Clinical Insights Concerning Molecular Testing in Patients Diagnosed with Acute Myeloid Leukemia

Dr. Eunice S. Wang: I think some of those genes on those panels actually incorporate inherited predisposition syndromes. And those don't seem very important initially at diagnosis because you're not necessarily going to targetable those. But they become incredibly important for, particularly for those patients with intermediate and adverse risk disease that are going to go on to subsequent allogeneic stem cell transplantation. Because we really want to know, do they have an inheritance syndrome, not only to guide their family members to get additional genetic testing and to identify some of these inherited producers families and clans, but also in terms of planning for transplant in terms of selection of a donor. So that's always something to consider. If you don't have that on your panel, but you are considering a younger patient for transplant, it is probably worth your while if there's a young patient, 30, 40-year-old MDS, AML family, primary history of family members having it or low platelet counts to take that additional step to get the germline testing.

Dr. Naval G. Daver: I think that's something we have at Raheem malignancy clinic, I think other centers are doing similar, where now we're doing more and more germline testing and we are finding germline predisposition that may then change the donor choice. We may be going for a sibling, but now we either have to wait, which could take six to eight weeks to get the germline on the sibling if there is a predisposition found in the patient, or we just go for a match unrelated donor if we can find. So I think this is more like five years ago, I don't think we ever talked about this, but now this is becoming more and more prevalent. So Amir, maybe if you could just talk us through the current NCCN recommendations for molecular testing for the community and others were listening.

Dr. Amir Fathi: I think in general, cytogenetics or FISH, depending on what's available are important in order to identify patients who are favorable risk or adverse risk, but mainly favorable risk because it does impact the choice of treatment for younger patients. Most of us would probably incorporate gemtuzumab, oligomycin in addition to seven and three, and down the road it impacts the choice of consolidation, of course. So cytogenetics is essential for both prognostication as well as choice of treatment. A complex stereotype oftentimes swims in the same lane as a P53 mutation. In general, those patients historically have not done well with honestly anything we have to offer. So some centers, not all, may choose not to go with a very intensive route for patients who have a P53 mutation, although that is still I think open to debate. Mutational testing I think has been mentioned already, by the panel here. You have options, one way is to do PCR testing and generally that's more rapid, can generally get that back in a couple of days, max hopefully. And that can give you information regarding both ITD and TKD-FLT3 mutations as well as an NPM1 mutation, and also the IDH1&2 mutations if that is important. And in older patients, I would argue that certainly IDH1 mutational status is important because you can make the decision regarding azacitidine and ivosidenib, which I assume we will talk about shortly. And FLT3 mutations obviously are also important in terms of choice of treatment, particularly with intensive induction in terms of adding midostaurin and perhaps in the near future, quizartinib as well. I think from my perspective, those are the steps in terms of cytogenetic molecular mutational testing that are essential upfront to get that rapid testing, whether it's by PCR, NGS with those targetable mutations as well as chromosomal data to make decisions regarding treatment.

Dr. Naval G. Daver: So just to wrap up this portion, a lot of times people in the community say, "Well, but is this really practically valuable? What percentage of these patients have this?" So if you take a young patient, if you look for APL core binding factor inversion 6821, FLT3, and TP53, that is about 50% of patients if not more. And these could potentially change your frontline approach, each of these. And then the other mutations may change your approach. Like Dr. Wang was saying, now these splice mutations, AXL1 others may actually start making a thing that this patient may need a transplant where you may initially not have been sure. So I think that this is very real world, this is not just academic centers, academic exercise. It could change 50, 55% of your frontline treatment and then it could also change your transplant decision for another 20, 25%. So I think it's very valuable stuff for us to do.

Dr. Margaret T. Kasner: And I would argue for two other points. One is the only reason we know those things about the slicing mutations is because we've been getting them. And so academics does lead to the real-world, and what was targetable five years ago is very different than what was targetable 10 years ago is just certainly different from what will be targetable five years from now. So even if you are not at an institution where you personally have a trial that might, Dr. Wang's very involved in the MLL and the Menin inhibitors and the MPO1 targeting drugs. And that may not be available at your center, but it may be a referral thing. So you do the testing on your patient, even if you send it and it's back after you started, it doesn't mean it doesn't have value. And unfortunately, the relapse refractory setting is very real for many of our patients. And knowing that about your patient's original leukemia is very important, but also testing at the point of relapse is also very important because they may have been FLT3 when they started and they are no longer, they may not have been FLT3 when they started, and now they are. And so, FLT3 inhibitors weren't in your arsenal for that particular patient, and yet now they're FLT3. So, both having the information about your patient's leukemia and retesting at each relapse, I think is really important.

Dr. Naval G. Daver: I think you bring a very important point, and NCCN does as well as the ELN panel do recommend retesting at the time of initial relapse, especially for targetable mutations, FLT3-IDH1, 2, maybe in the very near future, hopefully so MLL NPM1. So, I think this is also something to highlight. I mean, you're going to-

Dr. Amir Fathi: I just wanted to briefly just echo that both of those actually, I think FLT3 particularly plays a lot of peekaboo, comes and goes. So, I think it's important for us to sort of keep track of it. But it is true also, like for example, the DDX41 mutation, which is a familial predisposition, we didn't really know to sort of test for that or to identify patients. When it showed up in our NGS panel and we started to test for it, all of a sudden, we're starting to detect it. And it's really impactful because siblings can have it, family members can have it, impacts your donor, impacts the choice of how aggressive you want to be. So, certainly these mutations and their discovery and their application, even a little bit further down the road as we're sort of inducing patients, I think is very valuable.