Previously Untreated FLT3-Mutated AML

Transcript:

Harry Erba, MD, PhD: Let’s get more toward the precision medicine. We’re going to start with the golden child of precision medicine—not you, Mark.

Naval Daver, MD: It could be Mark.

Harry Erba, MD, PhD: It could be Mark, but he’s not a child anymore. Why don’t you talk about advances in FLT3-mutated patients, especially for the previously untreated FLT3-mutated patient.

Mark Levis, MD, PhD: There’s been a lot of activity in the field after a long slog through the wilderness. We have the results of CALGB 10603, RATIFY, which was the randomized study of induction chemotherapy with or without the first-generation FLT3 inhibitor midostaurin. While it resulted in what many people thought was only a modest benefit in survival, it was real and it was believable. And as we’ve been alluding to with transplant, for the patients who got that and then went to transplant, a big fraction of those seemed to be cured. That was a big first step: that you could improve outcomes with this approach.

Then along comes the next player, quizartinib, because quizartinib was approved in Japan, and that’s approved in the relapsed setting. Fast on its heels was the drug gilteritinib. You’ve got this approach initially directed at the relapsed/refractory setting, but in the up-front setting you’ve got midostaurin. These better drugs or more targeted, more efficient drugs, second-generation drugs, are now being studied in the up-front setting head-to-head with midostaurin—or in the case of quizartinib, against placebo.

There is a trial called QuANTUM-First. QuANTUM-First got started in the middle before we knew about the results of RATIFY: the midostaurin results. It was carried out initially in the United States before the RATIFY results were known. When the RATIFY results went nowhere, ethically, I have to give midostaurin to my patient. That’s OK because midostaurin didn’t appear in the rest of the world for quite some time until the study finished accrual in the rest of the world. We have a study out there much like RATIFY: induction with either placebo or quizartinib. You can get quizartinib after transplant, and quizartinib is a very different drug than midostaurin. It is the opposite end of the spectrum. It doesn’t work against the TTD mutation, but it is very potent, is very selective, and might be the best drug to fold into the induction setting. Chaos is coming when the results of that are read out.

Harry Erba, MD, PhD: Let me come back to midostaurin and the RATIFY trial. It included both TKDs and ITDs, low and high allelic burden. Does it matter?

Mark Levis, MD, PhD: Not in the least. The FLT3 disease—TKD, high allelic burden, NPM1 mutated, which is a big modulator of how patients do—behaved exactly as we expected it to in the context of the trial. If you had a TKD, you did better than if you had an ITD. If you had an ITD, you did better if you had less of it. If you had an ITD and you had an NPM1 mutation, you did better. In all categories, midostaurin had the same benefit marching on up. It didn’t matter. Midostaurin should be used in all categories. Prognostically, it’s interesting to know, but it doesn’t influence your initial outcome or your initial treatments.

Harry Erba, MD, PhD: Rami, I’m going to put you on the spot about some. While the FLT3 inhibitors are being developed like that, there’s also been continuing work trying to figure out how to prescribe 7+3 [cytarabine, daunorubicin] from 1973. There have been large randomized trials. To summarize 3 of them: there was the ECOG E1900 trial, the MRC [Medical Research Council] trial with 90 mg versus 60 mg of daunorubicin—the ECOG E1900 was 45 mg versus 90 mg—and a Korean trial of 90 mg daunorubicin versus idarubicin. Those studies show that, in the FLT3-mutated subset, there seemed to be a benefit for 90 mg, yet midostaurin was developed on a backbone of 60 mg. Does it matter? And what do you do? Do you use a higher dose of daunorubicin?

Rami Komrokji, MD: I totally agree. Those studies were done in the context where we did not have novel therapies or active therapies, so the question was always 45 mg, 60 mg, or 90 mg. At least with the ECOG E1900 group study, that there was an advantage of the 90 mg in the FLT3-mutated patient. With the midostaurin study, with the survival benefits shown in that patient population, the study was designed targeting that population. We’ve adopted what’s done on the study, going down to the 60 mg as you mentioned. Later on, the study suggested that 60 mg is probably as good as 90 mg. The original ECOG study was 45 mg versus 90 mg daunorubicin. In this era, we are probably beyond looking at that the anthracycline dose. Hopefully in many subsets of patients, we’re going to go away from anthracycline.

Mark Levis, MD, PhD: I tell my fellows, if you’re in a room with people talking about what dose of the chemotherapy you should use, you should just leave.

Naval Daver, MD: Just do IDA [idarubicin]. That’s what we do.

Mark Levis, MD, PhD: That’s what we do.

Harry Erba, MD, PhD: That’s why no one ate dinner with me last night.

Rami Komrokji, MD: Fellows sometimes ask what dose. We’ve just adopted this if we are doing anthracycline, daunorubicin at 60 mg. In older patients, idarubicin is an equivalent choice. I don’t think we’ve ever showed that those are better, but we could talk about this. We have more exciting stuff.

Harry Erba, MD, PhD: Let’s move on to the more exciting stuff then.

Transcript Edited for Clarity