Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia - Episode 5
Transcript:Elias Jabbour, MD: Let’s move to the second part of our day today, and essentially we started with, Marty, you mentioning the minimum to be done before starting therapy. You mentioned the FLT3-ITD, the internal tandem duplication, and the point mutation. So, Mark, you did a lot of studying in that field. I would like to know from you, what is the impact of having FLT3-ITD or kinase domain mutation? Allele burden, are they similar? And then after that, what you said just as a therapy, and how they take the tyrosine kinase inhibitors available to work.
Mark J. Levis, MD, PhD: So, I’ll start first with whether or not the mutation is present. And, again, it goes back to a lack of standardization of assays. The original definition of whether or not a FLT3 mutation was present was based on an arbitrary cutoff point, which we now know is probably inaccurate, but nonetheless, the community sends their sample out to a lab, and they’re reported back either positive or negative. They’re not told how much is present or what burden of the mutation is present within a leukemic population.
We’re moving in a different direction now. Literally, the presence of an ITD mutation at any level probably predicts for the ability for the patient to relapse. But, at diagnosis, there’s no question — you can show that patients with a lower burden of the mutation have an overall better outcome. I will point out there’s still no standardized assay to determine that burden. And so, that remains a problem in the field.
Elias Jabbour, MD: But, between the ITD mutation and the tandem duplication, are they similar as a prognostic impact?
Mark J. Levis, MD, PhD: You mean at the tyrosine kinase?
Elias Jabbour, MD: Correct.
Mark J. Levis, MD, PhD: No. So, when you get back the results that the patient has either an ITD or a tyrosine kinase domain (TKD) mutation, clearly the tyrosine kinase domain mutation all by itself, I believe, actually has a slightly lower overall outcome, but nowhere near the impact of the ITD mutation. The ITD mutation is the bad one.
Elias Jabbour, MD: Correct. And the reason I’m asking this question is because we have a plethora of new drugs today, FLT3 inhibitors, first- and second-generation. Having a kinase domain mutation or ITD mutation, will that have an impact on how you select your therapy?
Mark J. Levis, MD, PhD: Well, we anticipate the first therapy that’s FLT3-directed that’s going to be available very soon is midostaurin. Midostaurin actually affects both types of mutations. It’s equally effective against the tyrosine kinase domain mutation and an ITD mutation, both in the lab and clinically.
Elias Jabbour, MD: So, before I move to Dr. Stone, who presented data last year of the RATIFY study, I want to ask you a question. For FLT3 inhibitors, shall we use them only if we treat a mutated patient — ITD or kinase domain mutation? Is there any role for such agents in patients who are wild-type?
Mark J. Levis, MD, PhD: I would argue fairly strongly that the highly selective, highly potent inhibitors going just after FLT3 mutations don’t have much of a role for FLT3 wild-type. Selective ones such as midostaurin, I actually think could very well have a role.
Elias Jabbour, MD: There was a study by the Germans 2 years ago, reported and published, about choosing sorafenib (Nexavar), for example, in patients who are wild-type. It showed improvements in event-free survival.
Mark J. Levis, MD, PhD: It did. But, in fact, sorafenib is one of those agents that’s less selected and has a number of targets. When you focus on the more selective ones, I think you’re really working specifically through FLT3 mutations.
Elias Jabbour, MD: So, Richard, finally we have a randomized study that’s shown a superiority of the FLT3 inhibitors — midostaurin in AML. Can you tell me more about this trial you presented and where you see the drug going?
Richard M. Stone, MD: You’re referring to the RATIFY study, also called CALGB 10603, which is really quite a herculean effort by many people around the world involving academia, the United States government, and the drug company, Novartis, to mount a double-blind, placebo-controlled, prospective randomized trial of standard chemotherapy with placebo or standard chemotherapy with this multi-kinase inhibitor, midostaurin.
So, 717 patients were enrolled. The arms between the people who got chemotherapy plus midostaurin versus chemotherapy plus placebo were fairly balanced. There was a slight gender imbalance, but they were fairly balanced. They were stratified according to the type of FLT3 mutation, whether they had a tyrosine kinase domain mutation or a high- versus low-allelic burden of the ITD mutation. And the primary endpoint of the trial was overall survival uncensored for transplant; just come as you may, see how you did. The trial did meet its primary endpoint of showing reduction in the risk of dying by about 23%, and those patients were randomized to midostaurin.
