Combinations are the Future in FLT3-Mutated AML - Episode 7
Examining the need to achieve a true CR (complete remission), especially with recent targeted therapies in relapsed/refractory acute myeloid leukemia.
Jessica K. Altman, MD: You mentioned true CR [complete remission] vs CRh [CR with partial recovery of peripheral blood counts] vs CRi [CR with incomplete hematologic recovery]. When you and I first started, a CR was a CR, and that was all that really mattered. We knew that anything less than a true CR was not as good. With the use of targeted therapies, we’ve moved away from our reliance on CRs. How important do you think a CR is in a patient with relapsed disease?
Naval G. Daver, MD: That’s a great question. I do think there is value to less-than-CR responses. All the published literature until 2014 or so was on intensive chemotherapy—3+7, FLAG-Ida [fludarabine, cytarabine, filgrastim, idarubicin], MEC [mitoxantrone, etoposide, cytarabine]. And there, I would not hesitate to say that the true CR is clearly the benefit. There may be some with the CRp [CR with incomplete platelet recovery], for whom you at least have a full recovery of neutrophil, but everything else really had the same outcomes similar to a nonresponder. But yes, with these targeted therapies, especially in relapsed disease, absolutely.
Achieving disease clearance is very important because the goal is transplant, right? If I have a first-salvage FLT3-mutated 40-year-old who got 3+7 midostaurin and relapsed 8 months later, and I give him azacitidine-gilteritinib or venetoclax-gilteritinib or whatever combo, and I get him into a marrow remission clearance and have a transplant donor ready, I’m going to go to transplant. I’m not going to wait and see if he has a full count recovery or not.
Now, transplanters may ask more about MRD [minimal residual disease]. To them, it’s not about, “Did the platelets stay at 60 per mm3, or did they go to 103 per mm3?” Or, “Did the neutrophil go to 0.9 per mm3, or was it 1.1 per mm3 and now I feel good when it’s 1.1 per mm3?” No. They’re like, “We have nice flow and PCR [pathologic CR].” Are you comfortable that you have really eradicated the disease? Yes, you could wait a month and get the count recovery, but we don’t care about that. That’s where the field is moving. Using molecular clearance by PCR or flow is going to be more important than the kind of subjectivity of platelet recovery kinetics and neutrophils. What are your thoughts?
Jessica K. Altman, MD: I agree with your statements exactly, though we need to be mindful that we don’t really know the optimal time to assess for MRD. Let’s say we’ve given someone something like gilteritinib-venetoclax, which we know can be very myelosuppressive and clears out their bone marrow. If we are testing for MRD at a time of aplasia or hypoplasia, however we want to define that, MRD testing is not likely to be as sensitive as if the bone marrow is cellular. So we all need to get on the same page in terms of determining optimal timing for MRD assessment. I agree with you completely. I don’t care if the platelet count is 101 or 99 per mm3, or even if the platelet count is 20 or 120 per mm3. I care about who’s at play in that bone marrow, and what’s going on.
Naval G. Daver, MD: Yes. We actually just did analysis in Blood Advances that showed that in relapsed AML [acute myeloid leukemia], achieving MRD negativity—this is done by flow—and going to transplant did not significantly improve survival over just achieving a marrow remission going to transplant. However, when you look at the patients who achieved MRD negativity, their chance of making it to transplant was better. If you take it from the time point of treatment initiation, those who achieved MRD negativity had a better chance because they had a longer remission and could get a transplant. They did better. But if you just say, “I’ve got a person in marrow remission, transplant, are you ready?” And they say, “The MRD is positive,” that would actually, in our analysis, say, “No, you should take him.” This is counterintuitive to what we all thought, which was that in the front line we all agree without any doubt that MRD-negative status of any nature is always better. But in relapsed disease, it may not be the same. We’re moving toward MRD. As you said, there are many questions. Hopefully, with some of these studies, we can answer some of these questions.
Transcript Edited for Clarity