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Digging Deeper Into the TP53 Mutation in AML with Rory Shallis, MD, Yale New Haven Hospital
Digging Deeper Into the TP53 Mutation in AML with Rory Shallis, MD, Yale New Haven Hospital image

Jul 14, 2022 / 11:00AM - 12:00PM EDT
HealthTree Podcast for AML

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Episode Summary

Rory Shallis, MD
Yale Cancer Center
Interview Date: July 14, 2022

The TP53 mutation in AML is considered to be a high risk mutation and occurs in approximately 5-10% of patients. This genetic mutation has been difficult to treat, often being chemoresistant with a poor prognosis, however, the research indicates progress is being made in this area. 

In this show, Dr. Rory Shallis, an AML expert from Yale Cancer Center, summarizes the TP53 mutation, the challenges it presents and the importance of clinical trials in the treatment of this mutation. Dr. Shallis covers several new drugs in development to consider as part of your treatment options available for this mutation.

Thanks to Our Episode Sponsor

Full Transcript

Kerith: Welcome to today's episode of HealthTree Podcast for AML, a podcast that connects patients with acute myeloid leukemia researchers. I'm your host, Kerith Amen. We'd like to thank our episode sponsor, Bristol Myers Squibb, for their support of this HealthTree Podcast for AML episode.

Before we get started with today's show, I'd like to mention an upcoming event that we will be hosting. Next week on Tuesday, July 19th, at 2:00 p.m. Eastern, we will be hosting a virtual HealthTree Round Tables for AML event. We have invited two AML experts to join us – Dr. Uma Borate from the James Comprehensive Cancer Center at Ohio State University, and Dr. Naval Daver from MD Anderson Cancer Center. They will be joining us to give a mid-year update on AML news, emerging novel therapies, new research, and clinical trials. I hope you all will join us for what will be a very informative discussion with plenty of time to ask the doctors questions. You can register for all of our events by visiting our website, healthtree.org/aml/community/events.

As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Shallis a question during our Q&A period at the end, you will need to call in via telephone to 515-602-9728 and press 1 on your keypad when you're ready to ask your question. Now, on to our show today.

The TP53 mutation in AML is considered to be a high-risk mutation and occurs in approximately 5% to 10% of patients. This genetic mutation has been difficult to treat, often being chemo resistant with a poor prognosis. However, there is a lot of research happening in this area with a number of clinical trials and drugs in development. We hope that the continued focus and research holds promise for this very difficult mutation in order to improve outcomes for these patients.

Dr. Rory Shallis from the Yale Cancer Center in New Haven Connecticut is here with us today to help us learn more about the TP53 mutation in AML, the current treatment options available, and which clinical trials to consider as part of your care. We are so happy to have you here with us today, Dr. Shallis. Thank you so much for taking the time out of your busy schedule to join us and discuss the TP53 mutations.

Before we get started, I'd love to provide an introduction for you. Dr. Shallis is an assistant Professor of Medicine in Hematology at Yale University School of Medicine. Dr. Shallis is focused on the care and research of patients with myeloid malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome. He currently serves as either principal investigator or sub-investigator in over a dozen clinical trials with the majority aimed at improving the outcomes of patients with AML and MDS. Dr. Shallis also conducts research with the Cancer Outcomes, Public Policy and Effectiveness Research or COPPER Center at Yale University. He is an author on more than 75 peer-reviewed publications and book chapters, most of which he was first author on. His work has been published in many prestigious journals. Welcome to the show, Dr. Shallis.

Dr. Shallis: Thanks for the invitation and that very lofty introduction. It's a pleasure. Thank you.

Kerith: Thank you. I would also like to say just personally, what an amazing cancer center Yale is. I spent a lot of time there. My husband was diagnosed with CML and blast crisis in November of 2017, which then became a relapsed refractory AML. Though his battle was short, and ended just after four months, we spent a lot of time in the Smilow Cancer Center with Dr. Steven Gore and Dr. Amer Zeidan. The team of doctors and nurses there were so amazing. I'm really just so grateful for the care we received when we were there. I can't say enough wonderful things about Yale and the hospital there. Thank you.

Dr. Shallis: I have to agree with you. It's a good team. You named a specific few, but it's a large team that works well together and that’s why I'm happy to be a part of it.

Kerith: Yes, so many people make up that wonderful team. Let's jump into our questions for today. Start with the basics. Can you tell us about the TP53 mutation and how you test for it? Are there different types of TP53 mutations?

Dr. Shallis: Sure. Good question. I like the basics to set up a foundation for why we're talking about it, why it's important. TP53 is generally what we call a tumor suppressor gene, a critical one at that. It's located on a particular area of chromosome 17. We have several. This is a gene which, like many genes encodes in all genes, encodes a protein which is the p53 protein, and it's doing the dirty work. This is basically a protein which responds to a number of stressors or insults that the cells receive. This is things like DNA damage, and not to get into the weeds about the specifics, but it's essentially responsible for coordinating a lot of that repair. If that repair of that cell really can't be fixed, it basically coordinates the cell to itself die. We call this apoptosis among many other functions.

