Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 6

MRD Monitoring in FLT3 ITD AML

January 25, 2021
Harry P. Erba, MD, PhD, Duke University School of Medicine

Alexander E. Perl, MD, University of Pennsylvania

Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

Adam Bagg, MD, University of Pennsylvania

Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute

Harry P. Erba, MD, PhD: Sasha, I know you must have just as many thoughts as Eunice does on this. I am going to go to your expertise, and you can then do whatever you want. Here is my question for you: I gave somebody 7+3 chemotherapy and midostaurin, and I then gave them HiDAC [high-dose cytarabine] and midostaurin and sent off 1 of these fancy MRD [minimum residual disease] assays for the FLT3 ITD, not the usual PCR [polymerase chain reaction] assay, the FLT3 ITD MRD assay, and it is completely negative. Does that patient need a transplant still? Should I go with the MRD as the marker or the biology of the disease?

Alexander E. Perl, MD, MS: I am happy to say that I have absolutely no idea. I do not have data that will tell me what to do with this particular mutation at this particular time point. That is always the issue with MRD: What is the assay, what is the time point, what is the lesion, and how are you determining that there is MRD present or absent? For example, in the patient you mentioned, were they NPM1 mutated at diagnosis? If so, what happened to that mutation? Did they have another marker that you would want to track and a balanced translocation or something like that? We can see a FLT3 ITD mutation in other contexts.

Did they have ELN [European LeukemiaNET recommendations for diagnosis and management of acute myeloid leukemia in adults] adverse-risk disease? No matter what, I want to transplant them because the survival is terrible outside that, even when you see MRD negative disease. MRD is most helpful in telling you what to do in somebody who is on the fence in that intermediate range. For the patients who have poor-risk biology, I have not seen convincing data that MRD negativity is a strong predictor of long-term success with chemotherapy. If you have adverse-risk disease by karyotype, MRD is not all that helpful.

The converse is not necessarily true. In core-binding factor disease, there are pretty good data to say that, if that persists by molecular, then that is something you can ignore. You cannot. It is not something that is not going to go away even though there is some old literature that says it can sometimes persist in remission, similar to the example that Eunice mentioned. I do not want to hang my hat on that in a patient like this with a FLT3 mutation.

There are newer assays looking at the burden of FLT3 ITD mutation as something that you can measure: something you can watch go down and something you can potentially change by transplant. We have incorporated that into post-transplant maintenance studies, such as the MORPHO study, the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] 1506 trial, which gave gilteritinib vs placebo posttransplant but enrolled patients pretransplant for this very question. If you have MRD positivity pretransplant and then went on to get a transplant, what happened after that? Do those patients benefit from maintenance? For the converse, if you did not have detectable MRD, is there a benefit of maintenance in that setting?

What I can say is that there is a small amount of pretransplant data that Chris Hourigan recently published from a prior BMT CTN study looking at reduced intensity vs myeloablative transplant, where he did not have the diagnostic specimens. But if he detected a FLT3 ITD mutation at a cutoff of 10-4 pre-transplant, there were no survivors at 1 year. Presumably, the transplant-related mortality is not that high, so these were essentially all leukemic relapses post-transplant, so that is a bad scenario.

I do not know about MRD negativity and what that predicts in this day and age for adding a FLT3 inhibitor in the frontline setting. We still need to get that off the frontline studies. Those studies are currently enrolling, so let’s wait until we have the data before we make decisions. If you see positivity, that is not a good sign. We should be transplanting those patients. I would say that, outside a trial, you should be giving those patients maintenance.

Harry P. Erba, MD, PhD: We have a lot of questions and a lot of work that we have to do there.

Transcript Edited for Clarity