Treatment Options for AML Patients with IDH2, RUNX1, or DNMT3A Mutations


Eytan Stein, MD, continues the discussion of AML treatments with a look at the options for patients with AML and mutations.

Hetty Carraway, MD: We also talked about patients with other types of mutations, such as IDH mutations or even RUNX1 or DNMT3A mutations. What’s your approach to this patient population?

Eytan Stein, MD: Patients with IDH mutations generally—or maybe IDH2 specifically—tend to respond to whatever treatment you give them. They tend to respond quite well to intensive induction chemotherapy. They also tend to respond relatively well to a lower intensity therapy, such as azacitidine or an HMA [hypomethylating agent] and venetoclax. I don’t make my treatment decisions for IDH2-mutated patients based on the specific mutation. I make those decisions based on what we talked about earlier: the relative fitness and unfitness of the patient. For example, if I had a 45-year-old patient who had an IDH2 mutation, I’d give them intensive induction chemotherapy. There are no randomized data right now that suggest that adding an IDH inhibitor to intensive induction chemotherapy improves survival.

There’s a phase 1/phase 2 experience that looks very good. But of course, in every phase 1/phase 2 experience, when you combine IDH inhibitors with intensive induction chemotherapy, there are various forms of bias across all those experiences. I’m excited about a randomized placebo-controlled phase 3 study being conducted in Europe by HOVON [Dutch-Belgian Cooperative Trial Group for Hematology-Oncology] and the AMLSG [German-Austrian AML Study Group] that’s randomizing younger patients with IDH2-mutated AML [acute myeloid leukemia] to receive intensive induction chemotherapy with an IDH2 inhibitor or intensive induction chemotherapy with placebo. I’m hoping that’s going to answer the question regarding whether adding a targeted therapy against IDH2 mutations to the backbone of 7+3 is beneficial when it comes to survival.

When it comes to initiating intensive chemotherapy while I wait for molecular testing results, whether I do it or not, the only molecular test that’s actionable when it comes to intensive induction chemotherapy is whether the patient has a FLT3 mutation. The good thing about all the FLT3 inhibitor trials is that the addition of the FLT3 inhibitor to the backbone of 7+3 occurs on day 8 of treatment. That gives you an 8-day window to find out whether the patient has a FLT3 mutation.

But maybe the bigger issue is that once you find out they have a FLT3 mutation, you have to get the prior authorization to get them their FLT3 inhibitor and whatever copay assistance you need, and unfortunately that can take time. It can take even 1 to 2 weeks in certain cases. I wait to start intensive induction chemotherapy to the point where I’m sure that if the patient has a FLT3 mutation, I’ll have their FLT3 inhibitor on hand on day 8 so they can start treatment. If I know I’m going to have that result and have the medication on hand by day 8, I don’t have a problem starting treatment a little earlier when it comes to intensive induction chemotherapy.

Hetty Carraway, MD: I completely echo your comments about patients with FLT3 mutations and starting a FLT3 inhibitor on day 8. We’re sometimes challenged by our patients with core binding factor leukemia, the inversion 16 and translocation (8;21) and the addition of GO [gemtuzumab ozogamicin] to the backbone of induction chemotherapy. The 2 cases that we’re challenged by in terms of doing the induction therapy and adding to the backbone is both the FLT3 inhibitor, which we typically don’t have a problem with, and the favorable risk with GO. Are you challenged by that at all? What’s your timeline like in New York?

Eytan Stein, MD: It’s an interesting question because for a variety of reasons that are probably too complicated to get into right now, we have been a non-GO institution. We never give it. That’s a discussion over a drink in a bar about why we don’t give it.

Hetty Carraway, MD: You might imagine it would be challenging if you did give it to patients in terms of the turnaround time.

Eytan Stein, MD: Of course. We get our FISH [fluorescence in situ hybridization] results back relatively quickly, but it certainly is challenging. If you were a place where you gave GO, especially because there seems to be a benefit, I’d want to wait for those FISH results. This is a little off topic, but a lot of these results from a technical standpoint can be done quickly. At large institutions, or if you’re sending it out to an external vendor, the issue often has to do with the resourcing that’s available to have the personnel turn these things around. I’m hoping one day we’re able to turn these things around quicker than we currently do.

Hetty Carraway, MD: I’ll echo that, but we handle this by relying on our pathologists at our institution. If our pathologists are looking at the morphology and they’re worried about a core binding factor leukemia in morphology alone, we give it. We don’t wait for the FISH tests. We’ve learned that we haven’t missed that many, based on relying on and communicating with our pathology experts.

Eytan Stein, MD: That’s a very good point.

Hetty Carraway, MD: Sometimes you don’t need all the fancy testing.

Eytan Stein, MD: Yes, I totally agree.

Transcript edited for clarity.

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