Combinations are the Future in FLT3-Mutated AML - Episode 8

Combination Sorafenib Plus HMA in R/R AML


Naval G. Daver, MD, leads the discussion on the use sorafenib in combination with hypomethylating agents (HMA) for the treatment of relapsed FLT3-mutated AML.

Naval G. Daver, MD: Let me ask you about another drug that we didn’t talk about but has been the backbone for many years: sorafenib. For many years, we have used azacitidine-sorafenib. This was in the NCCN [National Comprehensive Cancer Network] Guidelines and has been a nice workhorse for us. What’s your experience with this regimen, and what are your thoughts? Is there a place for sorafenib today in FLT3-mutated disease?

Jessica K. Altman, MD: It’s interesting, Naval. I actually have that on my list as a question for you. I was hoping you could provide insight on this topic. Ever since your center published the data with azacitidine and sorafenib in relapsed FLT3-mutated disease, I have been utilizing that as a regimen if a clinical trial isn’t available. I’ve been trying to think, because I knew we were going to be speaking about this, of the last time I used that and when thought I’d use that again. The regimen of sorafenib and azacitidine has really fallen out of favor with the approval of gilteritinib. I used to use it when I didn’t have gilteritinib available. For the patients who responded, I would take them to stem cell transplant. In fact, I have even had some patients for whom I’ve used it afterward, or for a relapse after transplant. I’ve been able to give that and do DLIs [donor leukocyte infusions] and then continue that therapy and have success. But I’ve been racking my brain as to when I’m going to be using an HMA [hypomethylating agent]–sorafenib regimen. What are your thoughts?

Naval G. Daver, MD: I would say that very rarely in somebody who’s failed multiple FLT3 inhibitors, we’ve used it as a last-ditch effort, and with very limited success. With the availability of gilteritinib, midostaurin, and even trials open with quizartinib, in terms of people coming through those, usually they’re resistant to everything. Usually other things, not FLT3, are driving resistance. So it’s very limited.

The 1 area we still have used the regimen, although its use is decreasing here as well, has been in the post-transplant setting. There are 2 randomized studies, 1 from the German Cooperative Group and 1 from China, showing that post-transplant, FLT3-mutated patients, whatever induction they got with or without a FTL3 inhibitor, made it to transplant. And post-transplant, they’re in front of you. They randomized patients to just observation, which is what we all used to do 5 years ago, vs sorafenib maintenance. Both studies showed that sorafenib maintenance significantly improved all parameters. This has led to the use of sorafenib by many of us in the US and Europe. That’s the 1 area we’d still use it. Even there, we’ve seen a lot of interrelationship toward gilteritinib. There’s a phase 3 study in that setting that hopefully will read out later this year. But that was where we used sorafenib. So it’s hard to find any area left for using sorafenib.

Jessica K. Altman, MD: For your current patients post-transplant, are you utilizing sorafenib? Or are you utilizing gilteritinib or another FLT3 inhibitor, recognizing that we do not have the results of the randomized post-transplant study comparing gilteritinib with placebo?

Naval G. Daver, MD: I’ll answer that, and then I’ll ask for your say as well, because that’s a tricky question. There’s no clear right answer. We’re using gilteritinib. We have already moved to using it just based on the single-agent activity and the tolerability. Gilteritinib is a very well-tolerated drug, so our transplanters are also happy post-transplant. We use that, and it’s dosed at 80 or 120 mg. In some people, we do see liver transaminitis and things like that. In those instances, we have to go to 80 mg, which is all right based on the phase 1 data. But that’s been our go-to regimen. However, we are waiting for the randomized data. What about you?

Jessica K. Altman, MD: Same. Frequently, you and I and our colleagues like to wait for data. But this is an area where we’re not waiting, and we’ve adopted gilteritinib post-transplant when insurance will cover its use. We also used to use sorafenib, both before we had the German data and since then. Recently, we’ve obviously moved to gilteritinib.

Transcript Edited for Clarity