Recent Advances in Treatment of Acute Myeloid Leukemia - Episode 13

Relapsed/Refractory FLT3-Mutated AML


Harry Erba, MD, PhD: Mark, is there any mutational profile that allows us to predict who might respond to a second-generation drug like quizartinib?

Mark Levis, MD, PhD: Not really. In general, there is a mutational profile that will tell you whether chemotherapy is going to be hopeless, and that’s the high mutation burden, the high ITD and VAF, or high ITD allelic burden. Those patients do abysmally, and they do abysmally no matter what. We saw it with gilteritinib, a great drug. We saw it with quizartinib. When you have a huge burden of disease, and that’s what you’re looking at with a high allelic ratio, that’s a troublesome patient population. Trying to use chemotherapy on that is almost absolutely futile. That’s about the only predictor, at least in the relapsed/refractory setting.

Harry Erba, MD, PhD: Dan, did you see the data on transplants after quizartinib?

Dan Pollyea, MD, MS: Yeah.

Harry Erba, MD, PhD: Do you want to talk about that?

Dan Pollyea, MD, MS: The end point is getting patients to a transplant after you can salvage them in the relapsed setting. By the way, not that any of these studies has the capacity to be designed in a noninferiority way; that’s too difficult and numbers are too much. As a clinician, I don’t necessarily need to see superiority for a well-tolerated pill when we’re talking about chemotherapy. The fact that we have 2 therapies out there that have a better survival than chemotherapy is just gravy for me. That’s way above the bar. The message is that these patients can be salvaged in a relatively well-tolerated fashion and can have very promising longer-term outcomes and maybe we’ll see cure. That’s the message, and I think that was always the goal.

Harry Erba, MD, PhD: Siddhartha Ganguly gave a very passionate presentation in the oral session from the point of view of a transplanter pointing out higher remission rates, good for getting patients to transplant; the longer duration of that remission, good for getting them to transplant; and the lower toxicity. All these things good for transplant.

Naval Daver, MD: In what he showed, in his last, he gave a nice summary, and there are a lot of caveats because there is always internal bias, individual biases when we take people to transplant. We see the patient is never captured, but it was 6 to 7 months with quizartinib alone. If you achieved a remission, went to transplant, went to 12 to 14 months, and if you gave post-transplant, which is really the key, people will question. They did in that session: What is the benefit of this 1 intervention? I agree, it’s marginal, but when you do that intervention, you do the transplant, and you do the post-transplant maintenance, then eventually, they showed 25 months in that subset who could get remission transplant, post-transplant, which is unheard of. Three years ago, for a relapsed FLT3, we would say nobody is going to go more than 5 months.

Harry Erba, MD, PhD: One of the things that is undermining our ability to bring drugs along in AML [acute myeloid leukemia] is that bridge to transplant. At this point, unfortunately, it remains the only curative option for relapsed/refractory disease, so it has to be considered as part of the package.

Mark Levis, MD, PhD: Yet the regulatory authorities regard it as an irritation.

Harry Erba, MD, PhD: Mark, tell us about the drug that did get approved for relapsed/refractory FLT3-mutated AML.

Mark Levis, MD, PhD: These drugs were gilteritinib followed close on the heels of quizartinib in the developmental pathways. They were even being developed together at 1 point by the same company. We at Johns Hopkins [Sidney Kimmel Comprehensive Cancer Center] were all involved in it, and we looked at all the things that can go wrong in a FLT3-mutant patient, FLT3 inhibitor trial. Not that there’s anything wrong with the drug, but what not to do in your trial, whom to include, how to do it. The analogy I make with gilteritinib is this: gilteritinib sits back there and watches everybody go on in and spring all the traps and fall in all the holes, and then they just go on in afterward and claim the prize. It’s a great drug, but that’s why it happened so fast, because we got to learn from all the mistakes we made in trying to develop the earlier drugs.

When we came in with a developmental plan for gilteritinib, it moved very quickly. It’s a well-designed drug. It’s extremely well tolerated. It does hit the TKD and the ITD mutation. It does not have KIT suppressive activity, so it’s less myelosuppressive. They got a level for CRh [complete response with partial hematological recovery], CR Bahamas—whatever you want to call it. It’s a great drug. We’re using it in a maintenance trial right now. It’s being tested head-to-head against midostaurin under a variety of circumstances. It’s different from quizartinib. It is less potent. I still like the concept of quizartinib early on, maybe gilteritinib later on.

Harry Erba, MD, PhD: In that randomized trial, a 2:1 randomization, more patients had CR [complete response], CR plus CRh, more patients got to transplant and the primary end point: median overall survival was improved by using gilteritinib as opposed to chemotherapy.

Mark Levis, MD, PhD: There was a big fat difference in the survival curve. You can see it from across the room in those patients, but still, everybody dies. Not everybody, but basically only 1 of 7 patients is a long-term survivor with both drugs. We have a lot more work to do.

Harry Erba, MD, PhD: What’s instructive and should be remembered is the performance of the chemotherapy arm. A lot of people were like, wow, the chemotherapy did very poorly, but Mark, you led the lestaurtinib study and the MEC [mitoxantrone, etoposide, intermediate-dose cytarabine] and HiDAC [high-dose cytarabine] in that study also did miserably.

Mark Levis, MD, PhD: Yeah, it was falling off a cliff. This was a fall-off-a-cliff survival curve. Again, taking a FLT3-mutant relapsed patient and giving them chemotherapy is not madness, but it’s a pretty abysmal option.

Harry Erba, MD, PhD: These drugs are being evaluated not only with intensive chemotherapy but with hypomethylating agents as well. We’ll see where that gets us for that subset of patients who can’t get intensive chemotherapy.

Transcript Edited for Clarity