Krishna V. Komanduri, MD: I want to talk about some specific trial results. David, do you want to talk to us about the ZUMA-3 study of axi-cel (axicabtagene ciloleucel), or what used to be called KTE-C19? And then later, perhaps Michael can tell us a little bit about the ZUMA-4 study in pediatric ALL.

David Maloney, MD, PhD: So, this is being reported at this meeting and it’s showing encouraging results with the axi-cel product in adult ALL. I think at this point, it’s very preliminary and they’re still in the, technically, dose-escalation phase, which has turned into a dose de-escalation phase. They’re currently enrolling the third dose level down from their initial dose, 0.5 times 10 to the 5th cells/kg.

So, they saw high rate of tumor response, but also a fairly high rate of toxicity. Almost all patients had cytokine release syndrome and a significant proportion had neurotoxicity. They were managed aggressively with tocilizumab and steroids. I think it’s really, really encouraging and we really desperately need a drug for adult ALL. I think it’s encouraging.

Michael Pulsipher, MD: Yes, the ZUMA-4 study is tracking that. It’s a very similar stage. I’ve had the same experience decreasing the dose we were very aggressive with, this particular product, in fact just giving tocilizumab very, very early on. We’re now at the lower doses not needing to do that. One important thing to understand about this particular trial is the patients who go probably need a transplant afterwards because this particular product is designed to be paired and be a bridge to transplant.

David Maloney, MD, PhD: I think that’s a really, really great point and quite controversial. I think that tisagenlecleucel data support not going on to allogeneic transplant. Our data in Seattle generally would support that if you’ve never had a transplant, then you probably should get a consolidated allograft for ALL. If you’ve already failed an allograft, then I’m not as enthusiastic about doing a second one if you’re in complete remission. But again, I think we need longer follow-up to be able to say this.

Michael Pulsipher, MD: We very much do. This is going to be an important question. Some people are taking an intermediate road where they’re following some of the 4-1BB vectors. And if patients have persistence, then they’re not moving to transplant. Others are moving to transplant if they lose the CAR early. A lot of study needs to be done in order to resolve that question.

David Maloney, MD, PhD: Yes, I think there’s one practical issue that people always ask me: How to you measure the CAR? Well you don’t actually really have to measure the CAR if you monitor the patient for B-cell recovery. So, if you see CD19-positive B cells in the blood, you don’t have effective CAR T cells because they’re not functional. Whether the PCR says you have them or not, they’re not functional. So, you can actually use just surrogate B-cell recovering the blood as to know whether you’ve got functional CAR T cells.

Krishna V. Komanduri, MD: Great points. I think this notion that in both the pivotal trials of tisagenlecleucel and axicabtagene ciloleucel, there were patients who went to an allogeneic transplant. In some cases, again, we don’t know whether those patients needed to go to allogeneic transplant. These are things, I think with further clinical trial results, we’ll need to understand. I think how MRD could guide that or other measures could guide that.

David Maloney, MD, PhD: But I think Mike mentioned earlier that it’s the group that loses their CAR T cells really quickly or has endogenous B-cell recovery really quickly that seems to have an increased risk of relapse. Patients who have CAR T cells are ongoing B-cell depletion for a longer period of time and we don’t know how long. I like to think of it as maybe it’s you need some area under the curve where you have to have a persistent CAR T-cell expansion and persistence to eradicate the malignancy, but you probably don’t need it for life. We clearly are having some patients in long-term remissions where we can’t detect the CAR T cells any further.

Michael Pulsipher, MD: Well, David—something to add to that—if you look at the tisagenlecleucel experience, only 12% of patients went on to get transplants. Those who have had persistent B-cell aplasia at 1 year and who relapsed afterwards is very rare, and that has been borne out with a much longer experience at the Children’s Hospital in Philadelphia. The interesting thing about that is we know if ALL maintenance therapy matters. So, if we treat patients for a year or 2, perhaps we need ALL cells to escape from the niche, to begin to cycle. So, something to happen, a period of coverage. But I do agree, at some point, I think we’ll have a better idea about whether they need 1 year, 18 months, or however much with active CARs in order to be cured.

Krishna V. Komanduri, MD: That’s a great point. So, I’m going to ask you another question since blinatumomab is a drug that has been often used in pediatric ALL patients. How do you see blinatumomab? And again, you did talk about, obviously, the critical role of allogeneic transplantation, which is still important for some of your patients who have failed frontline therapy. So, how do blinatumomab and allogeneic transplant fit in for you sequentially in the context of a relapsed or a refractory pediatric ALL patient?

Michael Pulsipher, MD: This is very controversial in the pediatric field because the Europeans, who do more transplantation in CR-1 than we do, are very content and feel like they can cure 75% to 85% of their patients with allogeneic transplant. But yet, they’re doing very intense upfront therapies and have a number of long-term toxicities associated with that. Right now, in pediatrics, what most people would suggest is that a late relapse or first relapse can be treated with chemotherapy and can be put into remission. And if there’s MRD negativity, you should do a transplant and not necessarily do CAR T cells. That may change over time.

The role of blinatumomab is really being worked out because people are working blinatumomab into chemotherapy regimens, where in first remission patients, they may be able to have increased cure rates and decreased amounts of chemotherapy. So, that’s one role that’s being really carefully explored and may be beneficial in both pediatric and adult ALL.

For resistant or refractory patients, I actually use it rarely because I have access to a lot of CAR T-cell protocols and CAR T cells are more effective. But probably the most beneficial role is using it when you have patients who have only MRD and have a great donor. Those patients can then be put into remission and then go to transplant, because the rate of getting an MRD-positive patient to MRD negative is quite high, in the 80% range. But with resistant disease where blinatumomab will only put about 30% to 40% of patients into remission, CAR T cells are by far superior in getting those patients into remission.

But all that said, I share David’s worry. We need more data about this, but CD19 antigen escape is a big worry. CAR T cells are very effective and we want to avoid anything that’s going to lead to increased CD19 antigen escape.

Krishna V. Komanduri, MD: And I think that’s one of the approaches to that and Crystal Mackall at Stanford and others are now working on these combined antigen-targeting approaches. And it’s possible that either dual infusion or sequential infusion of CD19- and CD22-targeted constructs, or products, that’s part of the process that might help to deal with that in the future.

Michael Pulsipher, MD: Absolutely, right.

Transcript Edited for Clarity