MDS 2023 | The prognostic impact of IDH mutations and the role of IDH inhibitors in MDS

So IDH mutations which occur in about 10 to 15, 10 to 20% of patients with acute myeloid leukemia occur in a smaller proportion of patients with myelodysplastic syndrome. They occur in about 5% of patients overall with myelodysplastic syndrome, but together it’s 10%. So IDH1 mutations happen in 5% of MDS patients and IDH2 mutations occur in another 5% of MDS patients. What the outcomes of these patients are and what the prognostic significance of having an IDH mutation in myelodysplastic syndrome is, I think is a little bit controversial. Overall, though, it would seem that having an IDH mutation probably portends a higher risk of transformation to acute myeloid leukemia. So overall, I think it’s a higher risk mutation to have an IDH1 or IDH2 mutation in patients with myelodysplastic syndromes. You know, the big question, of course, is the second question that we’re going to talk about today, which is what is the role of IDH inhibitors in patients with myelodysplastic syndromes? Similarly, to what we see in patients with relapsed and refractory acute myeloid leukemia, when you give IDH inhibitors to patients either with relapsed and refractory or newly diagnosed myelodysplastic syndromes with an IDH mutation, what ends up happening is that about 30 to 40% of those patients will go into remission. That is 30 to 40% of patients, if they’ve got elevated blasts at diagnosis, they will clear their blasts and they will also have hematologic improvement. There’s a smaller percentage of patients that might not clear their blasts but also still have hematologic improvements. So, there is certainly a benefit to having to getting an IDH inhibitor if you’ve got myelodysplastic syndrome. Now the thing is that the IDH inhibitors probably are not curative, or I would say definitely are not curative in the sense that it does take time for these drugs to start working. And after they’ve started working, it’s very likely that the patient will end up relapsing eventually. So, what we want to do when we see a situation like that is you want to add on a second agent in this case, a drug like azacitidine, the hypomethylating agent, which is the standard of care in patients with myelodysplastic syndromes. So you want to add that on to your IDH inhibitor to see if you can augment the response. One of the things I’m going to be talking about today is a clinical trial that was done by Dr. Courtney DiNardo and her colleagues looking at the combination of azacitidine with the IDH2 inhibitor, enasidenib, and that showed actually quite good results. They had a number of patients who achieved a true complete remission and I think that that’s something that’s quite exciting. Overall, I think the question is going to be how do you incorporate IDH inhibitors in combination with other therapies to help these patients do better? IDH inhibitors alone may be okay for some small subset of patients, probably not for everybody.