutated IDH has this property to convert into 2-hydroxyglutarate and, actually, 2-HG. So 2-HG, measuring 2-HG, is kind of like a biomarker of this as well. You see these patients that have the mutations, have very high levels of the 2-HG.

And so the concept of these drugs is that you will inhibit that mutated IDH and with that revert to the normal respiratory cycle. That will bring down the 2-HG that has, again, these proneoplastic characteristics. And indeed, we do see this. We see that patients, once you give them these IDH inhibitors, their 2-HG goes way down. And very quickly. So that could be an early predictor or an early biomarker that the drug is starting to work.

The other thing that’s fascinating with this drug is that, as you do that, you see a differentiating event. So at the beginning, some of these patients were taken off study quickly because we didn’t understand them well and their blast count was starting to go up. And we said, “Oh, no, progressive disease. Take them off,” et cetera. And now we’re learning that it’s actually part of a differentiating effect that the drug has.

So these mutations happen. There’s IDH1 and IDH2. And each one of them happens in grossly about 10% to 15% of the patients. There’s some correlation with age. Older patients with trisomy 8, it happens more in patients with trisomy 8. We referred to this earlier, that it appears to be perhaps a founding mutation for the AML. So this has led to the development of these inhibitors.

At the moment, most of the inhibitors have been either IDH2 inhibitors or IDH1 inhibitors. Interestingly enough, IDH1 mutations happen also in other cancer, glioblastoma being very prominently represented. IDH2 appears to be more of a leukemia mutation. So the first drug that came was AG-221. That’s an IDH2 inhibitor, and, it showed a remarkable clinical activity even in the Phase I study. And again, perhaps some of the early failures were not failures. It was just this lack of recognition at the beginning of this differentiating effect.

There’s another drug, AG-120, which is the equivalent but an IDH1 inhibitor. That has also given us remarkable results. Both of these drugs have reported in the Phase I study around 40% to 50% of patients with responses. There are a number of other drugs that are being developed, more IDH1 inhibitors than IDH2. And there is a very interesting drug that’s a dual IDH2 and IDH1 inhibitor. It’s a little earlier in the development. And at the moment, it’s being used in clinical trials for patients who have experienced resistance to one of the other ones. But it is an interesting drug, because it has the dual effect.

So these are fascinating drugs, because it’s a completely different pathway. It’s not a proto-oncogene or something like that. It’s just a completely different concept, but it’s proven to be remarkably effective and very well tolerated, by the way.

DR STONE: I totally agree. And I’ve seen some unbelievable responses in my own patients on these drugs, some of whom — you’re allowed to go on some of the trials if you are deemed to be unfit for chemotherapy. And, I mean, it is really rare to expect a single agent to work so well in AML, but so far I’ve got a few amazing responders, single agent, never had chemo in their lives. That’s all they’ve gotten, and they were in remission.

One guy is an 86-year-old psychiatrist who has never seen any chemo or anything else for his AML. He’s been on the drug for a year and a half. He rode the Penn-Mass Challenge. He rode 27 miles on his bike at age 86.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions