Mark R. Litzow, MD: Rachel, we’ve been going back and forth for a little bit talking about numbers here. Can you talk about the sensitivity of these assays and how we interpret some of those results?

Rachel E. Rau, MD: As Ryan mentioned, in the United States we predominantly rely on flow cytometry for our MRD [minimal residual disease] assessments. We use a threshold of 0.01% or 10^-4. The sensitivity of that assay is pretty well established. PCR [polymerase chain reaction] I believe is about the same. The next-generation sequencing that Ryan discussed, the DNA-based method, reports down to 10^-6, but I know it can be more sensitive than that. I think that raises the question of, how sensitive is too sensitive? And then when I speak with all of my patients at the end of induction, I say even though by the metrics we use to measure your disease, we don’t see it, we know it’s there because it will come back if we stop your treatment now.

So, if we know it’s there, how much of it do we need to be prognostic is an important question. And we’re actually studying the incorporation of this extremely sensitive modality in our upfront B-cell ALL [acute lymphoblastic leukemia] trial right now. We’re taking our patients who are flow cytometry negative and we’re testing them by high-throughput sequencing MRD. There is some literature to suggest that patients who are, at the end of induction, MRD negative by both flow cytometry and MRD have an incredibly excellent outcome in the 98% event-free survival range in our population.

Mark R. Litzow, MD: Jae, I wanted to ask you, sometimes in my practice I get into situations where the patient is persistently MRD-positive after multiple cycles of therapy. Perhaps I switch to blinatumomab, and they’re still MRD-positive; how much do you keep treating them to try to get to MRD negativity or do you say, you’re not going to get there and we need to think about moving toward a transplant sooner rather than later?

Jae Park, MD: I think that’s the challenging situation there, too. Blinatumomab is typically what we use in B-cell ALL for patients who are MRD positive after one or two cycles of therapy, and if they’re still MRD positive, I think that’s really a time point to decide that this is the best we’re going to get because we don’t really have other options. There may be some other therapies, but it doesn’t make sense to give some multiagent chemotherapy or enroll on some other clinical trials for these patients to get to MRD negativity when there is no guarantee they will be MRD negative. They may actually relapse during that time. And then we may also lose the window of opportunity to go to transplant in a relatively stable and controlled disease setting.

I don’t think there’s any straightforward approach, but for me, after one or two months of a treatment if their MRD status is not changing, then those are the patients who we’ll just take to transplant. And it may depend on the level of MRD there, too. I think if it’s certainly a low level, less than 0.01% or 0.1%, then you may consider those relatively lower levels of MRD to go to transplant; but with the high level of MRD, although I may try a little bit more, it all depends on the condition of the patients, their previous lines of therapy, what additional therapeutic tools we have, and if there’s a reasonable chance I’m going to achieve that MRD negativity. Because, again, there is the chance that we’ll be successful either way, so I think it’s really just the comfort level, the data, and whatever tools we have. But it certainly presents a challenge.

Mark R. Litzow, MD: Rachel, you alluded to this a little bit earlier. Tell us about that patient who’s persistently MRD positive, how you approach that as a pediatrician.

Rachel E. Rau, MD: That is one of our most challenging scenarios as well, for sure. It’s, fortunately for us, a bit rarer in the pediatric side than the adult side. But we will use every available option to try to get them to MRD-negative status because we know that it dramatically impacts your post-transplant outcome. There’s a nice study by Michael Pulsipher, MD, looking at how even if you’re MRD positive by next-generation sequencing, you still have a much inferior post-transplant outcome, a much higher risk of relapse after transplant. And so we’ll even employ CAR T [chimeric antigen receptor T-cell therapy], blinatumomab certainly, inotuzumab ozogamicin, or other agents to really try to get them into MRD-negative status before sending them to transplant because their chances of being cured are much greater if we can get them to that state.

Ryan D. Cassaday, MD: I think one of the challenges is really, at least in my opinion, that transplant is really probably the only thing that’s going to be able to give that patient a chance of long-term remission. And we always have to be mindful of the fact that these therapies we’re giving to try to achieve that level may not work. It may make patients sicker. It may preclude them from moving ahead with the therapy that we’re ultimately trying to get them to.

So it’s a particularly challenging situation and I think it’s even more challenging in older patients, where we can’t necessarily assume that myeloablative conditioning is going to be able to mop up what’s there. If you’re talking about a patient who’s in their 60s or has a lot of medical comorbidities, where their only realistic chance of a transplant is with non-ablative reduced intensity conditioning, going into a transplant like that with persistent MRD is almost certainly not going to work, so that’s another really challenging situation. Hopefully there’s some novel approach to the transplant that can be offered or something like that.

Transcript Edited for Clarity