There are a number of mutations. Yes, this is a large gene. I think it's about 25,000 bases. Each base can theoretically be mutated. There are several mutations that can occur at every base. There is – [0:06:36] [Indiscernible] about it. There are thousands of mutations that are possible. Not to say that all really behave the same, but most do.

The way we test for these mutations, there are several platforms. Probably, the most commonly used is what we call next-generation sequencing, which many higher impact centers, including ourselves, we do in-house using our own technologies in our own laboratories. Other places will use third party platforms that essentially send it to a place to do the same sequencing of the gene. It's compared to what we would normally expect, and the differences are reported to us. That's when we know how to interpret it.

There are other methods that are emerging, but not quite ready for primetime, I'd say just yet, just because this next-generation sequencing or NGS can take -- I mean there are some rapid panels which take a few days, but some take up to two weeks. For many patients, this is not quite relevant, but for others, it can determine clinical trial candidacy. I would argue in many cases, the frontline therapy which we would argue would be standard for this particular molecular subset. Some of those emerging ways of detecting is earlier looking at protein expression among the cells in bone marrow specifically. It does appear to be a pretty good predictor for the presence of a TP53 mutation.

Kerith: One thing I feel like there's been quite a bit of discussion about lately is waiting for all of the cytogenetics to come back before you initiate the treatment. Can you speak briefly about that? Is that something that here in TP53, in the case of TP53, would be important to wait for everything to come back? Or can you start some treatment, and then add on potentially? I know I might be getting a little bit ahead, but since we're talking about the testing part.

Dr. Shallis: No. It's a good question. I think it gets to the larger treatment paradigm that is evolving. I mean, if you asked me ten years ago when we didn't really -- we, I mean I wasn't really practicing at least in this subspecialty -- there wasn't really much weight placed upon the biology, at least from a TP53 standpoint or complex cytogenetics. Once that data became available, like I said, it could be one to two weeks later, we just give the provider a sense that disease is either likely to be stubborn or maybe offer the opportunity for other down the line treatments.

There have been a number of studies which have shown that it is okay to wait to really define the disease biology for many patients. Not all patients. There are some patients that unfortunately, present to us quite sick, with organ strain dysfunction, and really with disease which is quite aggressive and active. We really can't wait, in which case, we use our tried-and-true “standard options.”

However, if the patient is doing relatively well, maybe some minor symptomatology, blood counts aren't terribly low to the point where we're needing transfusions all the darn time, there's no concern for bleeding, or really trying to intervene upon the disease, then we do actually wait. We wait for, as you called it cytogenetics, which is really one half of the pie. Cytogenetics is really evaluating the larger portions of DNA that we call the chromosomes, looking for duplications, deletions, translocations, these sorts of things, and the number of events that we can find.

The other half is looking at more the molecular, more of the specific. You can say point mutations in this DNA which TP53 is one of the genes that we're evaluating. If the patient can wait, this is probably the prudent thing to do. One, like we talked about briefly, to identify maybe a specific trial that could be available for that specific disease subset. But two, there is some thinking out there, that patients with this particular disease, TP53 mutated disease, might not benefit as much from the “standard” in which case we might change it a little bit. We do wait for most of this data, if not all the data that will inform the frontline treatment decision, if the patient is safe to wait, which is most patients.

Kerith: That makes sense. Does TP53 often present with other mutations as well? Just out of curiosity.

Dr. Shallis: Actually, it's one of the molecular subsets of AML that actually has a low rate of co-mutation. We call it TP53 wild-type disease. You're going to find at least one mutation in the disease. I mean, pretty much all of the AML is going to have at least some abnormality from a cytogenetic standpoint, meaning the chromosomes or molecular standpoint, meaning you can identify a mutation. Most, you're going to have more than one.

TP53 is the exception from a mutation standpoint. It does associate with a significant proportion of what we call complex set of genetics or complex karyotype, including other subtypes among the set of cytogenetic aspect. But from a mutation standpoint, not so much. In fact, if you're looking at some of the classical AML-associated mutations like IDH1, IDH2, FLT3, you're talking in the order of single digit percent. It's actually not a heavily “co-mutated” molecular subset.

Kerith: What are the specifics for the TP53 mutation? What percentage of patients have it? Is it more common in a certain demographic of patients?

Dr. Shallis: These mutations are detected, I think your intro said 5% to 10%. I think that's accurate. Probably, I’d say closer to 10%. I guess, we're splitting hairs. There are specific subsets of disease for which it's been enriched, meaning in which you're going to find it at a greater rate upwards of like 25%, 30%. This is generally among patients that have what we call a secondary AML, which is including therapy-related AML. This term, it might be a misnomer, but basically disease which is arising out of just at least having a history of having received prior chemotherapies and usually, particular kinds of chemotherapies, and/or radiotherapy for things like breast cancer, lung cancer, which are game changers.

There are other kinds of rarer subtypes. One of which is acute erythroid leukemia where nearly all patients will have a TP53 mutation. With regards to demographics, not so much really, at least that we can detect or which I'm aware. I would say no. It's not really a patient specific factor that can determine a higher likelihood of having this mutation in the disease cells. It's more of the disease subtypes.

