Blinatumomab for Patients with MRD-Positive ALL

Transcript:Mark R. Litzow, MD: I want to touch on the approval earlier this year [2018] of blinatumomab for MRD [minimal residual disease]-positive patients. I was frankly surprised that the FDA approved blinatumomab in that setting. A number of years ago, they said that MRD is an endpoint they weren’t going to consider. In fact, the study that showed the promising results was actually done in Europe because it wasn’t felt that that would be accepted here in the Unites States. But blinatumomab, they saw an outstanding response rate. Eighty percent of patients converted from MRD positivity to negativity. So it’s quite impressive data, and the drug is I think tolerated better in that setting as well. So how are you using blinatumomab in this setting, Bijal?

Bijal D. Shah, MD: The hardest thing for me is identifying that MRD-positive patient when they’re still MRD-positive. And that’s why I mentioned that I increase my duration of monitoring for MRD in my adult patients, to try and pick up on these relapses. When that paper first came out, the first thing I did actually was; I shouldn’t say the first thing, not long after, I e-mailed Nicola Gokbuget [MD] and I e-mailed Monika Bruggemann [MD] and I said, how are you finding these patients? How often are you monitoring for MRD using allele-specific PCR [polymerase chain reaction]? Because I want to find them when they’re MRD-positive, too. I want to find them before I see a fulminant relapse. And I was surprised to hear that there is monitoring that extends beyond the maintenance phase. Because in my practice, that wasn’t something I was necessarily routinely doing. And so that was the first thing that came to mind is how to identify the patients to take this approach.

I do suspect, and we’re going to see data emerging with time, that the patient who is MRD-positive after some very intensive course of therapy is very different. Meaning that that patient I would actually call, if there were a term I could use—MRD refractory—from the patient with MRD relapse. And I suspect the MRD relapsed patient is going to do better than the MRD refractory patient. And I only say that having tried giving blinatumomab in that setting for some of my patients in the past and not seeing quite as pronounced activity.

Anthony S. Stein, MD: There are data from the German study when they looked at using BLIN [blinatumomab] for CR1 [first complete remission] MRD-positive, CR2, CR3. And the best results are CR1 versus 2 versus 3. The response rate is higher, and then when you followed patients out, the survival is better when it’s in CR1, versus 2, versus 3.

Bijal D. Shah, MD: Which is fascinating to think about. You have to wonder why. Is this something about their T cells that’s impacted by sequential therapies or is there something else going on?

Anthony S. Stein, MD: Probably.

Jae Park, MD: I think probably it’s a combination of both.… Especially in the immunotherapeutics approach, there are so many variable parts, which in chemotherapy, we only had to think about the tumors and the sensitivity of the tumors to chemotherapy. Now, with immunotherapy, it’s not just all about the tumors, it’s actually what’s happening to the immune cells because we’re activating immune cells to kill the tumor cells. We have to … think a little bit broadly, what is really the best setting to use when the T cells are healthiest, healthier. So then maybe less treated patients, and … the responsiveness may also differ as well as the T cells at the same time.

So I think that is encouraging, but a lot of the immunotherapeutic drugs, there is a better response, CR1 to CR2 and CR3, which I guess in a way we can argue it’s not too surprising. Of course, all these drugs are going to do better in the earlier lines of a setting than the later lines of a setting. I don’t think we have a clear answer to why but we can speculate that that may be. But it argues, and I think strongly, that this should be moved to the front, earlier lines of a setting to be used.

Mark R. Litzow, MD: What do you think, getting a little bit off topic here, about Ivana [Gojo, MD]’s data at looking at blinatumomab with a PD-1 [programmed cell death protein 1]?

Anthony S. Stein, MD: There’s an abstract that’s presented at ASH [American Society of Hematology] where I think it’s people from Hopkins [Johns Hopkins School of Medicine] have added first a checkpoint, a PD-1 inhibitor. So it’s a phase I study first of adding a PD-1 and the next phase is to add ipilimumab to the study. I think at least in the abstract there were 8 patients treated and 80% CR rate.