And, as Mark already mentioned, that benefit was seen in all 3 genetic subgroups: TKD, high ITD, and low ITD. So, that was encouraging that we had a drug that actually improved survival. It wasn’t dramatically improved. The 4-year median survival changed from about 44% to 51%, which is highly statistically significant because it was a large trial. One important sub-finding of that trial, which I would like to emphasize something that Marty said, is the role of allogeneic transplant. Patients who got randomized to midostaurin and who got a transplant during first remission did really well with a plateau, and there was a survival curve in the 60% to 70% range.
Elias Jabbour, MD: And taking oral pills with chemotherapy was not a concern.
Richard M. Stone, MD: Right. I’m glad you brought that up. There was no increased toxicity in those who were randomized to midostaurin versus placebo except for a slightly higher instance of grade 3 rash.
Elias Jabbour, MD: From an extrapolation in ALL, for example in Philadelphia-positive disease, if you give TKI and chemotherapy continuously, you have better outcome than if you give it intermittently. You think the use of the 3 inhibitors should be given continuously, or just like 10 days, 15 days?
Richard M. Stone, MD: Well, I’ll let Mark make some further comments. All I can say is in the data from the trial, during each cycle of the induction — because you could get two, most got one—you get it for 14 days on days 8 through 21, 8 being the day after the chemotherapy, and that was also true for the high dose Ara-C consolidations. There was no midostaurin or FLT3 inhibitor maintenance after transplant. So, right now, we can say that drug needs to be used in that way. Although, the reason it was used in that way is because prior trial showed that giving it for a longer period of time was not well tolerated. But, theoretically, you might want to do one.
Martin S. Tallman, MD: That’s in the RATIFY study. The drug was given in induction, consolidation, and maintenance. So, in all three major phases of therapy. Do we have any information to suggest it’s more required in one phase than another?
Richard M. Stone, MD: I think the most important is the upfront phase. First of all, not that many patients got it during maintenance. Not that many patients even got it during consolidation. Many were pulled off for transplant, they relapsed, or they weren’t deemed to be in remission by one means or another. So, I think absolutely. The cell kill in the beginning is probably enhanced by giving midostaurin. In the complete remission rate, if you relax the definition, was better in midostaurin and that bit about first remission transplant benefiting, just like they seem to do with Vyxeos (cytarabine and daunorubicin liposome). So, it implies but it doesn’t prove that you got to a lower cell kill by giving it early.
Mark J. Levis, MD, PhD: But, Elias’s point is important because lots of patients couldn’t continue taking the drug for a variety of reasons — either they went to transplant or whatever. Using the Philadelphia chromosome-positive ALL as an example, it still makes good biologic sense that the longer exposure you have to the inhibitor, the better patients will do. In other words, you might postulate if patients could have gotten the drug after transplant, would they…?
Richard M. Stone, MD: It might make it better. Although, as you’ve often said, the clone may not be there any more or it’s a different biology than Philadelphia-positive ALL where you get a founder mutation you’re shooting at with the TKI.
Elias Jabbour, MD: To you, Mark, about the question. We discussed at the beginning that having FLT3-ITD mutations is intermediate-risk disease, especially if you have the burden of 20% to 30%. My question to you is, if we give this drug and we reverse it, do you think we can go back and re-classify AML as good risk if they have FLT3-ITD mutation?
Mark J. Levis, MD, PhD: I personally don’t. I personally would still move towards allogeneic transplant in the foreseeable future, and then still try and arrange for some sort of maintenance therapy. I still stick to the paradigm of Philadelphia-positive ALL with that.
Martin S. Tallman, MD: Do you think we’ll ever have a FLT3 inhibitor potent enough to obviate the need for an allogeneic transplant?
Mark J. Levis, MD, PhD: We’re testing that right now in the large randomized study. However, I don’t believe so. I don’t believe a FLT3 inhibitor can cure a significant fraction of these patients alone with chemotherapy. I think at the present time, you need an allogeneic with that.
Elias Jabbour, MD: So, maybe the new generation of FLT3 inhibitors.
Transcript Edited for Clarity