Mark R. Litzow, MD: Minimal residual disease [MRD] has gotten into many of the guidelines that we use and certainly in the adult world, we rely on the NCCN [National Comprehensive Cancer Network] guidelines. I’ll ask you Jae, if you could comment a little bit about the NCCN guidelines. Is there anybody who you think shouldn’t have MRD testing when you’re seeing patients?

Jae Park, MD: I think all patients with ALL [acute lymphoblastic leukemia] should be tested for MRD. I think we should definitely be thinking about them. We should not only be thinking about them, but actually doing the test to get the results because it has a direct implication for therapy for a good number of those patients and making a decision about whether to use transplant or another therapy as well.

So, it is a little bit challenging to be building the guidelines in adult ALL treatment with the optimum timing, mainly because we don’t have one standard regimen that everybody agrees on. I have to say at the end of this cycle, that cycle, that cycle, so with a caveat there, the general timing that we do testing for MRD is after induction 1, which is usually the 4-week time point given whatever the regimen they used, whether it’s hyper-CVAD 1A [cyclophosphamide, vincristine, doxorubicin, dexamethasone] versus a pediatric or pediatric-inspired regimen, or some of the other regimens. I think that’s a clear time point to get them tested. But you can argue that on the basis of that four-week MRD, we don’t really necessarily make the treatment change decisions at that time, but it identifies our higher risk patients.

With MRD we do follow up the induction 2 or consolidation, depending on which regimen, which will end up being about the 3-months mark for most of the patients, whether it’s getting induction 2 or consolidation or another cycle of hyper-CVAD.

I think those are more important markers that can potentially impact the treatment decision making. The NCCN guidelines loosely use the term of induction. After induction, after initial consolidation, some of these regimens have a long consolidation so I personally check every time I do a bone marrow biopsy, the bone marrow aspiration. There are a couple of different ways to test MRD, and we will talk a little bit more about them, flow cytometry or the PCR [polymerase chain reaction]. But not every institution, not every place, may have the optimal way to do them, but there are certain times where it’s important to do. But throughout the consolidation, we make recommendations depending on the regimens, which ends up being every 2 or 3 months while they are on the regimen. And then the maintenance therapy as well.

I think the maintenance part we also left a little bit loosely defined in terms of the recommendation because of bone marrow frequency, bone marrow aspirate assessment frequency, during the maintenance phase. For adult ALL oncologists it is not well defined. For certain regimens, they’ve done protocols every 3 months for the first year, every 6 months for the second year, but it all depends. But the one thing we want to emphasize is this: If it’s not induction 1, consolidation, then you stop monitoring them. If they are MRD positive, then you change the management. If they are MRD negative, you want to follow that MRD level to make sure that those are staying negative to, again, optimize the management based on the level.

Mark R. Litzow, MD: Yes, it does seem to me that at least in the adult world it’s not etched in stone when we do these measurements, and I think it is somewhat regimen-dependent. Can you give us a pediatric perspective, Rachel? I think maybe you have it a little bit better defined since your regimens are a little more uniform.

Rachel E. Rau, MD: And they aren’t completely uniformed certainly, but I think everyone has a pretty defined induction that’s 4 to 5 weeks long, and I think that MRD time point is proven most prognostic. However, I think this is lineage dependent as well because in B-cell ALL, that early time point is highly prognostic. In T-cell ALL, we have to take a little bit longer to clear and doesn’t seem to have the same impact on outcome, and therefore that second time point for the patients with T-cell ALL seemed to be most critical in terms of clearance and correlation with outcome.

Mark R. Litzow, MD: When it that second time point?

Rachel E. Rau, MD: At least in the Children’s Oncology Group [COG], that’s after consolidation, so that’s another two months of therapy after induction. That does vary from consortium to consortium, but that seems to be more prognostic for our patients with T-cell ALL in particular.

