AML Induction Strategy and Molecular Testing

Transcript:

Harry Erba, MD, PhD: As we go through this panel discussion, I’m going to look to each of you to make the point about how some of these new agents have improved outcomes for patients. Then the pushback has to come from clinicians, to pathologists, and to our universities or our local hospitals, as to what we need to take the best care of patients. We have to show the value of that. Naval, can we wait for this information?

Naval Daver, MD: Yeah. The value that is gained by getting this information and the ability to select the appropriate therapy, or additional therapy, whether it’s midostaurin, FLT3, whether it’s CPX-351 [cytarabine-daunorubicin] in the secondary ML [myeloid leukemia]. Whether it’s HMA [hypomethylating agents]—VEN [venetoclax] or HMA-IDH in older adults who are IDH mutated, the general improvement in response rates, as well as survival, is much more important than rushing into therapy and then finding out later that we could have done something better.

There were also data at this year’s ASH [American Society of Hematology Annual Meeting & Exposition]. The German colleagues Christoph Röllig, et al, presented a large analysis of German cooperative group studies from the SAL [Study Alliance Leukemia] group. We have to preface this by saying that these are patients who went on trial, so I don’t think it’s a direct extrapolation of what can happen in the community, because we know there are some patients who are sicker and did not go on trials, and there has to be individualized decisions about whether you can wait.

It looked as if, for a large majority of patients, when they were being monitored by an academic center in Germany, being followed closely, there was no difference in the outcome, waiting 5 days or more. They made the point that it’s more important to get the molecular, the FISH [fluorescence in situ hybridization], and the cytogenetic information. Waiting did not seem to impact the outcome, but getting the right decision did impact the outcome. I’m not saying if you have somebody at 70,000 white blood cell count with pulmonary infiltration, you wait, but those are the outliers. For the larger majority, you could do it.

Rami Komrokji, MD: There is something else we always talk about concerning waiting. Waiting doesn’t have to mean you’re not doing anything, because it could be like putting those patients on Hydrea [hydroxyurea], or you could choose some low-dose AraC [cytarabine]. You would start some treatment like tumor lysis prophylaxis. Waiting could be doing stuff; it doesn’t mean that we are not doing anything for those patients. The major decision on the patient’s major treatment or the main treatment induction strategy can wait.

Harry Erba, MD, PhD: Rami, that point was made during the question-and-answer session that they did not include the use of hydroxyurea in that wait time. Many patients may have received it, and I find it very effective at lowering the white blood cell count. It gives you time to treat infections and get tumor lysis under control.

Rami Komrokji, MD: This is where I find getting the rapid FISH back helpful. If I’ve got a patient on the borderline—high white blood cell count, unstable—I want to start treatment. I can reassure myself that I’m not dealing with a TP53 mutation. I’m more willing to wait, but you can still grade it. The lower, more indolent AMLs [acute myeloid leukemias] are less aggressive ones. I almost always know we are not touching them until we have a more comprehensive picture.

Harry Erba, MD, PhD: Before we leave this section, Mark, talk a little about the difference in prognostication between FLT3-ITD and FLT3-TKD. And what about the allelic burden?

Mark Levis, MD, PhD: It’s important to understand that the next-generation-sequencing test is what’s going to get you your FLT3-TKD. That is a point mutation in the tyrosine kinase domain of FLT3 affecting maybe 7% of AML patients walking in the door, which is not a huge prognostic impact, but it has a big impact on your choice of therapy. You’ve got to know about this. That’s likely going to be reported on the next-generation panel. The PCR [polymerase chain reaction] assay, which is still what most people are doing to identify the more common FLT3 mutation, which is an ITD mutation, internal tandem duplication, is going to be available sooner if the clinician knows to ask for it.

That’s a much more important mutation to know about prognostically, and there’s another layer of information that goes along with it, and that’s the relative amount: the allelic burden. Most oncologists are used to describing things with a VAF [variant allele frequency], and I’ve seen diagnostic companies now reporting the FLT3-ITD as a VAF. We have this old-fashioned thing where we divided the amount of mutants by the amount of wild type, and that was called an allelic ratio, which no one else uses for anything else in oncology. Regardless, it’s the amount of ITD mutant that you’ve got. The more you have, under any circumstances, whatever you’re doing, the worse off you are. These are not standardized assays. In the ELN [European LeukemiaNet] guidelines, which clearly state the 0.5 allelic ratio, they state that above 0.5 is bad and below 0.5 is not so bad. If you repeat that same assay 3 times, you get 3 different results.

I don’t recommend using the allelic ratio to make big treatment decisions. I can see that assays that show there’s more ITD present are bad, but I don’t advise using it for clinical decision making.

Transcript Edited for Clarity