Molecular Testing for Acute Myeloid Leukemia

Harry Erba, MD, PhD: Hello, and welcome to this OncLive® Peer Exchange® titled “Acute Myeloid Leukemia: 2021 Perspectives on Testing, Systemic Therapies, and Transplantation.” I’m Dr Harry Erba from the Duke Cancer Institute in Durham, North Carolina. Joining me in this discussion are my colleagues Dr Courtney DiNardo from [The University of Texas] MD Anderson Cancer Center in Houston, Texas; Dr Vinod Pullarkat from City of Hope in Duarte, California; Dr Mark Levis from the Johns Hopkins University School of Medicine in Baltimore, Maryland; and Dr Dan Pollyea from the University of Colorado in Aurora, Colorado. Today we’re going to discuss a number of topics pertaining to the contemporary treatment of acute myeloid leukemia. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions around treatment selection. Let’s get started on our first topic. I’m going to turn to you, Mark, to lead us through a discussion of what testing should be done—specifically, molecular testing when considering therapy at the time of diagnosis or for the patient with refractory relapse.

Mark Levis, MD, PhD: I get this question a lot from community oncologists who are trying to manage these patients, and I’ll take it in 2 parts. For the newly diagnosed patient, all of us have this problem. We want all the data all at once, and we know it’s going to trickle in over the next 1, 2, or 3 weeks, but you can use this strategy with newly diagnosed patients. You want to identify mutations that are going to impact their treatment right away. You want to start the 7+3 [cytarabine, daunorubicin, idarubicin, mitoxantrone] regimen, or I want to make a decision. Do I want to go with HMA [hypomethylating agent] and venetoclax? Do I want to do something intensive? One trick we use is FISH [fluorescence in situ hybridization]. This comes back quick. You usually can get FISH to rule out APL [acute promyelocytic leukemia] and FISH to identify the core binding factor in a day or 2. Even the diagnostic hub that they’re sending it out to now has the input to give you because if the patient has APL that changes your treatment, but if you have a core binding factor—an A21 or an inversion 16—you’re not reaching the peripheral 3 inhibitor. You’re not necessarily worried about HMA-venetoclax . You get that back fast. Usually, we’re starting something intensive off and using gemtuzumab. The other thing you get with FISH is complex karyotype: a 5q or 7q. If those are screwed up in the FISH—in other words, they’re coming back lighting up in the FISH—then I say, “I might have a patient with a TP53 mutation.” I don’t necessarily want to pull out intensive therapy. I can get that back quick.

With this agonizing over, I can’t do anything until my next-generation [sequencing] testing comes back 2½ weeks from now. It’s not that important in many cases. You can rule out a lot of stuff with FISH. The other important thing to remember is your FLT3 ITD test, the PCR [polymerase chain reaction]…is not done with next-generation [sequencing] testing routinely, meaning you’ll get that back within a week also. That is an actionable mutation. You can add your FLT3 inhibitor after intensive therapy or maybe make adjustments to your HMA and venetoclax , or your low intensive regimen. If you just know what’s going to be able to come back quickly, you can go to your diagnostic hub and say, “I want the updates on the FISH. I want the PCR fast because that’s going to change my management.” Yes, when next-generation [sequencing] testing comes back, I can make final prognostic decisions. Finally, in the relapse setting or the refractory setting—I cannot stress this enough—every time a patient has a change in their disease status, relapsed or refractory, halt and get a full complement genetic test if the disease evolves. There, you’re really starting to get desperate, and you better have all your options available.

Harry Erba, MD, PhD: That was great. It perfectly reflects exactly what I do. I prioritize the FISH because those are the therapeutic options, and if you don’t have anything that suggests something other than the 7+3 [cytarabine, daunorubicin, idarubicin, mitoxantrone]—your favorite induction regimen—you can get the FLT3 back over the next several days after you’ve started 7+3 [cytarabine, daunorubicin, idarubicin, mitoxantrone].

Mark Levis, MD, PhD: You can do that even with a diagnostic company. A lot of committee oncologists send it out, but they can get updates from those companies routinely.

Harry Erba, MD, PhD: Let me challenge you a little there. In the relapsed/refractory setting, you said to do the entire mutational panel. I would focus just on IDH and FLT3 because those are actionable.

Mark Levis, MD, PhD: True, your options are pretty grim in the relapsed/refractory setting. I usually like to have a full picture of what I’m dealing with; that’s all. Yes, IDH—we have IDH linked to next-generation [sequencing]. It’s not a focus panel, so usually it doesn’t need next-generation [sequencing] coming back.

Harry Erba, MD, PhD: Dan, how are we doing with testing? Dan and I have been working on an AML [acute myeloid leukemia] registry where 80% of the sites in it are community based and 20% are academic. Dan has looked at these data on testing recently. Dan?

Dan Pollyea, MD, MS: Thanks, Harry. There’s slow progress. I don’t think any of us are satisfied with where we are. We all acknowledge the importance of this testing and, as Mark laid out really nicely, how to think about it and how to prioritize this important and complicated area, but it’s important to understand that this hasn’t been universally adopted. We still have more work to do to improve the education around this area. We found that the majority of sites and centers are sending some form of extensive molecular testing. We found that, as we would have expected, it’s higher in the academic setting than in the community setting, but it’s still good in the community setting.

We have lots of room to improve and continue to beat this drum. As Mark said, the impact on our patients from a prognostic therapeutic perspective is clear. It’s important to remember the light speed with which this has happened. It was only just over 10 years ago that the first cancer patient had human genome sequencing done. That happened to be an annotation, something we’re very proud of in our community. Since then, it has become essentially routine to do targeted resequencing and to know every single gene at play in our patients. It has been so fast. This has all happened so fast. The upshot of that paper is—I’m pretty encouraged by it, and it also shows the work we have to do.

Harry Erba, MD, PhD: Having been in this field for 30 years, I remember that, as a fellow and junior faculty, you do not go to bed at night until you start the 7+3 [cytarabine, daunorubicin, idarubicin, mitoxantrone] regimen because that’s all we had.

TRANSCRIPT EDITED FOR CLARITY