A Potential Role for IDH-1 Inhibitor Olutasidenib in Relapsed/Refractory AML?

Expert perspectives on the potential role of IDH1-targeted therapy, olutasidenib, in patients with relapsed/refractory acute myeloid leukemia.


Jorge E. Cortes, MD: Let me go to another setting where we have specific agents: the IDH1- and IDH2-mutated patients. This isn’t a small subset of patients. It’s not as common as FLT3 but frequent enough. Brian, we’ve had an IDH2 inhibitor for a while, bosutinib, and more recently an IDH1 inhibitor, olutasidenib. How do you use them in this context? What’s your approach on these IDH-mutated patients in refractory relapse?

Brian Andrew Jonas, MD, PhD: It depends on the context. If an older patient got azacytidine-venetoclax in the front line, then I’ll typically use a monotherapy approach with an IDH1 or an IDH2 inhibitor. There will be a discussion about which IDH1 inhibitor to use, but historically I’ve used azacitidine and ivosidenib prospectively when I’ve encountered that situation. I’ve been able to salvage patients. Post-venetoclax failure outcomes aren’t as promising as they are in the first line. It gets a little more interesting when you have a younger individual who’s still a candidate for high-intensity salvage chemotherapy. We don’t have a study like ADMIRAL, where gilteritinib beat high-intensity chemotherapy; we don’t have such data for IDH inhibitors.

For some patients, depending on if they had a very long first CR [complete remission] or other favorable features, I might still be inclined to use a high-intensity salvage approach instead of IDH monotherapy. It’s been mentioned that the sensitivity of IDH-mutated patients to venetoclax makes those combinations appealing as well in the relapsed/refractory setting if they haven’t already seen the drug. There’s a lot to be learned in that subpopulation, but I don’t necessarily go straight to the monotherapy in a younger patient if high-intensity therapy is still an option.

Jorge E. Cortes, MD: You make a very good point. There are a couple of things I want to mention. Soon we’ll be able to choose between IDH1 inhibitors with the recent approval of olutasidenib. The pivotal phase 2 study showed results that look attractive in some ways; the response rate, the CR rate, was 35%. The 2 attractive things in terms of efficacy were the high rate of CRs—most of these were CRs—and more important, the duration of the remission. That was almost 2 years, which seems much longer than what was reported on a similar study with ivosidenib. Although they look similar, there are some differences in population. It’s hard to tell, but it’s very attractive. Also, they don’t have QTC prolongation, although they have labor toxicity. Those are the things we must sort out.

One doctor used to say that the research of a drug comes after approval because that’s when we’re able to do some of these things. To the point you were making about the younger patient who may still have an option for transplant, these are very good drugs. The results are good, and they’re well tolerated, but the response rate is 35%. For the younger patient for whom you’re still trying to proceed with transplant, is that enough? Are you better off with a nontargeted [therapy], perhaps giving us a better chance of response? Of course, these patients probably would have already had a 7+3, so you’d be talking about some flag or something like that. Those are some of the questions that we still have to address. We have all these drugs, but there are 2 camps. With the IDH1 inhibitor, you might ask, why do we need another drug? We cannot have enough drugs. We’ll figure out which to use. I don’t think we have a blanket answer. I’m glad we have options. It’s always a better thing for patients.

Transcript edited for clarity.

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