This video features Peter Abdelmessieh, DO, MSc presenting on Acute Leukemia. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
So to, I've been tasked to talk about acute myoid leukemia. Um pulling out a bunch of abstracts that I thought were important to uh the treatment of acute my leukemia and applicable to practice. Thank you for having me here today. These are my disclosures. Uh The topics I'd like to cover today are uh you can't look uh forward without looking backwards. And even though it's only been about 3.5 years that alas has become the standard of care for patients with uh AM L that cannot be fit for intensive chemotherapy. It's still important to look back and take a look at the long term outcomes of uh that combination in this disease. Uh They also was an abstract that I thought it was interesting that updated, that looked at the updated E L N guidelines, which is something else I'd like to talk about. Um Does it change the diagnosis of AM L or M DS in, in patients with these diseases and the impact that's had on outcomes? Uh Two other things I'd like to cover uh are targeted agents in this disease, which I think will be what we are going to be doing in the future. Um I think intensive of chemotherapy alone is not as effective as combining it with either a targeted agent or using only targeted agents in this disease. And I do think that therapies such as this are easier to handle on patients and will likely be have to be given in the community setting as opposed to strictly in academic centers. And I'd like to start with agents that are already out there. So um looking at a study adding guilt or to the backbone of Aneta claques and patients with, with repo, am I also would like to introduce two other uh targets that our interest and I think will make their way to the front line setting or the second line setting. Uh for this disease, one would be the role of men inhibitors and two specific subtypes of AM L. And the third being the role of anti CD 47 specifically in T 53 diagnosed AM L uh or all substances of AM L I think that's a target that uh you will be hearing about in the future and will likely be available in about 2 to 3 years. So the the first uh abstract from ash that I'd like to uh highlight um is again, looking back at uh the outcomes of patients that are treated with Zola uh for the um for the management of patients with AM L that are not fit for intensive chemotherapy. And considering that the immediate age of acute leukemia is about 65 this is a a pretty big subset of patients that we see in practice. Um Like I said, previously, this kind of combination essentially changed the outcomes and the landscape of acute mild leukemia for uh for the better. And we'll show that with the next slide or two. Um This looked at 3 to 5 year survival and it also took a look at certain subset of patients that, that have a greater benefit than others. So as you can see from the slide, um essentially, these patients were folks that could not uh receive intensive chemotherapy. Um and they, they just compared a society which at that time point was the standard of care compared it to adding this oral drug called theola. And as you can see by this very, very impressive curve, there is a clear benefit. In fact, if you take this curve out all the way out to 54 months, you still have patients alive, about 20% of patients uh in this subgroup are still alive at 54 months. And that's kind of unheard of um in patient elderly patients of AM L that is now a possibility. Now, 20% is not, we could still clearly improve upon this. But what this shows is long term benefit from this kind of combination therapy as opposed to just aiding alone, aiding alone really only responds about 25% in terms of C R rates. But the addition of the Atlas has almost tripled that response rate. So this highlights really the importance of this combination and the sustained, prolonged survival and benefit by using this combination, which is now considered the standard of care. Um This kind of I put this slide in here is also from this abstract, I just wanted to highlight the importance of something called M R D. Um that's either called minimal residual disease or measurable residual disease. I favor the latter. Um These are patients that although might be in ac R per se um based on count recovery or lack blasts, they still have persistent disease. And I highlight that only because a lot of the companies that uh community physicians and even academic physicians are using to assess um certain markers such as N N P one or binding factor mutations. Uh These companies also have these tests available and simply just have to ask them. But it's an important that we have to show that if you do attain M R D negativity, which is looking at um PC R or flow um to a 10 times to minus third level and you're able to attain it to that new guideline of what is now considered M R D, you're, you're going to benefit the best. And I think this is really just another thing that might not change practice currently, but something to be aware of as more and more targeted agents come about. And if your patients are unable to obtain this M R D negativity, uh that would be a time point where you can offer these patients alternative therapies or additional therapies. And we'll get to um an example of that in an abstract that I selected later on. This was another paper uh looking at a but what it did is it, so if there was any kind of difference in outcomes based on the new updated E L N risk stratification, um The leukemia, the uh European leukemia network uh is how we tend to stratify AM L patients in this very heterogeneous disease. And it was recently updated and I think it's an important thing to be aware of and rather than base it entirely on blast count and specific mutations, it's taken a bit of a um a more heterogeneous approach to this very heterogeneous disease. And essentially what it, I think the biggest changes that have come about with it is that if you've had an AM L defining mutation, regardless of blast count, it's called AM um that'd be like N N P one and or binding factor mutation. So if your blast count is eight and you've got those mutations, it's AM L. And the other big difference I feel is that they've kind of created this M DS AM L overlap for patients that have 10 to 20% blasts, but certain mutations and this it's, it, it's not