Kerith: Why has this mutation historically been difficult to treat? What are your thoughts on this today?

Dr. Shallis: That is the question because, I guess, identifying why this is the case. It's hopefully going to foster the better science and better therapies to really get some folks more mileage and put more folks into remission. Of course, that's really one of the first major hurdles to having better disease control, but also hopeful cure.

It relates to the biology of the protein itself. In this gene, encodes a protein -- like we discussed -- has many functions that relate to pretty important things like DNA damage, oncogene activation, oxidative stress, among a couple others. These inputs into that protein essentially influences all the downstream things which are pretty critical to having healthy cells, DNA repair, apoptosis, mechanisms of metabolism, translational control, and cell cycle arrest which all relate in one way or another.

When this is dysfunctional, most of these mutations -- and this might be a decent segue into at least why some of the novel therapies that are emerging might not really be perfectly “targeted.” This is generally a loss of function effect meaning that when mutated, this protein is not working as opposed to other things that we've seen AML, where they're either overactive and stimulating a pathway. This is one in which were the pathways done. It can't do these functions.

When you're exposing these particular leukemic cells to let's say chemotherapy, classical chemotherapy, it knows how to weather the storm. It doesn't drive the cells down these pathways to die. It's actually what we call inherently resistant in many cases. This has been shown really for decades, really 30, 40 years of intensive multi-cytotoxic agent regimens. Seven plus three is a classic one. We have a number of other similar combinations. The rates of remission are slightly lower.

I'd say, that's probably not as much, not as impactful, as really the other half of the -- more than half. Among patients who are able to get into remission or after the disease go into remission, they don't just stay in remission for very long. It’s in the order of, for many folks, it's months. That's really, I'd say the higher-level reasoning for why at least we think why and it makes sense. This particular molecular subset is just very darn stubborn.

Kerith: You started to touch on this a little bit. Let's move into the treatment options. What are the current standard treatment options available for TP53 mutations?

Dr. Shallis: In brief, the current standards for this particular disease are the same that are available for AML as a whole. We generally separate them. We dichotomize it into intensive, and some people say non-intensive. I think it's more accurately described as being less intensive. The intensive versions, we mentioned 7+3 briefly which is the combination of cytarabine plus anthracycline.

This has been a combination since literally the early 1970s, because it works. It is a standard for literally close to half a century for a reason. There are different iterations or modifications to this regimen and new formulations including Vyxeos is the brand name, so many others called CPX-351. These are some of the classical intensive regimens, but the rates of remission probably are in the order of anywhere from 20% to 40% percent. Some data sets, maybe as high as 50-ish.

There are, as I was saying, less intensive induction options, which are either as monotherapy or more recently now combinations that are built upon a backbone on top of what we call the hypomethylating agents which is a colloquial term, many other folks will call it a DNA methyltransferase inhibitor or azanucleoside, things like azacitidine or decitabine, which are pretty much sister medications slightly different mechanisms of action, but generally fell to the equivalent and shown to be equivalent in studies.

We, as a community, have tried different ways of delivering these medications when you're on longer schedules. Probably, the one combination approach has represented I’d say a paradigm shift for really, I’d say that some of AML patients, in particular those patients who are regarded as really not being appropriate to accept the risks of intensive therapy. This is the addition of venetoclax, which now, at least when combined with azacitidine is shown in a randomized Phase III trial to be superior.

However, as you would guess, just given what we've talked about previously and hopefully affirming why, I think, we regard this as being a stubborn disease. The addition of venetoclax doesn't appear to -- it's not a game changer for this particular disease subset. Now, this doesn't mean that we're unequivocally not offering it. I mean, this is debate among our group, tumor boards, and across the country, internationally as well. What does venetoclax really add? We're left with the standard things. Now, this doesn't mean that all hope is lost. This is certainly evidence for some of these newer agents to be studied in a clinical trial and of course, developing newer ones in the first place. Hopefully, that wasn't a dissatisfying answer, but I do think that's the accurate one.

Kerith: Thank you. When you're treating TP53, are patients developing resistance to the standard treatment options? Or are the current treatments not getting them into remission? Or maybe it's both?

Dr. Shallis: It's probably both. We do know that, again, harkening back to why this is a stubborn disease which is really related to the fact that p53 protein is important. When it's not working, the cells just -- they can't die. These are preferentially -- not preferentially -- these are the proportion of the tumor cells specifically. I would say that there's inherent resistance. Inherent resistance.

Now, perhaps there are other acquired mechanisms of resistance that developed throughout the course of treatment among this molecular subset, but I'd say that the substantial proportion is really the disease that is just inherently out of the gate resistant. Even though it's somewhat sensitive to the treatment, the longer you expose a patient to treatment, you're essentially going to select out for the cells which have this mutation, and have this dysfunctional protein. Eventually, this becomes the dominant clone within the bone marrow and blood. That's when we kind of – it heralds the disease either becoming progressive or relapse among patients who are fortunate to go into at least some form of remission. It's more inherent resistance unfortunately.

