TP53-Mutated AML & MDS: Why Clinical Trials Are Your Best Option | Dan Link, MD | #ASH24

I'm Dr. Dan Link. I am a professor at Washington University in St. Louis. I'm a chief of the Division of Oncology and deputy director of the Sightman Cancer Center. I had the opportunity and privilege of chairing an education session at ASH on a particular type of acute myeloid leukemia in which they carry mutations of a gene called TP53 or P53 for short. Unfortunately, P53 mutated AML or myelodysplastic syndrome is the worst type of AML or MDS with a very poor prognosis. We had three speakers, myself, Dr. Marina Konopleva at Einstein and Dr. Hugo Fernandez at Moffitt. So there were several take home messages. From my talk, it's very important that the physicians accurately analyze the patients with leukemia or MDS to make sure that they actually have the P53 mutation. Not one copy, two copies. Very big difference. And so I think that that has a big impact on how well our patients have one copy versus two copies of the mutation and treatment. So that was one of the big take home messages. The other thing is we were discussing at the session is about there are things called hotspot mutations, which just means they're more frequent. There are particular mutations in a gene that are more frequent than you would guess. They're called hotspots. And so there's a lot of controversy about how they work and what they do. And I think we've all, I think there's an emerging consensus that these mutations act as what's called dominant negative, which means they're worse than having no copy. They actually inhibit the wild type copy. So that helps us understand the disease and also again, you know, design therapies. We also had a really nice discussion about treatment. And it was very good, but a little sad, a little depressing, because we've tried many therapies and I would say so far we don't have a major clear new advance. I think that there are some emerging therapies that are being tested, but they're early phase. So people are looking at different combinations. And I think the take home message is there is no accepted therapy that works. And so we really encourage physicians and patients to look for clinical trials because the current state of therapy, the current standard of care is really not very good. Then the last part of this thing, we were talking about transplant. So right now getting a allogeneic transplant, a transplant from somebody else is our best chance to cure patients with this P53 mutated AML or MDS. Still, their response is much worse than a normal AML, another type of AML. So for patients who are fit or young enough and can tolerate, have a good donor, I think this is where we would recommend that if you can tolerate it, consider a transplant. This obviously needs to be done in a specialized center that has expertise in this area. And then the other thing is, you know, it's a little discouraging where we are right now, but there are some new things on the horizon. Immunotherapies, things like CAR-Ts, we've heard about those. People are trying to develop those for P53 mutated AML. Not there yet. People are looking at immunotherapies. Again, success so far has been limited, but there are clinical trials that are looking at this. And there's different combinations that people are looking at. My own laboratory recently identified that P53 mutated leukemia cells have a specific vulnerability. Okay, P53 makes these cells do weird things. Okay, we can exploit the fact that it does that in a way that we think. So we've got a two drug combination that we, at least in the laboratory setting, can kill these guys in a synergistic way. So one drug works a little bit, one drug look, but combined they work really well. And they work really well, specifically for this type of bad P53 leukemia. So this is being moved forward into a clinical trial that we hope to open up in the next six months or so. And we will certainly make this the community aware of this and encourage people to consider this for their patients. You should ask your doctor. Okay, so you know, out in the community, some of these trials are very sophisticated and they really need to be done at a larger academic centers. And I think our oncologists in the community know this. So, but I think as a patient, what you can do is advocate for this. If you've got, if you're diagnosed with P53 mutated leukemia or MDS, there is no standard of care that works well. So I would say get a referral to, I mean, an academic center, get an opinion about the latest trials, get an opinion about transplant for you. This is what I would strongly recommend. I would say this is a tough disease, but I can tell you that there is a huge scientific community that's working on this and we're constantly trying new things. And there are things that are emerging early in the laboratory that are moving into the clinic. So I would say, you know, look, you know, hang in there, you know, try to find out what the latest clinical trials are, you know, and I think we're going to crack this nut Sunday, okay? But, you know, hopefully sooner than later.