Progress in the Treatment of AML

Harry Paul Erba, MD, PhD: I want to thank all of you for this rich and informative discussion. Before we conclude, I’d like to get final thoughts—a few minutes only, not a dissertation; don’t pretend you’re Harry Erba and go on for a half hour—from each of you on exciting new developments and emerging agents. I’m going to start with Dr. Fathi to discuss what’s exciting him about immunotherapies like ADCs [antibody-drug conjugates], and BiTEs [bispecific T-cell engagers], and things like that.

Amir Fathi, MD: Just briefly to answer your question, Harry, I think it’s an exciting but early field. There are a whole host of targets that are potentially relevant in AML [acute myeloid leukemia]. The oldest targets are CD33 and maybe CD123. There’s a range of antibodies, antibody-drug conjugates, novel bispecific agents, novel DARTs [dual affinity retargeting molecules], CAR T [chimeric antigen receptor T cell] therapies that are now actually looking at additional targets in addition to those I mentioned, such as CD7.

CD47, a naked antibody, seems to have some legs, at least in combination with hypomethylating therapy in MDS [myelodysplastic syndrome] and in AML. We’ll see ultimately where that data is, but it seems to have some promise potentially in patients who have TP53 mutated AML. The surface of the leukemic cell as opposed to the alterations within it may also potentially provide us with novel approaches to treatment.

Harry Paul Erba, MD, PhD: Thank you. Mark, give us your thoughts about moving the second-generation FLT3 inhibitors in combination with initial intensive chemotherapy.

Mark J. Levis, MD, PhD: It’s nice that we have lots of choices but we really need to move into refining what we have and how to use them. Is there an advantage to using a more potent selective inhibitor up front and transitioning to a type 1? Is there a reason to be using maintenance, a FLT3 inhibitor after transplant? In whom and using MRD [minimal residual disease]? In other words, we actually have the drugs, I think. We have to learn how to use them. We have to go back to good old-fashioned discipline and do very careful large-scale trials with very specific molecularly defined questions. There’s still lots of work to do but progress is being made.

Harry Paul Erba, MD, PhD: Dan, 1 of the most difficult subsets of patients to treat are those with TP53-mutated AML. Anything besides 10 days of decitabine out there?

Daniel Pollyea, MD, MS: Gosh, I hope so. But you’re right: t’s been a long time, and this has proven to be resistant or refractory to most of what we’ve thrown at it. There’s some hope now. APR246 is something we’ve seen several presentations on, a specific TP53-directed therapy for patients with that horrible mutation. Both in MDS and AML, there is some real promise.

The biology of the way that drug works is really exciting and different, and we’re all anxiously awaiting to hear more. Some of the stem cell–directed therapies may have the ability to neutralize, to some degree, TP53. When you look at venetoclax combinations, response rates are in the 50% range—lower than non-TP53-positive patients probably, although statistically we still haven’t quite seen that. But certainly the response durations are not as long for sure with TP53-positive patients. But venetoclax is still certainly an option to consider, and then other stem cell–directed therapies. Amir mentioned magrolimab, a CD47 antibody that has some stem cell–directed therapeutic potential, seems to maybe have some activity in the TP53-positive subset. Around the corner I’m hopeful this will be something we can work on solving soon.

Harry Paul Erba, MD, PhD: Thanks, Dan. Gail, you get to talk about the hottest topic that we have right now on our inpatient service, and it’s not COVID-19 [coronavirus disease 2019]. It’s CAR T cells. CAR T cells in AML—is there a future there?

Gail J. Roboz, MD: Well, we want there to be a future there. With CAR T cells, the appeal has been, “Hey, wait a minute, that’s curing some people.” So we have cures with CAR T-cells. What can we do to move curative therapy to patients with myeloid disease, patients with AML? Our most powerful immunotherapy is transplant. We cure some patients with transplant, but transplant is a pain. We don’t cure a lot of patients with transplant, so what about CAR T cells? The land of the myeloid hasn’t come to full bloom yet. I’ve been particularly interested, as you know, in looking at allogeneic CAR T cells.

Definitely 1 of the glitches with CAR T cells, which is profound, is that the patient has to be able to hang out until the cells are manufactured, and they also may have some extensively beaten up cells that may or may not survive what’s needed. Neither the patient nor the T cells may be adequate to get them to CAR T. We haven’t had this available for younger patients. It’s not worked in myeloid. What about taking really robust, fantastic cells from somebody else and hitting the right target. We’re looking at CD123, but as was already mentioned, there are numerous targets in AML. What about having those cells eliminate the possibility for graft-vs-host disease? We want to overcome issues of T-cell persistence. But that would be a very hot topic for AML, with at least the allure of potential cure since CAR T cells have cured other patients with other hematologic malignancies.

Harry Paul Erba, MD, PhD: Thank you again, and thanks to our viewing audience. We hope you found this OncLive® Peer Exchange to be useful and informative.

Transcript Edited for Clarity