Bijal D. Shah, MD: Which is incredible.

Anthony S. Stein, MD: Correct. I mean it’s only 8 patients.

Mark R. Litzow, MD: These were MRD-positive patients?

Anthony S. Stein, MD: No, these were relapsed/refractory patients.

Mark R. Litzow, MD: All relapsed.

Anthony S. Stein, MD: Yes, relapsed/refractory patients.

Mark R. Litzow, MD: So PD-1 plus ipilimumab?

Anthony S. Stein, MD: I think from the abstract it looks like, because I didn’t go to the actual oral presentation, they’ve completed adding the checkpoint inhibitor. And I think the next cohort is going to add on the ipilimumab. And they had more toxicity….

Bijal D. Shah, MD: I was going to say with 80% I’m not sure I....

Anthony S. Stein, MD: That’s correct. You have to expand the number of patients and see what you get.

Bijal D. Shah, MD: But it is incredible results. And getting back to what you were saying about T-cell exhaustion and how that may be influenced by the number of prior lines of therapy, perhaps, and that may be something that we’re overcoming with this addition. I’m not sure. I’m just really excited to see it.

Anthony S. Stein, MD: That may be another place where you look at the new, novel therapies, where you look at BLIN versus CAR [chimeric antigen receptor] T cells. Maybe earlier on you would use BLIN. Later on you may want to use CAR T cells to get a better response because CAR T cells with MRD disease has a very good response rate.

Bijal D. Shah, MD: I think that’s also extraordinarily controversial, depends on who you ask. But if you ask me, I say, yes, that’s a great idea. But I think some of our pediatric colleagues may have expressed some concern about CD19 loss and how that may be influenced by blinatumomab.

Jae Park, MD: I think that’s a very important point to raise though, and I have my own opinions about using these type of agents. Depending on what is available in the CAR T-cell therapy; at least in adult ALL, there’s not approved an product available after the age of 25. It’s hard to deny an effective therapy in anticipation of a still-in-investigation agent. But at the same time, I don’t know whether, if they’re refractory to blinatumomab with CD19-directed therapy, they are going to retain the CD19. And I don’t know whether it’s going to be really bad or not. We don’t know, but I don’t think so. But, if they do become CD19-negative, that means they responded very well to the therapy, and therefore who knows, they may not really benefit from the CAR T, and maybe you should pursue another approach.

So, for that matter, I think it’s hard to argue not to give blinatumomab. But sometimes I don’t think we understand enough. Sometimes I think actually getting some CD19-directed therapy with B-cell depletion before may actually help the CAR T-cell therapy to work better. You may actually debulk them a little bit before CAR T cells go in, and there’s antigen kind of competition. But T cells may expand slowly because of blinatumomab-based binding ... on the CD19, therefore you may get a slower kinetics of T-cell expansion and less toxicity, and then maybe there’s a good response.

Bijal D. Shah, MD: Exactly.

Jae Park, MD: Speculate. It’s all speculation.

Anthony S. Stein, MD: If you do use BLIN, they lose their CD19, you’re going to have CD22 CAR T cells available.

Bijal D. Shah, MD: And hopefully that also pans out, but it does bring up the need for randomized trials. I think that’s really what the take-home point is because a lot of this is retrospective, so there’s always going to be some hand waving that’s part of that. But we need to, to your point, it could be that you want to treat with blinatumomab to ferret out, meaning if you believe that it’s a preexisting process, to ferret out your 19-negative clones because now you’ve just saved some umpteen thousands of dollars and not exposed that patient to CAR T knowing that they would have emerged with a 19-negative relapse in the same context.

Anthony S. Stein, MD: Here’s the thing. When you’re using BLIN for MRD-positive disease, if you’re worried that a patient is not going to respond to the BLIN, you can do a bone marrow at around day 14, day 15, and you’ll know. Because, by that time, most patients would have already become negative, and also you can make sure that the patient isn’t progressing through the BLIN, so you don’t lose anything.

Transcript Edited for Clarity