Alan Burnett, MD, FRCP, of Cardiff University, Cardiff, UK, discusses the use of measurable residual disease (MRD) in acute myeloid leukemia (AML). Prof. Burnett highlights its utility as an independent predictor of outcome and questions how much MRD could displace other risk scores, as well as it’s possible indication of chemosensitivity.
Transcript (edited for clarity)
The word measurable, this is the way to refer to it rather than minimal. Now, we’ve got a methodology issue here as well, by flow cytometry, this is not like acute lymphoblastic leukemia, where interpretation of what you see is fairly straightforward. It’s still a bit of an art form and it has to be done by experienced viewers of the data, but there are several studies, mostly European, not all, but mostly European studies, where there are some excellent labs showing that MRD status is an important independent predictor of outcome...
The word measurable, this is the way to refer to it rather than minimal. Now, we’ve got a methodology issue here as well, by flow cytometry, this is not like acute lymphoblastic leukemia, where interpretation of what you see is fairly straightforward. It’s still a bit of an art form and it has to be done by experienced viewers of the data, but there are several studies, mostly European, not all, but mostly European studies, where there are some excellent labs showing that MRD status is an important independent predictor of outcome.
In our own experience in older patients in the UK, this emerged as the most important risk factor for outcome for older patients once they had gone into morphological remission. In general terms, if you look at a marrow that’s said to be in remission by conventional criteria 50% of them will still be measurable residual disease positive using an assay that’s sensitive by about 1 in 10^4. So, if they’re morphologically in remission and MRD positive they will do less well than those who are negative. Now, the issue is, to my mind, how much does that displace other prognostic factors that people build into risk scores or even the molecular stuff? Does MRD, measurable residual disease, tell you all you need to know to allow you to direct treatments? So, I think that’s a question – need a lot of patient information before we can resolve that.
The second issue is, what do you do about it? There’s a common assumption that MRD positivity is bad, not arguing about that, so give it more treatment and that’s a good thing to do. Well, our limited experience in the context of of a group of patients that were randomized when the MRD status was known, this is older patients, do they get more treatment or not, the decision was not based on MRD, it just happened that we knew the MRD. If the patients were MRD positive and they got more treatment – this is where you would think i’m going to benefit the MRD positives – that didn’t help. In the patients who were MRD negative who got more treatment, that helped. So, it may be that what MRD is telling us, that these are the chemosensitive patients, and they are the ones that you can actually cure.
The ones that are MRD positive are going to be more difficult, so the real challenge now is to get answers to that by randomized comparisons, not jumping to conclusions, and I think that’s going to be hard to restrain the enthusiasm. There are clearly molecular ways of doing it, which are more sensitive, are wee bit harder to set up, they don’t cover all the patients, but next-generation sequencing is coming along, it’s probably not quite there yet, but it looks as though that might lead to a more standardized assay. So, we’re particularly fortunate in Europe that there are some very good labs and people doing measurable residual disease incorporated into clinical studies. Interestingly, this is not proving to be widely accepted in the United States and I think this is really because of the system, I mean there’s a separation between the physicians and the labs in the US, and private labs churning out some numbers is not going to be very useful for MRD, in AML at least, so that’s only my opinion.