Durable Response With IDH1 Inhibitor in AML Spurs Analysis of Molecular Factors

IDH1 inhibitors, which have been approved for use to treat acute myeloid leukemia (AML), provide strong efficacy and favorable tolerability in patients with the corresponding IDH1 mutations. The targeted inhibitors olutasidenib (Rezlidhia) and ivosidenib (Tibsovo) have also shown efficacy in patients with IDH1-mutated myelodysplastic syndrome (MDS).

Now, with longer follow-up of the patient population who first received these agents for AML in a pivotal phase 2 trial (NCT02719574), some patients whose disease responded to targeted therapy had durable remissions lasting as long as 9 years. Additionally, some patients’ disease responded only after a longer period of treatment, encouraging persistent use of targeted therapy.

“They can have late or very late responses, so if someone doesn’t have another good option, I would not give up on this too early,” said Justin Watts, MD, associate professor in the hematology division at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine in Florida.

In an interview with Targeted Oncology, Watts spoke about the long-term durability findings particularly in a patient treated with olutasidenib whose case was reported on in Nature Precision Oncology as a functional cure for AML.¹ He also explained the efforts that are being made to identify which patients are most likely to benefit from IDH inhibitors and what unmet needs are being pursued by researchers in this field.

Targeted Oncology: Could you discuss the durability of responses with olutasidenib in AML?

Justin Watts, MD: It’s pretty incredible that you can get that at all with any single-agent inhibitor in relapsed/refractory AML. The IDH inhibitors are interesting. Their response rates are not really higher than a FLT3 inhibitor or menin inhibitor. if anything, they might be lower in some cases. We’re talking about single agents here, because those [provide] most of the data that are out there. It is a lot of heavy lifting, especially in AML, to ask of these drugs to not only to get a response, but then to maintain the response. I think that’s how active they are, even though sometimes you need combinations….

But the duration of response to most other inhibitors is just not that desirable. Sometimes, for some reason, you get lucky with IDH [mutations]. If the leukemia is dependent on that mutation and 2-hydroxyglutarate, and if you knock that out, and there’s not enough going on in the network of mutations in the cell to drive early resistance, you clear the clone and you don’t relapse.

Right now, that’s not [the case for] the majority of patients. We’ve seen it with all the IDH inhibitors, and we’ve also seen it in MDS. With olutasidenib, the rate of achieving a CR [complete response] or CRh [CR with partial hematologic recovery] is 35%.² You’re only talking about a little more than one-third of patients. Closer to 50% have some type of response, but you’re talking about 35% with a CR-type response, and the other ones totally don’t respond—half of patients don’t do well at all. Their survival is very short. Their [disease is] driven by other mutations.

But of that 35%, a significant proportion of those are going to have a durable response. The median duration of response from the study was over 2 years, which is unbelievable in a relapsed/refractory AML study. We’ve talked about that before, but the question is, why?

What characteristics were found in the responders to olutasidenib?

[Analyzing] the molecular features of those patients, they tend to have a lower mutational burden, usually a lower blast burden, which goes along with that total clonal burden, and they don’t have FLT3 mutations or RAS mutations.³ It’s not going to work if they have a FLT3 mutation, especially FLT-ITD; they need a FLT3 inhibitor. Usually, the variable allele frequency is not too low or not too high, it’s been in this range where the IDH [mutation] is situated in the clonal hierarchy to drive the leukemia…. Rarely it will be a clonal hematopoiesis mutation, and you might see the mutation persist in neutrophils, but no leukemia relapses.

Usually, the mutation goes away in these long responders, and we’re trying to see how many that is across the olutasidenib studies including MDS and AML, [which are] basically spectrums of the same disease in IDH-mutant leukemia, and get a sense of the 30% to 40% of great responders. How many have remission more than 1 or 2 years? Because if you make it more than a 1 or 2 years, maybe around 18 months, we see almost no relapses. We’ve seen patients now [over] 8 years in remission. It’s not just secondary-type AMLs. We’ve also seen it with NPM1-mutated AML.

When someone can stay on a pill and have that kind of functional cure—it’s hard to say absolute cure, although we have done deep sequencing and not found anything—that’s fantastic. The tolerability of these drugs over time just lets the patient stay on them as a maintenance indefinitely in some cases. If you make it past that hump of about 1 year, you stay on and from what we’ve seen we can be pretty sure that that patient is going to be safe. These are older patients who don’t need a bridge to transplant or qualify for a transplant, and some of these are younger patients, and they did go to transplant and maintain their response afterwards.

What next steps are youe taking in terms of research for IDH-mutant AML and MDS?

We need a comprehensive look at these molecular features that I’ve alluded to, and response and duration of response, which we’re trying to put together for all of the patients treated on the olutasidenib trial. There has been something similar done with ivosidenib, and probably also with enasidenib [Idhifa], which is a little bit different because there are 2 different isoforms and other things going on there.

We’ve also done some work on how long you should continue these [agents] if they’re not in CR or CRh, and we’re finding more and more that in the patients who have stable disease, their [blood cell] counts got a little better.³ The longer you continue them, the better they do. They can have late or very late responses, so if someone doesn’t have another good option, I would not give up on this too early. We may have had even more responses if we had known that. If you think a patient’s [experiencing progression] or just not responding, sometimes these drugs can take longer [to show benefit]. But if they’re clearly progressing, then they need to come off.

Lastly, combination therapy is what we’re most interested in, [as is] how to incorporate IDH inhibitors into the frontline setting or save them for sequencing in the relapsed setting. Some of the post-venetoclax [Venclexta] data, at least with olutasidenib, look promising, but I think we should generally not save for later and use our best drugs up front. So we are working on triplet strategies, both here at the University of Miami and also at [The University of Texas] MD Anderson Cancer Center, in both older and younger patients with frontline triplets with venetoclax and a hypomethylating agent plus olutasidenib.

I think it’s interesting to explore that in younger patients, which we’re trying to do and avoid the toxicity of intensive chemotherapy. We’re looking at that as well. If we can cure these patients with this triplet strategy, or for the younger ones, where appropriate, provide a better and safer bridge to transplantation, the question of IDH maintenance also comes up post transplant, and it’s very tricky. It may be more relevant in IDH2, but we still have a lot to learn there, as well as the role of IDH inhibition potentially in clonal hematopoiesis and even earlier states to low-risk MDS. IDH is a unique mutation running the spectrum of clonal hematopoiesis to full-blown AML. I think there is a lot of room to intervene with these inhibitors with different combinations at different stages of disease.

REFERENCES:

1. Watts J, Nong T, Micin K, et al. Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML. NPJ Precis Oncol. 2025;9(1):211. Published 2025 Jul 1. doi:10.1038/s41698-025-01013-5

2. de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;7(13):3117-3127. doi:10.1182/bloodadvances.2022009411

3. Cortes JE, Roboz GJ, Baer MR, et al. Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial. J Hematol Oncol. 2025;18(1):7. Published 2025 Jan 16. doi:10.1186/s13045-024-01657-z