DR STONE: This was the CALGB 10603 RATIFY trial. The trial took so many years to develop and read out that the name of the Cooperative Group changed from CALGB to Alliance during the time that it was incubating. But it was an attempt to determine if adding an FLT3 inhibitor to patients with mutant FLT3 in AML who were being treated with standard chemotherapy would be better than adding a placebo to standard chemotherapy.

And the standard chemotherapy was, indeed, daunorubicin at 60 mg/m² per day for 3 days and cytarabine at 200 mg/m² per day for 7 days. And if they were in remission, they could get high-dose ara-C-based therapy. And then they got maintenance with midostaurin or placebo for 12 months afterwards. So it was a prospective randomized, double-blind, placebo-controlled trial, the crème de la crème when it comes to clinical research.

So the tough news was that, to define the 30% of people with an FLT3 mutation, we had to screen about 3,300 people to get the 714 that ended up on the trial. So it really took incredible academic/industrial collaboration and international collaboration to be able to do a trial in a relatively rare disease and in a relatively rare subset of that relatively rare disease. But, fortunately, those who were randomized to the midostaurin had a 23% reduced risk of death. The hazard ratio was, thus, 0.77. It was quite statistically significant. So something about getting midostaurin, whenever they got it, was better than getting placebo.

And, of course, the devil’s in the details. Why did this occur? What about transplantation? We may talk about that. It turns out that we estimated when we designed the trial, based on the current practice in the midpart of the first decade of the 21^st century, that only about 15% to 20% of people would get transplanted. Lo and behold, 57% of the patients on this trial got a transplant at one point or another. So that obviously affected the statistics.

And when we looked at the effect of midostaurin for those who were transplanted in first remission, when they had “presumptively” received midostaurin relatively recently, there was a clear-cut reduction in the risk of death in those people. If the people didn’t get transplanted until they went into second remission, presumably maybe even years after they received the midostaurin or placebo, there was no benefit to having been randomized to midostaurin.

So it seems to me, at least, like there’s a package here: Chemo plus midostaurin followed by transplant in first CR may be the best way to go if you have FLT3-mutant leukemia, based on the data from this trial. And even if you censored for transplant, there was still a benefit. So it wasn’t all about transplant. The way I read this is, there was probably a more superior disease reduction in those who got midostaurin, although we didn’t do MRD to actually confirm that.

DR LOVE: What about side effects/tolerability issues?

DR STONE: Again, placebo control gives you a good window on this. Except for rash, there were no statistically increased Grade 3 side effects, or Grade 3 to 4 side effects, in those who were on the midostaurin compared to the placebo.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions