Harry P. Erba, MD, PhD: Sasha, 1 of the most common mutations we will see in our patients with AML [acute myeloid leukemia]—as Eunice mentioned, it is targetable in initial therapy and the relapsed/refractory setting—is the FLT3 mutation. Of course, we know there are several types of mutations, but the most common are the ITD and TKD. Do these have the same frequency and prognostic significance?
Alexander E. Perl, MD, MS: No, they don’t. The FLT3 internal tandem duplication mutations are both more common and more sinister, not so much for initial response to chemotherapy, but there is a higher relapse rate. Although things are getting better with the addition of FLT3 inhibitors to frontline chemotherapy, I don’t think we’ve eliminated the risk attributed to FLT3 mutations in terms of the survival of patients. As you mentioned, patients can have a FLT3-ITD or a FLT3-TKD mutation. They may even have both, and these may be independent clones or even in the same cell as we’ve studied. What also can vary is how much of the FLT3 mutation is present with a higher aggressiveness being associated with a higher ratio of FLT3-ITD to wild-type mutations in patients who have that mutation. In general, we want to know a lot of information about the FLT3 gene, not just if a mutation is present or absent. We want to know which mutation is there and how much mutation is there to a certain extent.
One challenge in the patient with a FLT3 mutation, if there’s a FLT3-ITD mutation, is how you know whether this patient needs a transplant. Studies have looked at the allele burden as a predictor of that in the presence of an NPM1 mutation, but there’s not an international harmonized agreement on how to measure that. We don’t have an IS [international scale] percentage the way we would have for BCR-ABL mutations, where we can say that if a patient has a low ratio, don’t transplant in the presence of NPM1, or if a patient has a high ratio, they should be transplanted. In my practice at the University of Pennsylvania Perelman School of Medicine, I err on the side of referring these patients for transplant when possible. If they have good transplant donor options, and they’re fit patients, the outcomes have generally been favorable.
We are starting to get data comparing our results with other laboratories in the context of clinical trials. We’re enrolling patients to a study comparing midostaurin vs gilteritinib, and I get a study-designed lab tests for allelic ratio on that study on anybody we enroll. We also get an in-house test, and they’re not always the same. In fact, they seem to be consistent from patient to patient within the lab, but they don’t necessarily line up exactly. This is something we’d like to solve in the field, so if we’re using this to make decisions, every lab comes up with the same answer. It would be nice if this were something with a normal value, so you could say it definitely falls in this range rather than out of the range, but we don’t have that yet. I’m cautious to use allelic ratio to recommend transplant.
Harry P. Erba, MD, PhD: It’s interesting that you say that, Sasha, yet smart leukemia doctors in Europe have developed the ELN [European LeukemiaNet recommendations for management and diagnosis of acute myeloid leukemia in adults] 2017 and now 2020 risk stratification and guidelines, and that allelic ratio is very important. Although I agree with you, let’s get a third clinician. Eunice, at Roswell Park Comprehensive Cancer Center, how important is allelic burden in determining treatment algorithms for your patients?
Eunice S. Wang, MD: We also are on the side of saying that presence of any detectable FLT3-ITD mutation confers a worse prognosis. We measure the allelic ratio, but much of the data that have been acquired with the FLT3 inhibitors have demonstrated that those inhibitors are equally effective in patients who have high allelic ratio as well as those who have low allelic ratio, and in some cases in patients who have TKD mutation. I routinely refer all my patients who have FLT3-ITD mutation for transplant. As you know, the RATIFY trial data with midostaurin demonstrated that the benefit of midostaurin could not be disentangled from the benefit of performing an allogeneic stem cell transplantation and first remission for individuals who achieved the most clinical benefit from that FLT3 inhibitor.
Harry P. Erba, MD, PhD: Yeah.
Eunice S. Wang, MD: Following that evidence-based trial is what we do. I have a question for the group: What about TKD mutations? Certainly ITD mutations can be detected specifically at the time of diagnosis with PCR [polymerase chain reaction] assays and with allelic ratios. Oftentimes, we don’t pick up some rarer or less common tyrosine kinase domain mutation until we get the results of the next-generation sequencing [NGS] panel back, and then the question is that, prognostically, they’re not as impactful as the ITD mutation. If you pick up a TKD mutation later, and maybe you didn’t do the tyrosine kinase inhibitor up front, what do you guys do with that information? Harry, do you continue? Do you still think a TKD mutation is poor prognosis? Would you add a tyrosine kinase? I’m sure there are some individuals in the community who are performing these next-generation sequencing or myeloid panels who aren’t getting results until 2 or 3 weeks later. The question I get is: “What do you do now that you’ve detected something, but it’s already a couple of weeks from 7+3 chemotherapy?” Do you still send them to transplant, or do you add a FLT3 inhibitor with their next cycle? What is your practice?
Harry P. Erba, MD, PhD: Personally, for the FLT3-TKD mutation, I’m not at all as certain about that single gene as a prognostic event in AML, so it’s the co-mutational pattern that goes with it that may drive my decision-making. Having said that, however, if a FLT3-TKD mutation is present, I will use midostaurin as part of the induction regimen. In fact, as you remember from the subset analyses, the patients who had the greatest hazard ratio for improvement in survival were the patients with TKD mutations, making some people wonder if the benefit of this first-generation FLT3 inhibitor is not just through inhibition of FLT3 but because of its inhibition of other serine threonine and tyrosine kinases that may also be active and driving the leukemia. I definitely use it there.
When we get to talking about FLT3 mutations, I’m going to come back to this, so I’m going to save it for later. I want Sasha to specifically discuss whether he thinks the benefit of gilteritinib, a second-generation drug that’s a type 1 inhibitor, is equal as a single agent in ITD and TKD mutations. If I see a TKD mutation, I will use—in its labeled indication—gilteritinib for those patients. Prognostically, it may not be as important, but that’s definitely a therapeutic target that I will take advantage of.
The whole thing about allelic burden is that it’s only 1 of the things that we know is driving prognosis. We don’t talk about the number of FLT3 mutations and ITD mutations that are prognostically important. The other thing is the length of the FLT3-ITD mutation as well as the position of the mutation. There were data presented at the 2020 ASH [American Society for Hematology Annual Meeting] from the RATIFY trial showing that, when the insertion is in the beta sheet of the TKD1 domain, those patients have a worse outcome. There is a lot we don’t understand about how to judge the prognostic significance of FLT3 mutations, but I agree with you, Eunice and Sasha. It’s like being a bit pregnant. We know what the outcome is going to be, but the ITD mutation is there.
Eunice S. Wang, MD: Yes.
Harry P. Erba, MD, PhD: I need to turn back to Adam. Adam, I want to get you back in this. What would you say to an investigator or a clinician who says, “I sent off the NGS panel. Why do I need to do the PCR test for FLT3 mutation? Isn’t that redundant? Are there problems with double charging and things like that?” How would you answer those questions?
Adam Bagg, MD: That’s a great segue to a question I was ultimately going to raise. Users of these technologies—clinicians and oncologists in the community—need to know what the PCR panel is telling us when it tests for FLT3 mutation vs what the next-generation sequencing panel is telling us when it looks for FLT3 mutations. Both TKD mutations, D835 in particular, are standard things we look for by PCR, the results of which you can get in a few days, maybe even less depending when the run is occurring with an allelic ratio. You’re restricted to knowing just what the ITD length is, what the allelic ratio is, and if there is a D835 mutation for most assays. By contrast, if you’re doing it by next-generation sequencing, the turnaround time is a lot slower: a week or more. You still get the information about the length of an ITD if it’s there, but you’ll get added information about where the insertion occurred. Next-generation sequencing can help with that and determining whether it goes into the beta-pleated sheet, which may be prognostically relevant. By sequencing, you’re not restricted to looking only at the D835; you may pick up that and other important gatekeeper mutations, resistance mutations. Both are going to pick up ITDs and mutations, but if you look at the details, there are differences. Although next-generation sequencing is quantitative, people are familiar with VAFs [variant allelic frequencies] of mutant vs wild type; that number does not easily translate into early integrations. You’re getting similar but different information from the 2 technological approaches: PCR on 1 hand, next-generation sequencing on the other.
Transcript Edited for Clarity