practice changing, but it's practice changing in what you can get covered for insurance companies. So most insurance companies don't approve AM L directed therapy if you've got a blast count under 20 based on the previous guideline in 2017. However, as AM L physicians, um there are certain subtype of patients, especially in the 10 to 20% blast count that we feel would benefit from AM L direct the therapy mainly that being the addition of the Medic aid. And now we don't really have to fight with insurance companies in order to get that combination for patients, we feel will benefit um where this healing guideline says it's ok to treat patients like they have AM L even though their blast count isn't exactly 20%. And the one thing I did want to highlight is there's a specific subgroup of a amount that has a T 53 mutation. Um I think this is a subtype of AM L that will will is very difficult to treat. In fact, I know it is um and we'll get into uh this subtype of AM L and treatments moving forward. Um But regardless of your blast count, this is a, this is a bad disease in terms of looking at outcomes. Um It's the the biggest difference seems to be that there's a separation of the cards and one caveat to this is that in the uh intermediate risk group, any patient with three positive disease was considered intermediate and not favorable. Um The E L N 2017 said if you had an N MP one mutation and uh had a flip lili burden that was less than 10.5, that you were considered favorable, they got rid of that. And that's why I think you see the separation. But what this does show is that much like with all types of AM o regardless of the treatment. If you favorable risk, even with a even you're gonna have a very good prolonged survival, about 50% in the favorable risk group. These are patients that don't generally get transplanted. So uh at 15 months, half your patients are still alive despite not getting intensive chemotherapy. And it's very encouraging. And again, I think the biggest reason for this differential that you see is due to the subtype of disease and that foot three is considered intermediate and not favorable in certain sub types. And they further looked at. And so the patients that had the greatest benefit and the patients that had the greatest benefit, regardless of um what the mutational status is. The ones that were did not have a P 53 had no flip three and had no K and ras wild type mutation patients that did not have a P 53 but had either A K s or a flit three mutated had kind of an intermediate benefit, still a benefit. But not as great as the patients that didn't have uh those three mutations. And as highlighted previously, patients with P 53 you can see no patients are alive at about 30 months. Um regardless if they got a so clearly, this is a, a type of AM L this P 53 mutated kind that does not respond to anything we've got at current time. And, and, and this is really just to highlight the importance of discussing the patient's expectations based on the genetic genotyping of their AM L uh as spoken earlier. Um But I'd like to change the focus of this talk now on to targeted agents for acute myeloid leukemia. And something that's um was presented at this recent ash was updated phase one, phase two data from MD Anderson looking at adding the inhibitor guilt to, to the backbone. That is aside in the now for the patient with upfront foot pre mutation AM L, it's important to know that a van uh the original A even trials with Dan Polier and Denardo did include those patients and they did have similar outcomes to patients that did not have flip three mutations. But there is this dilemma of do we need to incorporate a flip three inhibit in a frontline therapy like we do uh with intensive chemotherapy based on the Admiral study. And what this study did um was essentially threw all three drugs together at the dosing that we're all familiar with and did a day 14 marrow. And if that day 14 marrow showed a complete remission and no blast count treatment was stopped until recovery. And then we started at this consolidation dose which is uh two less days of Aine only seven days of the melas and continuous therapy of the guilt of. And I think the reason for this is the biggest concern uh is Cyto P as in Maral, uh which you'll see with a and so this study is very careful at moving before moving on to the phase two dose, um assessing uh for marrow plasia early on and continuous therapy. And in the frontline setting, it's hard to argue with 100% C R rate, which is what it did show. And even in the relapser factory, 70% response rate is quite impressive for any type of re relapser factory AM L. Um So this is clearly a very encouraging combination um that is sustainable as you can see by this curve. Uh any time the line flattens out regardless of how many patients are on the on in the study, which is not that many at this time point. It's quite encouraging. I will highlight though that I don't think this should be uh recommended in the community set or unless it's a relapse or pray patient that you might have a transplant lined up to the concerns of aplasia until uh proper phase three data or at least more encouraging phase two data is done. This combination can be quite toxic to the marrow. And even more importantly, uh Banta claques and guilt to it and have a lot of interactions with commonly used drugs. And a great deal more has to be done in the clinical trial setting before uh we can combine these three drugs. I feel more comfortable either combining guilt written with Azal or V Azo for these patients, but still quite encouraging. An example of if you're not able to attain an M R D negative state, or you feel like your patient has a high risk for relapsing with a even adding, perhaps considering adding a combination therapy. So a targeted therapy in combination like Guilin can help um improve the outcomes of patients with this disease. And then on that theme, I'd like to mention two drugs that are not currently FDA approved um or really just targeted agents that are not FDA approved, but I do feel will be in the future. And I've shown great promise because they're actually targeting specific mutations in the disease. And one of them, this class of drugs that is called Met inhibitors. There's about three or four out there. Uh The one I wanted to highlight was S N X 56 13. This is the one that's now