Kerith: Are these patients always recommended for a stem cell or bone marrow transplant if they are deemed fit candidates?

Dr. Shallis: Oh, man. That's an important question. One that I think, probably, stirs up as much debate as what is the appropriate frontline strategy. Patients, as a whole, patients that have poor or adverse risk AML are generally recommended to be considered for transplant. We're talking about an allogeneic hematopoietic stem cell transplant as part of their consolidation strategy. This consolidation is the phase of his treatment which comes after induction, after a remission has hopefully been induced. Consolidation is really building upon that remission, mostly because -- unfortunately, took about 35, 40 years of time and patience to realize that you can't stop an induction.

The subset of disease which we're talking is the one, as which we talked about briefly, is the one which even among patients that are in remission, they're not likely to stay in there for very long. Maybe, if you're going to use a pretty good consolidative modality or strategy like this transplant, you should use it as soon as you can.

The rub is that a lot of patients are not reasonable candidates, either because they're not able to accept the risks of the intensive therapy; 2) they either don't achieve remission; or 2b) don't stay in remission long enough to actually get the transplant plan; and 3) unfortunately, there are some patients -- I've had a handful of patients that have achieved those two things we talked about, but they don't have the third, and that's having a suitable donor available which can be improved at the moment. That is a deficit for many patients.

In talking about this specific molecular subset, yes, this is an unequivocal adverse risk disease subset. You generally think that, fine, let's go with transplant. This is the one molecular subset of disease where there is debate about whether does it really provide benefit? This disease is pretty darn stubborn. Are we really moving the needle? Having patients go through a non-trivial procedure that does carry morbidity and an appreciable risk of mortality. For some folks, it's not low. Putting up through this for an unclear, but probably not very high chance of really benefiting, let alone being cured of the disease.

I'm not a nihilist about this. There are some providers out there which say, you know what? Is it really worth it? I’d probably take a guess that most of us in the community, as leukemia specialists, would still offer it and say that maybe it will at least provide some benefit. There have been some analyses, some of which we've been a part of, that this is difficult to really account for analytically from a methodological standpoint to the lot of biases and things for which you have to really be mindful of when looking at a comparison.

There does appear to be at least among those patients who can get the true transplant, a benefit. I would say, yes, they should be strongly considered. Two, if it's possible or feasible, it is generally recommended. There is some nuance to that.

If you want to talk about it, we can say briefly that there is some thinking or some data out there to suggest that the depth of remission might inform whether or not transplant is worth it or patients likely to benefit that the remission mostly being defined. This is an exploratory research sense at the moment being defined as, well, can you detect the mutation anymore? For the patient who is in remission, and you're using the same techniques that detected it out of the gate, if it hasn't “disappeared.”

Even though it probably hasn't disappeared, it just dipped below the level of detection, the iceberg is still there, but it's at least below the surface a little bit. Those patients that are getting a good response might be the ones who are more likely to benefit from transplant. That was a lengthy answer, but there was a lot to unpack there. Sorry.

Kerith: No, that's okay. Would that be MRD testing or minimal residual disease testing? After induction?

Dr. Shallis: Correct, MRD testing -- the time point at which we test is still debated as is whether or not this is a real thing. I mean, there are limited analyses which show that we're talking to maybe a dozen or a couple dozen patients and some analyses, but these are the folks that tend to do better. We can no longer detect the mutation based on the classical platforms which do have a limit. The general accepted limit is anywhere from 3% to 5%. Meaning, out of 100 leukemia cells, if the mutation is actually in two of them, you might not detect it even though it's still there. There is some limitation in really saying that that is how providers should really be using it. But to answer your question, yes. MRD testing by way of NGS or next-generation sequencing.

Kerith: Understanding that there are risks with transplant as well, what are the typical responses to the transplant? Are there therapies that are being looked at to help a patient either before or after a stem cell transplant?

Dr. Shallis: Good question. You asked a direct one, so I'll give you a direct answer. If you're looking at some of the largest datasets that have describe the outcomes of patients who are fortunate to get to some form of response or remission, fortunate to get to transplant, there's still some nuances. Well, what kind of transplant, and what kind of donor, et cetera. The rates of cure are low. I will tell you, it's probably no higher than 20%. That might be an ambitious estimate. In some cases, it's much lower.

Other groups have shown that it might be better in some circumstances like we talked about some of the pre-transplant metrics. This doesn’t apply to everybody. There are some patients who surprise us in a favorable way, and others in the opposite direction. That’s what I’d probably tell you is the estimate that I would offer. Would you mind repeating the second question? I forgot.

Kerith: I was wondering if there were any therapies that they're looking at to try to do before the transplant or after the transplant in order to improve upon the outcome.

Dr. Shallis: That's an important question. Actually, this gets to, really, you could say the third phase of AML management which is not really incorporated into, I'd say, most patient strategies. This is the maintenance phase. Maintenance, probably most relevant, at least in this population, for patients who have gone through a transplant. Mostly because this is a disease which has adverse risk.

Either the patient has embarked on a probably less intensive therapy which is indefinite and continuous until one of two things happen. One, either the treatment is clearly not working; or two, it works and then eventually stops working, or the other scenario would be yes, the intention is to proceed with transplant, get the patient there, and then see what happens. I mean there's immunosuppression, and really, just trying to strike the balance between the graft staying in place, and not causing problems, and putting pressure on disease, but not really prompting or promoting too much graft versus host disease which can be dangerous. But in many cases, reasonably controlled.

After that period has passed, this is a setting in which maintenance has been studied for actually a number of years. There have been around a number of, I’d say, relatively smaller trials because this is an already uncommon subset. It's not very common for patients to really -- most patients don't get the transplant, I tell you. It's uncommon of uncommon. But in smaller studies, people have tried to study maintenance azacitidine, maintenance of decitabine, these are the hypomethylating agents or thinking about the tranferase inhibitors we had mentioned it as part of the frontline strategy approach.

Comparative studies are a bit limited. Some have shown that yes, there might be a “benefit.” Most of this is relegated to what we call single-arm study. You’re not really doing a comparative trials maintenance versus no maintenance. You see which group of patients feels better. Some of the novel agents or newer agents are also being studied either as a single agent or in combination usually with a hypomethylating agent, and have shown, what I would describe as being, I'd say, encouraging outcomes, mostly because it's noncomparative, nonrandomized data.

Yes, maintenance is being studied. Whether it is being offered to all patients, probably not. Should it be? This is still debated, but I would probably venture to guess that many leukemia specialists and transplant physicians or teams are considering it and probably most patients are getting some form.

Kerith: Great. Let's talk about some of those drugs that are in development that have shown encouraging results to target TP53 mutation. I'll just let you go ahead and talk about whichever ones you'd like to discuss.

Dr. Shallis: Free reign. Sure. It's a grab bag actually, mostly because, going back to one of the things we talked about in comparison to other types of driving lesions, basically mutations that are acting like an on switch, and really allowing these leukemic stem cells and leukemia cells to keep doing what they're doing which is bad obviously. We had drugs which can reasonably and selectively bind to those on switches and turn it off. That's how patients can derive benefit, and then it does modify the disease as best we understand it.

This is a bit different mostly because this is a protein which is critical. It does a lot of jobs that keep the cell healthy essentially. When it's not there, at least in a functioning sense, the cells can pretty much stay malignant and are at that point, inherently chemo resistant to available therapies. As you can imagine, there have been some efforts to really target this protein, and try to really change the way it's folded. There are small molecule clinical inhibitors that have at least been hypothesized to restore it to what we call a wild-type conformation.

There have been a number of products. Probably the one that which got I'd say most press over the last few years is one which was previously known as APR-246. Now, it's known as eprenetapopt. There are a couple of initial single-arm studies, Phase I B2 trials which show that, hey, there's clearly some impressive outcomes of these patients. There were some randomized data in the MDS space which were disappointing, but you can say well, maybe that wasn't the same disease that can itself be debated. Maybe, there were some reasons as to why those patients weren't doing as well as compared to the standard comparator arm treated patients.

This is a drug which now probably is best regarded as not being a mutant p53 protein refolder or reactivator. It's now more likely acting upon disease in a number of other mechanisms, one of which is called ferroptosis, which has really been discovered over the last five years, and might be another realm to investigate for other therapies. This drug is still being studied in a number of settings, including the maintenance setting as well for which there were some recent, and I would say, generally encouraging data presented. But this is a drug which is slowed down in enthusiasm just because of the things we talked about.

There are other companies out there which are trying to piggyback that science and developing other what we call orals small molecule reactivators. Some for particular mutations, the one which is the classic in this sense is the Y220C mutation. Not a lot of these are present in AML, but maybe this will be moved into the AML space quite soon. I'd say from an excitement standpoint, most of what has garnered our attention, as a community, are those therapies which are really leveraging the immune system which if you think about it, it’s what the transplant’s really doing, transplant is about to really exert its benefit for most patients via a graft-versus-leukemia effect, which is essentially, these are adoptively transferred donor T-cells which are a good deal to the immune system.

Can we really do other things to activate it or retrain the immune system to find these tumor cells? One of the more, I'd say exciting things, that at least in the TP53 AML space, are those agents which influence what was known as the CD47 or SIRPα axis. CD47 is a transmembrane protein which -- it’s called the 'don't eat me signal', which interacts with macrophages which are a part of the immune system which really engulf or swallow and get rid of things that are targeted for destruction including tumor cells. CD47, it's found to be expressed on normal cells, but it's overexpressed. That's why it's a better target on malignant cells from a number of tumor types including AML.

There are a number of products out there that are being studied. The one which is probably furthest along as one known as magrolimab which is a humanized anti-CD47, IgG4 monoclonal antibody, promising efficacy data in single-arm studies to date. In fact, some of the initial data cuts on these single-arm studies showed that the median overall survival of treated patients was basically around a year which is, sorry to say, about double of what we expect with the standard stuff at the moment. But this was a relatively smaller study, single-arm, and like many of those studies, has to be replicated, and I'd say confirmed in a in a randomized trial.

Fortunately, there are randomized trials going on. There's one combining it with our standard approach being azacitidine and venetoclax. This is for unselected patients, meaning patients that had disease which has TP53, others that don't.

There's another trial which is hopefully going to be launched soon of which we're leading that is going to look at a similar doublet combination of venetoclax, but with the oral formulation of a hypomethylating agent known as the basically oral decitabine with magrolimab. This is going to be run through the NCI study which I will hopefully be leading nationally, maybe internationally as well. Those are probably some of the two that which I could say got the most press. There are other anti-CD47 agents out there. The clinical data for such is maybe not as mature just yet.

One other -- well, there are a couple -- but I'd say, if we're talking about the immune system, there's one that we probably can't ignore. This is the Kin3 inhibitor. Kin3 is another nonclassical immune checkpoint. I think it stands for T cell immunoglobulin and mucin 3 domain inhibitor. This is what was previously known as MBG453 or sabatolimab now.

These drugs eventually get fancier names. In combination with azacitidine, mostly in patients that have higher risk MDS, which is I would argue very similar, very similar to AML. I mean, I think the distinction is being blurred now, but among patients that have that specific disease, pretty good rates of remission among patients that have TP53 mutated disease. This is a drug which is, in the near future, going to be moved into more TP53 specific studies.

Other drugs like anti-CD123, bispecific antibodies, that has shown some promise, but this is another class of medications which is still being flushed out with regards to toxicity, administration schedule which is a big one. I would say inconvenient for many patients. I would say, compared to let's say, five years ago, a lot more movement and a lot more reason to be optimistic that as I recurrently said, the needle might be moved for patients afflicted with this arguably very stubborn and terrible disease.

Kerith: Are there still currently trials going on for eprenetapopt right now that patients can join, or is that cooled off now?

Dr. Shallis: There are trials that are still ongoing. I don't foresee any new trials that will be launched, but I'll defer that to the company that makes the product. There are active trials. I'd say, the one which is probably most active is in the maintenance phase, and ones that are looking at for folks that probably don't have a path to transplant, but this is still in flux. I don't foresee this drug, really, I'd say, being used in any newer combinations for frontline treatment in AML.

Kerith: I certainly have heard the most, at different medical conferences, about magrolimab. I've heard a lot of the trials about that as well.

Dr. Shallis: A lot more trials with regard to magrolimab. A lot of trials.

Kerith: Okay. As far as your thoughts on TP53 mutated patients participating in clinical trials, when do you think a trial should be considered? Should all TP53 patients consider joining the trial?

Dr. Shallis: The answer is yes. Fortunately, increasing understanding of the mechanisms of this disease as chemo resistance have fostered promise for more effective therapies. But that combined with hey, we have no -- the standard of care for this disease is argued. We don't really know. I think, hopefully, you'd agree by now through, this last bit of discussion, that they are insufficient. I would say the standard of care would be a clinical trial. Frontline throughout the patient journey, but certainly starts with the frontline treatment to get it into remission. Clinical trial, I'd say, is the standard of care.

Kerith: As far as finding clinical trials, can you talk a little bit about that? I mean, obviously, patients should talk to their doctors, but what if a trial is at another hospital and not the hospital you're currently being treated at? How would that work?

Dr. Shallis: It can work in a number of ways. This is a common question that we get. I mean, I’ve seen, among other providers in our group, many patients that are looking for a second, if not third and fourth opinions, or if they’re seeing me for the first time as a specialist, should I seek a second opinion? I always say yes. In fact, I can't think of a reason as to why I would not at least encourage that.

There are some situations in which maybe the disease is active and we might not have the time for someone to leave the clinic. God knows how long it's going to take to get to see another provider and another specialist at a higher impact center. That could take weeks. By the time they come back to me and we communicate with that provider, the disease might have caused a lot more problems that maybe could have been prevented. But yes, this is something that is encouraged.

I'd say the logistics of how to achieve that really depend on location. I think I'm fortunate to be practicing in the Northeast where there is a heavy concentration of centers that have good doctors and good teams and fairly large clinical trial portfolios, and access to the centers is pretty easy to accomplish. I would probably venture to guess that most centers are actually open to a phone call and saying, I'd like to see an opinion, seek a second opinion. In some cases, we do engage a small community actually. We do engage with other providers. The provider, he or herself can actually coordinate that second or third opinion.

People who are probably in an area of the country that are maybe not as robustly constituted by centers that have leukemia specialists might have more difficulty. This is not only from an access standpoint, but really travel, and say, there is a trial that's open. Some trials do require quite a bit. I think we're actually getting better about designing trials that align with the standard of care and don't place too much of a burden upon the patient where they have to get extra bloodwork or extra bone marrows to the point where they're traveling many, many extra hours in the week which, maybe over time, does improve as the patient progresses on treatment in a good way.

This can look a number of ways, but it certainly starts with at least establishing with the provider. I would say establish with someone who would be a leukemia specialist. This is a person who knows what's available in the clinical trial portfolio at that center and is very likely to know other folks at surrounding centers, and that can be helped from a coordination standpoint. This comes down to being plugged in and communicating well and asking.

