Novel Therapeutic Agents for Acute Myeloid and Chronic Lymphocytic Leukemia - Episode 4
Transcript: Daniel A. Pollyea, MD, MS: Midostaurin was approved in 2017 for patients who were eligible for induction chemotherapy and had a FLT3 mutation. And the midostaurin was added into the induction regimen, and there was a significant survival benefit with that…study design compared with the control arm who received induction chemotherapy with a placebo. So these were really exciting and encouraging data, because this was a herculean effort to get that study done. It took many, many years and many patients. And so now it’s the standard and an FDA-approved therapy for patients with a FLT3 mutation who are eligible for induction chemotherapy to receive that therapy plus the…midostaurin.
The mechanism of action of midostaurin is interesting. So, midostaurin is a drug that’s been around for a very long time, and its original intent was to target a completely different pathway, the protein kinase C pathway. But it did have some, at the time, off-target FLT3 activity, and it was sort of repurposed as a FLT3 inhibitor. It’s a relatively less specific FLT3 inhibitor than a lot of the very specific FLT3 inhibitors that are coming on the market now. But it’s interesting, because the patients on the RATIFY study who had a FLT3 tyrosine kinase domain mutation who were allowed on the study…also had responses to midostaurin, suggesting that perhaps the benefit of midostaurin isn’t restricted to patients with the FLT3 mutation but is sort of a more general benefit from other unclear targets that are implicated with midostaurin.
The prognosis of…FLT3-ITD is very clear. In almost all cases, it portends…poor outcomes, short survival, and a high relapsed rate. The prognostic significance of a FLT3 tyrosine kinase domain mutation is less clear. Particularly in the de novo setting, there are a variety of publications in the literature that suggest that it has a worse prognosis but others that equally suggest that perhaps the prognosis is not so bad.
In the relapsed setting, particularly in a patient who’s already been exposed to a FLT3 inhibitor for, let’s say, a FLT3-ITD mutation, the evolution or occurrence of a FLT3-TKD mutation is typically a very poor prognostic sign.
Well, you know that for a newly diagnosed AML patient who’s fit for induction chemotherapy—because midostaurin is FDA approved for patients with a FLT3 mutation in that situation—it really is the standard of care and the expectation that those patients have testing done for the FLT3 gene so that they can get the best possible therapy. Outside of that, until recently, we didn’t have approval for any other FLT3 inhibitor, so it was questionable exactly when or how you should test, although the default recommendation for most experts would be to test. However, just very recently in light of the fact that gilteritinib, a FLT3 inhibitor, is now approved in the relapsed refractory AML setting, I think it’s incumbent on us to…be very confident about our patients’ FLT3 status is that they can potentially benefit from a drug like gilteritinib. And other FLT3 inhibitors are likely to get approved, so this is only going to become more important—to know the FLT3 status of our patients.
Naval G. Daver, MD: The RATIFY study was a large, multicenter, phase III study that randomized patients receiving induction chemotherapy with 3 + 7 versus induction chemotherapy with 3 + 7 plus midostaurin, which is a FLT3 as well as a multikinase inhibitor. The primary endpoints of the study were overall survival. A total of 720 patients were randomized to receive either the midostaurin with induction or induction chemotherapy alone. It is important to know that midostaurin was given during induction and consolidation but not along with the 3 + 7. It was given on day 8 through 21 during induction, and again, 8 to 21 on each of the consolidations, followed by a maintenance phase where midostaurin was given continuously starting on day 1 daily without interruption.
The study did meet its primary endpoint of overall survival. The overall survival was absolute increase of 7% with the addition of midostaurin versus just induction alone. And it also showed a significant improvement in the CR [complete remission], CRi [CR with incomplete blood count recovery] rate when we evaluated all responses that occurred over time. So this established the use of a FLT3 inhibitor—namely, midostaurin—in the frontline setting in combination with induction 3 + 7 chemotherapy to improve overall survival in FLT3 mutated…and it is now recommended that we wait for the results of the FLT3 mutation testing before we start induction or, if the induction is started, to add the midostaurin on day 8 if the FLT3 mutation comes back positive.
In general, the midostaurin has been well tolerated in our experience, as well as in the published RATIFY data. The main issue that we see is rash, which was seen about 10% versus 5% in the midostaurin induction versus induction alone. This was not a very severe rash that required dose interruptions and definitely not discontinuation. This was managed by topical steroids and was usually transient.
So all in all, we’ve noticed that midostaurin was very well tolerated. There was concern for GI gastrointestinal toxicities, but we actually have not seen very significant GI toxicities in this regimen, and it may be because we give the midostaurin after completion of induction and not concomitantly. And based on this, I would recommend using FLT3 testing for all newly diagnosed AML, and if you find a positive mutation, to add the midostaurin to induction and consolidation.
Transcript Edited for Clarity