CAR T-Cell Therapy Use in Second Line Acute Lymphoblastic Leukemia

Richard M. Stone, MD: Is there a concern about somebody who gets blinatumomab, and they respond or they don’t respond, but then they relapse? Now, this patient comes to you for CAR [chimeric antigen receptor] T-cell therapy; is that a problem? 

Bijal Shah, MD: It’s not a problem. There are a few points that are worth thinking about. There was the abstract we presented, the ZUMA data, showing that prior blinatumomab, even if patients received blinatumomab as their last line of therapy and were refractory, did not impact the likelihood of response to CAR T-cell immunotherapy using what’s now called the Tecartus [brexucabtagene, autoleucel] product from Kite. There were 2 abstracts at this American Society of Hematology meeting that reached different conclusions, both multicenter, retrospective studies. 

The first from Nirali Shah, MD, MHSc, from the NCI [National Cancer Institute], their consortium of investigators suggested that maybe there is an impact on both CD19 antigen density and the likelihood of response to subsequent CAR T-cell immunotherapy. One of the problems with that is they did not control for how many prior lines of therapy the BLIN [blinatumomab] group had. We’ve seen in now multiple studies, the more heavily pretreated the patient, the less likely even CAR T-cell therapy is going to work, and that may be a reflection of T-cell fitness or other factors that we haven’t assessed. 

The second multicenter paper came from Liora Schultz, MD, from the Stanford University School of Medicine group., It was around 200 patients, all who had received the Kymriah [tisagenlecleucel] product, and there was no association between prior blinatumomab exposure and the likelihood of the outcome. Interestingly, the most powerful feature for both obtaining response and maintaining that response was tumor burden. Anything over 5% blasts or any patient who had extramedullary disease had only about a 35% likelihood of maintaining their remission over time in comparison to the groups who had lower disease burden, where it was about 50%, similar to what was seen on the pivotal ELIANA trial. 

Richard M. Stone, MD: If somebody uses BLINA [blinatumomab] to reduce the tumor, you’re happy with that.

Bijal Shah, MD: Perfect.

Jae Park, MD: One thing to add to Nirali Shah’s abstract about the prior blinatumomab showing the lack of efficacy or the durability of CAR T is that the vast majority of the CAR was using either tisagenlecleucel or the 4-1BB containing CAR in the pediatric, young adult patients. It’s unclear and more difficult to generalize given the kind of controversial data, and Bijal’s data and our data looking at blinatumomab, to assume that prior BLIN [blinatumomab] is all bad. There may be cases that could downregulate and then be bad, but it may also depend on a variety of different disease factors, the type of CAR they will use, and the sensitivity of the CAR and scFv [single-chain variable fragment] to the particular CD19.

Ryan D. Cassaday, MD: To get CAR T cells after blinatumomab, you have to have both received and had a failure of blinatumomab. While it’s not like blinatumomab is a curative therapy for a high proportion of people, there are some people who derive durable benefit from it. It’s not appropriate to look at those data and say we need to be giving CAR T cells first and not blinatumomab. The margin of benefit wasn’t huge, and you’re ignoring the fact that some people can get blinatumomab and do pretty well long term with that approach and not ever need CAR T cells.

Bijal Shah, MD: The challenge is trying to pick up on those patients. When we look at the median duration of response with INO [inotuzumab] and BLIN [blinatumomab], we’re talking about 3 to 4 months. It wasn’t a long remission, and so the question is can we deliver a therapeutic that gives us a longer remission safely? There are a lot of pieces to CAR T therapy. There’s apheresis, there’s collection, and there’s infusion. There are the typical pieces of the puzzle that we think about when we think about CAR T. I would not hesitate in using it in the frontline setting. We’ve seen durable remissions with CAR T-cell immunotherapy. Using effective therapy in the relapsed setting is exactly what we should be doing. There’s no reason not to withhold this.

Richard M. Stone, MD: We have to deal with the reality that CAR T-cell therapy is not yet approved in the first-relapse setting. We can debate about this business about relapsing after transplant in CR1 [first complete remission], but it’s not approved. Right now it’s a second-line therapy in people under age 25.

Bijal Shah, MD: What’s remarkable on that same retrospective view by Dr Schultz, was how many patients received it as their second-line therapy. It was a high percentage.

Jae Park, MD: They presented similar data last year with a different group, showing in a real-world setting that it depends on how you define the second line because MRD [minimal residual disease] positive…. That’s how some of us are getting it approved.

Bijal Shah, MD: I’m talking about a patient who gets chemotherapy, is MRD-positive after some number of cycles of chemotherapy, and receives CAR T-cell therapy next.

Transcript Edited for Clarity