Kerith: I think you hit on two really important points. We talked about, here at HealthTree, the importance of finding a specialist, though that can sometimes be difficult if you're in more rural areas. We do have a list of specialists on our website, on the HealthTree website, that can help with that. We also have a clinical trial finder tool on our website because I know that for me, when we were going through this with my husband, the clinicaltrials.gov website is extremely hard to navigate as a layperson.

At HealthTree, we've tried to make it easier to find clinical trials with a tool that allows you to enter different search criteria with mutations and different drugs. I hope that people find that helpful because I would have found it extremely helpful when we were going through this diagnosis as well. Thank you for mentioning those things.

What do you think are the main challenges and questions that remain with the treatment of TP53 mutation? I guess, what do you think needs to happen in order to move the needle on this mutation?

Dr. Shallis: I'd say, it's America. Two things. One is better science, and this is happening. I'm not disparaging our scientific investigators because this is what fosters better agents and does better trials to tell us, is this working for our patients? That's really the second half. The trials, as they accrue patients, and patients get treated, and there are many trials especially of this nature, we get more information, we get more data. Even some of those extra blood works or extra bone marrow biopsies are helping us learn. It is cyclic. It's a very healthy interaction between science and trial. It's both.

That really also requires commitment from, in many cases, certain funding sources, including the federal government which is certainly on board with this mission. Clinical trust has to be available. You can have all the money. You can have all the science. You need investigators to actually feel comfortable. You'll be motivated to perform and execute them. I do think that's there.

The last few years is there's been a whirlwind of recognition, and enthusiasm for really trying to push this space further and really help people that have had, for the last many, many years, have not really had much to look forward to. I would say it's just like availability trials, and probably trials that are more specifically designed for this disease. Over the last few years, that has been the case. That's how I see this will move forward towards the positive.

Kerith: Specifically in your practice, is there something that you recommend to patients that have been diagnosed with TP53 mutated AML? Besides clinical trials, is there anything these patients can do to remain proactive about their disease?

Dr. Shallis: I think you answered it in the latter half of that question. Proactive. I mean it's a vague term. It means different things for different people. But that's really up to the provider that's sitting before the patient in the clinic room, or maybe it's in the hospital, and hopefully with family members or friends that can really serve as that support for encouraging and really assuring that that proactive nature is initiated and maintained.

Proactive, in a sense of staying fit as best one can. We see many patients that are not marathon runners, but hey, they walk one or two miles a day. That is healthy. That's more than I do in a day. To be honest, that probably does foster getting through treatment a bit better, eating a healthier diet. It's probably one of the more common questions we get is, what should I be eating? What should I be taking? Should I take multivitamins? Should I not be taking this, agent X, or over the counter this? My answer not to be -- it’s fine. Hopefully, it's never dismissive. If there was a pill, if not chemotherapy, if there was a pill, I would give it to you. If there was a specific diet, I would tell you. I mean I'd be doing it myself as well.

The best answer we have is being proactive with exercise to the point of not pushing oneself over the edge, but pushing oneself a little bit to the point where they stay conditioned, stay fit. If there was, God forbid, some adversity, some side effects in treatment like an infection, patients are more likely to have that cardial pulmonary and organ function reserve to get through it, maybe a bit easier. That's my answer, but I agree with you. Being proactive is, in my experience, critical.

Kerith: Thank you. I'd like to open it up now for caller questions. If you have questions about anything Dr. Shallis discussed today, you can call in to 515-602-9728. Once you're on the call, and ready to ask your question, press 1 on your keypad. I'll just give it a second here. It looks like we have a caller that ends with 1034. I will unmute you, and you can ask your question. Go ahead caller.

Caller: Hi, Dr. Shallis. Thank you so much for doing this show today. It's very helpful. I have a question, or several questions actually. When the patients mostly develop this mutation, is it from the get-go? I know you mentioned that in all different relapse patients and newly diagnosed patients. But when is it mostly developed, just over time? Then are there any therapies cause this mutation?

Dr. Shallis: Thanks. I didn't get your name, but thanks. Thanks for the question or questions. I would say, it depends on how you define develop, not trying to be evasive, but it's more likely than not I would say that this mutation is probably buried in disease and doesn't really become acquired.

There are some diseases in which it is acquired down the road with using fancier techniques, but probably in most cases, if it's not detected at the outset, depending on the biology of the disease, it probably rears its head later as the disease is proving that it's not quite chemo sensitive. It's a mix of both as we talked about earlier. I don't know if it really influences outcomes either way. It probably doesn't change our management, but certainly, if it's not detected at the outset using conventional techniques, that of course will change things.

With regards to things which are more likely to be associated with TP53 mutated disease, the answer is yes. There are specific exposures. I think this is what you asked about that. I'm more likely to associate with this. This is really related to, I'd say, therapy related disease, therapy -- and by therapy, I'm really meaning, prior chemotherapy exposure which I'm not saying was the wrong decision of course. Patients that receive radiotherapy, chemotherapies, hopefully have had an honest conversation with their provider for whatever tumor was being treated that there is a nominal but appreciable risk of developing these types of diseases like MDS and AML.

