Mark R. Litzow, MD: Let’s talk some more about that MRD [minimal residual disease]-positive patient, the one who we’re struggling with and challenged with. Rachel, you talked about the importance of getting them to MRD negativity. What are some of the considerations you take into account in deciding which agent you’re going to use, and when? How do you proceed in that situation?

Rachel E. Rau, MD: Our first-line agent for that particular patient scenario is blinatumomab. I think the data that have driven that decision are quite robust and have been shown in both adult and pediatric patients with B-cell ALL [acute lymphoblastic leukemia] and an MRD-positive state. That’s our first-line agent for those patients who are not achieving MRD negativity with our standard chemotherapy. The one concern we raise with that is if this a patient you ultimately deem may be a CAR [chimeric antigen receptor] T-cell candidate for the CD19-directed CAR T therapy. There’s of course some concern that blinatumomab may drive a CD19-negative situation where it wouldn’t be amenable to CAR T. So there’s always some discussion about, if this is a patient who might need CAR T, should we hold off and use something else instead of blinatumomab?

But the vast majority of patients, we’ll go to blinatumomab first because of its success and its tolerability. An extremely well tolerated agent I think is also a benefit in our population who are pediatric patients who tolerate chemotherapy better, but by that point they’ve been pretty beaten down by the regimens we’ve had to employ. And I know that’s a benefit on the adult side as well, the tolerability of the agent.

Mark R. Litzow, MD: I’ll say fortunately, we’re dealing with someone with a low level of disease, so we’re not going to tend to see the cytokine release syndrome that you see with blinatumomab in somebody who’s got a full-blown relapse. I think that is helpful. Ryan, in the adult world, how would you approach that scenario?

Ryan D. Cassaday, MD: Blinatumomab for the patients with B-cell ALL is usually what I aim for first. I could imagine some scenarios otherwise. If there was a Ph [Philadelphia chromosome]-positive patient, for example, and I had started chemotherapy and imatinib and their response wasn't very good but still relatively deep, I might continue the chemotherapy backbone but swap out the TKI [tyrosine kinase inhibitor] for dasatinib. Again, speaking to Rachel’s point about maybe not pulling the blinatumomab out of the quiver just yet. T-cell ALL is obviously a more challenging situation because we don’t have a real potent, effective therapy that works well for low burden disease. That’s a situation where if hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone] hasn’t worked, I might transition to an asparaginase-based regimen if it’s a patient I think can tolerate it. But that’s a particularly challenging situation.

I think CAR T-cell therapy certainly has a potential role in this space. Obviously, it is only approved right now for young adults and children, but as that therapy works its way into the adult space, I think it has a role. I think the data are so good with blinatumomab, it’s well tolerated, and we already have relatively long-term outcomes with that agent. So that’s likely still going to be the one I reach for treating patients with B-cell ALL.

Mark R. Litzow, MD: And it is FDA [Food and Drug Administration] approved.

Ryan D. Cassaday, MD: And it’s FDA approved specifically for that, exactly right.

Mark R. Litzow, MD: Jae, what about inotuzumab? That’s the other arrow in our quiver.

Jae Park, MD: I think as was alluded to earlier, blinatumomab is usually our first choice to get to MRD negativity for patients with B-cell ALL. If they’re persistently positive, and that’s what we were talking about earlier today, too, inotuzumab might be a consideration, especially if they received a multi-agent chemotherapy and asparaginase-based chemotherapy as well, then we don’t really have a lot of other chemotherapeutic options. You may potentially intensify them. But, if they’re chemorefractory, I’m not sure that is going to be a successful strategy. There’s now a lot of data with inotuzumab, specifically in the MRD setting. Obviously most of the data are coming from the morphologic relapse, salvage 1, and salvage 2 settings, and in the later lines of relapse.

I think it’s a reasonable approach to certainly use, either alone or potentially in combination with some immunochemotherapy. There are data to support use, not to say that combination therapies are better than monotherapy with inotuzumab. The concern there sometimes is the VOD [veno-occlusive disease], because these are the patients whose eventual goal is to get to transplant. If you use inotuzumab to get to transplant, if you’re able to get to MRD negativity after one, hopefully, or maybe even two cycles and you’re not getting that much of exposure to the inotuzumab, the risk for developing VOD could be minimized with avoiding the blood clotting agent and conditioning chemotherapy. There are other ways you could do so. But that raises a little bit of a level of concern, which is the reason we would not jump on it; again, we have FDA approved therapy with the blinatumomab. But inotuzumab could be a potential option for those patients who were not able to get MRD negativity with blinatumomab.

Mark R. Litzow, MD: Right. And inotuzumab, we like to always remind ourselves, is the CD22 antibody, linked to calicheamicin, reminiscent of Mylotarg [gemtuzumab ozogamicin], a CD33 antibody linked to calicheamicin, where we also saw some veno-occlusive disease. What about CAR T therapy, your experience and use in MRD-positive patients?

Jae Park, MD: I think that’s really the best setting, honestly. One of the better settings. I think we can get better results with the CAR T-cell therapy in that setting. Regarding the COG [Children’s Oncology Group], it is very good to hear there’s actually going to be a study designed exactly the way that I think we should be studying it. I’ll be anxious to know the results of those trials. But in the adult side, it hasn’t been really tested in early line settings just yet, although it’s been tested in the minimal disease setting. Some of our early trial data have shown that either way, with a couple different CAR T-cell therapies targeting CD19, the initial response rate is actually the same regardless of disease burden. You can have a 80% bone marrow blast, you can have 0.5%—very low level disease—you actually will get MRD negativity at the same rate, usually about 80% of the time.

But what really is different is the duration of remission or progression or event-free survival. So the long-term outcome is better if you actually receive CAR T-cell therapy at the time of a lower burden of disease. I think to your point, if the persistently MRD-positive patients have received blinatumomab or some other agents, I think that would be a perfect setting where we should be studying the CAR T-cell therapy. That hasn’t been studied yet. I think it’s going to work very well in that setting, but again we don’t have the data. I think it would be great, hopefully someday, that we can actually study it in adult leukemia world, the CAR T-cell therapy in the earlier line setting.

Hopefully we’ll get the product approved in the first place in the relapsed/refractory adult leukemia setting, and hopefully move it up lines of therapy. I think this type of immunotherapy, as we’ve learned from blinatumomab, works better in earlier lines, a setting of lower burden disease. I think leukemia cells have less chance to develop resistance and are easier to eradicate. I think we should certainly take advantage of that setting with this very important therapy.

Mark R. Litzow, MD: Do you think that CAR T is going to get approved for older adults in the not distant future?

Jae Park, MD: I think so. There are a couple obviously ongoing clinical trials, so we have to wait for those clinical trial results to come back. Even before, there were clinical trials even though they were not commercially developed, but institutional, academic institution led clinical trials to really truly demonstrate a clinical benefit in patients who have relapsed after blinatumomab or inotuzumab, which is very challenging patient population now. We know it’s going to work, and obviously what we are working on is the toxicity because adult patients with ALL unfortunately do get the more severe degree of cytokine release syndrome and some neurological adverse effects. However, we’re getting better at managing them, preventing them with earlier interventions. I’m very optimistic and confident it will get approved fairly soon.

Mark R. Litzow, MD: Good, great. That will be very exciting.

Transcript Edited for Clarity