Acute Lymphoblastic Leukemia: Future Directions in Therapy

Transcript:

Mark R. Litzow, MD: In our concluding few minutes, I’d like to ask each of you to talk briefly about where you see treatment headed in ALL [acute lymphoblastic leukemia]. It’s been a very exciting time in the last few years seeing all these new agents approved in both ALL and some of the other diseases we deal with. Jae, start us off with your thoughts about the future. You’ve done so much great work in CAR T [chimeric antigen receptor T-cell therapy], and that’s been a real major breakthrough.

Jae Park, MD: I think for ALL in general, this is always easiest to cure the first time. I think that my big point, and what we’re all doing, is trying to incorporate these very new, good therapies in the earlier line setting. Even as the therapy is getting better, we’re still dealing with 40% of the patients not being cured with the current regimens that we have now. Already as you alluded to, blinatumomab and inotuzumab are moving to earlier lines, so I’m hoping the same thing. We’ll see what the outcome is, hopefully we will improve incorporation of these agents, too.

I’m hoping that the CAR T-cell therapy targeting CD19 will be certainly moving to the front line, into earlier lines of therapy in lower burden disease. If it works well, we have to prove the pediatric data will be informative about the post consolidation. What should we do after they receive CD19 CAR T-cell therapy and have a great response and MRD negativity, or even NGS [next-generation sequencing] negativity? Now what do we do? Should we just observe those patients, or should we still be thinking about transplant or not? It’s a question now.

Hopefully in the future, the envisioning is that they can be received as just one infusion of the cells, a very potent therapy, and then patients don’t have to go through years of a maintenance therapy or some consolidation, so that we can minimize therapy. I think that will be exciting. And hopefully we will have a better therapy for the patients with T-cell ALL as well, because I think that’s been really challenging. We heard a little bit about the CAR T-cells also targeting some of the T-cell antigen. Certainly, it’s not as straightforward, but I think that also will provide some glimpse of hope for those more difficult-to-treat patient populations as well.

Mark R. Litzow, MD: Do you think off-the-shelf CAR T therapies are going to solve some of these processing issues that we deal with in some patients?

Jae Park, MD: I think it will provide solutions certainly for some of those patients, but not everybody is able to go to CAR T-cell therapy. It may overcome some of the limitations of T-cell quality or the potency or the issues with the patients, certainly for those patients who have had a lot of the chemotherapy to begin with. It may overcome that. And then because of immediate availability, it does make it possible to incorporate into the earlier line setting, too, as opposed to waiting for collection and then somehow coming up with a way to maintain that MRD-negative state before you give the autologous CAR T therapy.

But the allogeneic CAR T therapy or the off-the-shelf therapy or other cellular therapies that are immediately available may have the advantage of using it right then, as we’re doing with some of the BiTEs [bispecific T-cell engagers] and ADCs [antibody drug conjugates] now. Obviously, we have to see the clinical trial. But I think that immediate availability provides a good ease of incorporation into the earlier lines of therapy in the MRD setting, too.

Mark R. Litzow, MD: Ryan?

Ryan D. Cassaday, MD: I agree with virtually everything that Jae said. For me, better understanding of different molecular subtypes and knowing what to do with them is important, whether it’s targeted agents as the COG [Children’s Oncology Group] is using for the Ph [Philadelphia chromosome]-like ALL or maybe teasing out new molecular pathways that can be exploited in T-cell ALL. Hopefully by introducing some of these drugs, whether it’s the immunotherapy agents we have currently or targeted therapy down the road, we can start to spare some of the adverse effects of the cytotoxic chemotherapy. Also, a better understanding of the MRD techniques that we have is important, when to check it, how to check it. Those understandings I think will hopefully then allow us to more individualize patient-making decisions, so we’re not having to just lump all of the Ph-positive patients into a big bucket and transplant them all.

Mark R. Litzow, MD: Rachel, your thoughts?

Rachel E. Rau, MD: I think the pie-in-the-sky view is, can we stop pounding kids with so much chemotherapy and replace it with some of these better-tolerated agents, and I think AALL1331 is an excellent example of that. In the highest of high-risk patients, you’ve removed blocks of intensive chemotherapy and replaced it with an immunotherapy and had better outcomes—not just equivalent, but better—not only in terms of tolerability, but activity. I think that’s very promising.

I think what we’ve learned with the last few iterations of clinical trials in the Children’s Oncology Group is that we’ve hit the ceiling. We can’t just improve outcomes further by further intensifying therapy. We have to use different agents that act very differently, and that’s where the timing of immunotherapies coming on the scene right now is so exciting, I think. For now, we’ll prove in the up-front setting that they’re effective, but ultimately can we take out some of those really toxic and long-term adverse effect inducing elements of therapy and replace them with these agents?

Mark R. Litzow, MD: You all have done such good work with manipulating chemotherapy with changing the schedule, changing the doses. But we’re reaching a limit there as well. I think of acute promyelocytic leukemia and how that was the worst prognostic acute leukemia 30 or 40 years ago, and now it’s the best prognosis and we’re not using chemotherapy. I think I see us moving in that direction in Ph-positive ALL and I think with the Ph-like setting and some of these agents, we’re going to be in that direction as well. I think the future is bright.

I want to thank you all for this very engaging discussion.

Transcript Edited for Clarity