Radiotherapy and certain chemotherapies are more likely to be associated with this specific subtype of disease among AML patients as a whole. Beyond that, it's lesser data, but there are some non-therapeutic exposures as well like accidental, or you could even say weaponized radiation. We learned this, unfortunately, years of study from individuals who were exposed to the atomic blasts in Japan in the 1940s. There are other exposures which are probably still being teased out. I probably wouldn't say something like smoking for instance. I probably wouldn't say strongly that is definitively in risk for TP53 mutated disease. But that is an excellent question. It's a common question we get in the clinic as well.

Caller: Thank you so much. One more question, if you don't mind. Because I know a book was written about TP53. This is a big cross-cancer mutation. I'm just wondering if any other findings have been helpful in other cancers that are helpful to you in AML?

Dr. Shallis: Thank you. Was it genome? Genome was written 20 years ago. You're right.

Caller: No. There was an actual TP53 book written. It was a popular book. I'll have to look it up, but I can't remember the name.

Dr. Shallis: Me too. I mean, we actually didn't discuss. I mean it's worthwhile to note that this mutation is the most recurringly identified across ultimate types. About 30% of all tumors, AML is a bit less, 10% like we mentioned. This is a mutation which is the subject of a lot of attention and the target of much study.

With regards to AML as a whole, other tumor types that are fostering maybe a better understanding of AML biology and how to address it, I’d say it's limited. Most of what we're learning might actually apply to other kinds of leukemias like lymphoblastic leukemia as well. Looking at MLL KMT2A rearranged disease which can affect both AML and ALL. But solid tumor to the AML space, at least translating the science, not a whole lot I would say of which I'm aware, other than maybe some of the small molecule inhibitors that are hopefully going to be entering the AML space and study that are thought to refold and reactivated. I mentioned one earlier similar to APR-246 or eprenetapopt. That hopefully wasn't a terrible answer, but I definitely look forward to things to come.

Caller: No, that's a great answer, and I appreciate it. That book name is called p53: The Gene that Cracked the Cancer Code. That's what I was thinking of. Anyway, thank you so much. I so appreciate your time in doing this show today.

Dr. Shallis: Thank you.

Kerith: We have, hopefully, time for a couple more caller questions. I have a call from 7608. I will unmute you. You can ask your question now, 7608.

Caller: Hi. This is Diane in Long Island New York. I have two questions. I'm an AML RNR post-transplant TP53. This first question as I did research was that they looked at atorvastatin, so looking at statins at Kansas University since 2018. I wondered if you've known of any success using statins for TP53 AML.

Dr. Shallis: Hi, Diane. Yes, I'm aware of the data of what you're speaking. I’d probably tell you that that is probably not really close to being ready for primetime, and certainly should not influence any decisions to, out of the gate, take a form of statin. I think you had mentioned one. I'm aware of other data for atorvastatin. This is preclinical data and does not apply, at the moment, for patients with this mutation in AML. Statins, I mean, it's a great medication, and there are certainly reasons to take it to gain benefit, but this is not one of them at the moment. In fact, it might just predispose you to side effects that you don't have to accept.

Caller: So the data is not good for statins for TP53 AML yet?

Dr. Shallis: Keyword on yet. I won’t say the data is not good. I would say there's an absence of data.

Caller: My second question has to do with, did you look at Jane McLelland’s Starving Cancer book where she was a physician who use doxycycline, [0:57:28] [Indiscernible], and IV vitamin C to help her with her TP53 AML?

Dr. Shallis: Not aware of that book. I certainly wouldn't advocate for starving yourself. I would actually advocate for eating a healthy and well-balanced diet as we discussed previously because that is probably what's going to put you where someone else in similar shoes on a better path to really getting through certain types of therapies.

I think you mentioned vitamin C which is being studied in a number of spaces, and more recently, in the MDS space, in a particular subtype of MDS, I would say, and for which we don't really have the clinical data available just yet. I really, again, similar to your first question, can’t advocate or really support any additions from an over-the-counter standpoint with regards to these statins which has done over-the-counter, but also vitamin C. I’m not aware of that book, but I will look into it.

Caller: Yeah. How to Starve Cancer, Jane McLelland. I've been studying clinical trials a great deal because I've relapsed, and refractory. I really like magrolimab. I think I'm going to be talking to you about your study at Yale.

Dr. Shallis: We could talk about that online. That would be great.

Kerith: I'm sorry. I think that's all the time we have for questions today. The caller with the 0911, feel free to email me your question. It's kerith@healthtree.org. I will refer your question to Dr. Shallis.

That's all the time we have today. Dr. Shallis, thank you so much for joining us today. We're so grateful for your generosity with your time, and your willingness to share your incredible expertise with us. We would love to have you on the show.

Dr. Shallis: It was a privilege and an honor. Thank you.

Kerith: We wish you all the best in your clinical practice and your future research endeavors.

Dr. Shallis: Thank you again so much. Really appreciate it.

Kerith: Thank you so much. Have a great day everyone. Thanks for listening.

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