I think there are some really interesting data about time to clearance and also level of MRD that is prognostic based on genotype. The University of California published a wonderful paper early last year where they showed that not all MRD is created equal. They looked at not only what your MRD level was at a flat cutoff, but also on a gradient, and they found that the patients with favorable cytogenetics tended to do well even if their MRD was slightly higher at the end of induction.

We looked at our COG data and found that in patients, we have two favorable cytogenetic subsets that we consider: the ETV6/RUNX1 fusion patients and patients with hyperdiploidy, specifically double trisomy of chromosomes 4 and 10 in the Children’s Oncology Group. It was really interesting, we found that patients who had double trisomy of chromosomes 4 and 10 did fine if their MRD was between that 0.1% and 0.01%, with just standard nonintensified post-induction therapy. Conversely, when we looked at our ETV6/RUNX1 patients, they didn’t do well unless you intensified their post-induction therapy in that same range. For us, our genotype specific threshold is for the double trisomy patients in particular. I think it is very clean to apply the same threshold to every patient, but that may not be necessarily the case for all.

Jae Park, MD: What do you do for patients with T-LBL [T-lymphoblastic lymphoma]? I think that’s probably the one setting where MRD testing is not very strict, for patients who don’t have any bone marrow involvement and just more lymphomic disease and mediastinal mass where we don’t find anything. For those patients, there’s really no good tool. To your question about if there are patients who wouldn’t be tested for MRD, those patients would never really have blood or bone marrow involvement. We do PET [positron emission tomography] scan assessment, which is far from the MRD level by any means. I don’t know how the Children’s Oncology Group handles T-LBL, is there any risk stratification since you can’t use MRD?

Rachel E. Rau, MD: Right, it’s a relatively rare population so it’s been hard to do the same powered studies that we’ve done for patients with lymphoblastic leukemia. We are studying the impact of minimal marrow disease at diagnosis in our patients with B-lymphoblastic lymphoma in our most recent trials. I think we have a lot to learn in terms of how to stratify them. We don’t even know about cytogenetic features or anything, so I think we have a lot to learn, and I would be interested in hearing your experience.

Ryan D. Cassaday, MD: I will sometimes include PET scans, but I think it’s a pretty healthy extrapolation from the Hodgkin lymphoma and DLBCL [diffuse large B-cell lymphoma] literature to assume it has to be PET negative at such and such a time. Even with things like Deauville scores, we don’t really know if any of those tools apply to lymphoblastic lymphoma. So you’re spot on Jae, it’s a really challenging population to apply risk-directed therapy and response assessments to. In my experience, fortunately those patients tend to do pretty well, so transplant is usually not something I’m thinking about for most of those folks, but they’re definitely a subset that don’t do well and unfortunately, it’s hard to know who those patients are.

Mark R. Litzow, MD: Rachel, I think that you make a nice point that we tend to think, in a little bit simplistic way, that all MRD is the same. But it can vary by time point with these other factors that you weigh in. Our goal is to get people MRD negative. But I’ve always wondered whether the patient who becomes MRD negative after initial induction is the same as the one who’s MRD positive. And then you give them blinatumomab and now they’re MRD negative, you tend to think that’s not the same beast and that patient likely isn’t going to do as well. You’re happy they’re MRD negative, but you’re not as sure that it has the same significance.

Rachel E. Rau, MD: Mike Borowitz, MD, PhD, published a paper a few years ago that showed intensification of post-induction therapy led to earlier clearance of MRD. However, it’s a very interesting survival curve to look at because while they’re separated for a bit, they end up overlapping again. Therefore, it seems to delay those events. So blinatumomab may be quite different because that was standard intensification of chemotherapy. I think it will be interesting to see, now that we’re incorporating blinatumomab into upfront therapy more often, what that really does not only to your MRD clearance but ultimately to your disease-free survival.

Mark R. Litzow, MD: When it that second time point?

Transcript Edited for Clarity