Mark R. Litzow, MD: We’ve been alluding a lot there to MRD [minimal residual disease], and let’s get into the weeds of MRD testing and talk about that more. I mentioned at the beginning, we called this initially minimal residual disease, but people are moving to call this measurable residual disease. I do like that term because it reminds me that all the tests we do have levels of detection, and people who are MRD negative can relapse. We know that they still have residual disease there, just too low for our limits of detection. But I think as you have heard from what we’ve been talking about so far, it’s really emerged as I don’t think the only, but certainly one of the most important prognostic factors that we rely on in our management of these patients.

I think we still need to take into account obviously the individual patient. I think we need to take into account their genetic features. And we talked about the Ph [Philadelphia chromosome]-like ALL, some of the complex cytogenetic abnormalities that we can have. But I think we’re finding that measurable residual disease is replacing some of our traditional risk factors that we’ve relied on in the past. You alluded to some of those, Ryan: white blood cell count, age, things like that. I still take those into account to some extent, but measurable residual disease has really emerged as the most important factor. And the pediatricians, as so often we’ve seen, have led the way in ALL.

Ryan, we all know we don’t practice in isolation. Tell us a little bit about your interactions with your hematopathologist and any other members of your care team.

Ryan D. Cassaday, MD: I’ll start by saying that the first few years I worked at the University of Washington School of Medicine, I forgot that our in-house flow cytometry was the COG [Children’s Oncology Group] reference lab quality, so I would talk to people about MRD testing with this naive notion of, “Oh, this is how it is for everybody.” But of course, that’s not how it is for everybody. I think I’m really, really lucky to be able to work with outstanding hematophathologists who do this at a super high level. But, for those of us not so fortunate to be able to tap into that world class resource, I think it’s really important that, as Jae alluded to before, it really starts with the person doing the procedure, making sure that it’s that first pull of the marrow aspirate, 2 mL or 3 mL or so. You don’t want that first pull to be 10 mL and just hemodiluted. So, whether that’s the APP [advanced practice provider] who you work with or who is in your procedure suite, if it’s a radiologist, if it’s a pathologist, or whoever is doing it, I think that’s really important.

Knowing where that specimen is going to go is important. For us it goes to our laboratory, which is outstanding, but if you were in the community, your laboratory may contract with some outside facility that provides excellent reference laboratory quality flow cytometry. It may even come to the University of Washington. But, if it’s being run as an in-house assay, it’s worth talking to the pathologists about, “What’s the sensitivity of the assay you’re using? What color or how many colors are you using with your flow cytometry?” Because, if the level of sensitivity is 0.1% or worse, it’s going to be very hard to be able to utilize the data that are out there for MRD-directed therapy in a situation because you’re going to be falsely reassured.

If you’re in a situation where you don’t have access to good quality flow cytometry as diagnostic testing, that might be a situation where you look into the commercially available high-throughput sequencing assay that’s available, if your lab is able to coordinate that. Again, we don’t know exactly how to use that particularly assay necessarily at these particular time points to make treatment decisions. But I would argue using an MRD assay that’s maybe ahead of the curve, too sensitive, is probably better than using one that’s not sensitive enough. There are a lot of different touch points to potentially make sure that you’re optimizing the way that these specimens get collected, handled, and processed, so that the data you get back are reliable.

Transcript Edited for Clarity