Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 13

IDH1/2-Mutated Treatment-Naïve AML

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Harry P. Erba, MD, PhD: I am going to bounce back to Sasha [Alexander] to discuss something about IDH mutations, for which I have not been coming to him. Sasha, I don’t think of you as just the FLT3 guy, so don’t worry about that.

Alexander E. Perl, MD, MS: Good.

Eunice S. Wang, MD: I think of him as the FLT3 guy.

Alexander E. Perl, MD, MS: Well, I am the FLT3 guy, but I treat leukemias that have mutations other than FLT3, believe it or not.

Harry P. Erba, MD, PhD: That’s when somebody else is out of town, right?

Alexander E. Perl, MD, MS: Right, exactly, and when I cover.

Eunice S. Wang, MD: It’s when you’re cross covering.

Alexander E. Perl, MD, MS: Yes, exactly.

Eunice S. Wang, MD: You have an IDH guy, then you’re the FLT3 guy, and then there’s a TP53 guy.

Alexander E. Perl, MD, MS: It’s the left pinkie leukemia doctor and the right pinkie leukemia doctor.

Harry P. Erba, MD, PhD: I am going to put you on the spot. I am sure that you are up to the challenge, though. We have learned from the phase 1 studies of ivosidenib and enasidenib in patients with IDH1- and IDH2-mutated, treatment-naïve AML [acute myeloid leukemia] in small subsets that there is activity of those inhibitors. We have also learned from either phase 1b or randomized phase 2 studies of higher response rates of azacitidine with ivosidenib or azacitidine with enasidenib in patients with IDH1- and IDH2-mutated, treatment-naïve AML. There are high response rates, but we also saw the presentation by Dan Pollyea MD, MS, at ASH [the American Society of Hematology 2020 annual meeting] looking at the activity of venetoclax with azacitidine in patients with IDH1 and IDH2 mutations, which showed high response rates and impressively high survival.

My question to you is this: what should a clinician do? Ivosidenib is now approved for patients with previously untreated IDH1-mutated AML. You might be able to get enasidenib for your patient with IDH2 mutations, but we have azacitidine/venetoclax. Should you be doing mutational analysis to help guide choice, or do you start with azacitidine/venetoclax and use IDH inhibitors in the relapsed/refractory setting? What do you advise?

Alexander E. Perl, MD, MS: I can tell you what I do. There really is no study that tells us what we should do. What I generally do is this: if I think the patient is up to the treatment, and the treatment is exactly as Eunice has nicely described, then I give patients azacitidine plus venetoclax, and I expect a good response in a patient who has an IDH mutation. It has a high response rate, and it is quite durable. But it is not uncommon that we run into issues on subsequent cycles, where patients can get cytopenia, or they might have the tolerability issues or trouble getting in for the number of doses of azacitidine that they need to get, and they want an easier option at that point. When I am thinking about if we want to create a treatment break, if we want to move to something different, or if they should have progression, that is when I am more typically looking to give ivosidenib. I recognize that I can give that in the frontline setting, but there are few patients for whom I would choose it over an HMA [hypomethylating agent] plus venetoclax as a frontline option.

The population that might be most interesting is those who have had MPNs [myeloproliferative neoplasms] and progressed to AML. They have had high response rates to IDH inhibitors, and they were not studied at all in the VIALE-A trial nor the prior venetoclax development. Those might be good patients for whom we may look at an IDH inhibitor because they can have surprisingly good responses and durability of response in that context. Those are patients who may benefit from an IDH-targeted approach. Across the board, I have not used mutational analysis to guide whether I give a one or another regimen in the unfit group that is older. I have typically been using HMA plus venetoclax there.

Harry P. Erba, MD, PhD: The one place where I have considered ivosidenib and azacitidine is in someone who already comes in ill with infection, and I do not think I can get through a prolonged period of neutropenia. One of the interesting parts of Courtney DiNardo’s MD, MSCE, presentation at EHA [the European Hematology Association 2020 annual meeting] was that the blood counts, specifically the neutrophil counts, seem to be getting better in patients during their first cycle. It might be a place where you can consider ivosidenib with azacitidine, but I agree with you. I start in the labeled indication of azacitidine/venetoclax and then use enasidenib and ivosidenib in their labeled indications for relapsed/refractory disease.

Transcript Edited for Clarity