in phase two studies, there are other out there and no one knows which one is the best. They're all targeting it specific. Uh protein called me and mein is highly expressed in uh A MLS that have this K M T to a rearranged um uh mutation along with N N P one. As you can see by the slide, it's encompasses about 40% of AM L. So that's a lot of AM L that it encompasses. And the study that I'm presenting um is looking at relapsed uh or refractory patients, standard care therapy. And essentially what this does is it inhibits uh the pocket in which this gene operates. And this gene or people, people leukemia that express these mutations are essentially only in a leukemic state. And they're either in in cell arrest or driving towards only a leukemic state and are unable to differentiate properly, which is a common theme in in almost all leukemia is there are cells that don't that have some problem with becoming fully differentiated. And the greatest example of that being Atra and arsenic in the treatment of A P L. And in terms of its safety, it's pretty safe. But again, interesting to note that 11 of 16 patients develop differentiation syndrome again, makes sense with the mechanism of how the disease works. And I tend as, as a clinician, I tend to get very excited when an agent in this disease causes differentiation syndrome. I think you're actually altering the disease biology uh for the better as opposed to just delivering cytotoxic chemotherapy, very tolerable treatment. The only grade three outside of neutros expected in all types of animal treatments is Q T prolongation and it's only seen in five out of 52 people enrolled in terms of efficacy. About 30% of C R rates which is again, very, very encouraging. Um excellent in a relapse refractory AM L study. Uh used to usually your response rate is about 10 to 15% with anything that you're given relapser fracture. AM L I will highlight though that the greatest benefit seems to be in the K M T to a mutated patient as opposed to the N F P one mutated patient. Uh If you look at tease out the abstracts of the other um men inhibitors out there, it does seem that certain companies compound favors the N N P one over K M T two A and they also have different side effect profiles. So it'll be interesting to see moving forward which men inhibitor makes it to market first. I do think they will be made to market and for what sub type of AM L will be approved for. But again, this is merely a, a highlight of uh you know, drugs to come. And I do think this will either be combined with certain agents in the future or used as amount of therapy in relapse setting. Another very important um target that uh will be coming, I believe also to uh the clinic in in about 2 to 3 years very soon is the CD 47 CD 47 is essentially a don't eat me gene on my uh myelin cell. Uh It, it, it's a, it's a, it's kind of like P D one with solid tumors and it's shown that it's highly expressed on M DS and AM L cell lines last year. A phase 12 data was presented on the role map in combinations either cited even M DS that show, uh you know, very impressive, improved overall survival, which has now triggered a phase three study uh that is currently closed and we had opened in our center. And the results of this study um have also prompted a phase three study which we also have over here at Fox Chains. And I wanted to use this time to highlight a type of AM L that I think plagues every clinician out there and a mutation that plagues every cancer that we see. And that's p 53 mutated AM L and I stated earlier that AM L is a very heterogeneous disease with this specific subtype leading um all clinicians that treat AM L pretty much flu. And the reason for that is that it's a, it's a type of AM L that um kind of, it's a mutation that pretty much doesn't allow any of our current treatment to work and it does. So by keeping cell rest, it inhibits DNA repair and it inhibits apoptosis of cells. Uh This is a type of AM L that's very blastic patients blast count very rarely above 30%. Um Their marrows are always hyper cellular and it seems that whatever treatments we give, we cannot get rid of it. And it's likely because these cells are in kind of arrested state and don't respond to traditional therapy, which is all directed at breaking down uh DNA and, and inhibiting DNA repair. Like I said earlier, it's in about 10% of AM L. So not as much, it's not as rare as you might think. Um It's in about 30 patients, 30% of patients with treatment related AM L. So, if you're in a practice that's treated any kind of curative cancer like a stage two breast cancer or any anything that incorporates anthracyclines or to these patients will pop up. Um It is often associated with complex car type again, poor risk uh regardless of intensive chemotherapy. One year, overall survival is, is less than 30% median, it lasts about six months or whether you give hypomethylating agents at five days or 10 days, no differences. And even if you transplant these patients, the one year overall survival is somewhere between 10 and 15%. This is the type of a that we really have no current strategies that uh provide any sustained response for patients. Um And I would highlight that this kind of, we only were able to look at T 53 all these mutations that we're mentioning maybe about um six or seven years ago. So it just shows an evolution in the field or current improvement in risk stratification of this disease. And this is just another slide from pratt that again highlights regardless of the regimen that you give patients. The medium overall survival is about six months with or without transplant. I mentioned this subtype of AM L because this is one of the one few studies that even though it included all patients with AM L, it specifically looked at patients with T 53 mutated disease. In fact, twice as many patients have a T 53 mutations in this cohort and don't. And I think that's really important based on what I've just previously said about how difficult this disease is to treat. And this is a pretty tough slide to read, but just the way I would look about this is that anything that's blue and gray is good. So you see in the T 53 mutated patient that you have got about a 60% response rate, which is way better than anything else we have even with a, you're about 30% and in a wild time, you've almost got, you got an impressive response rate. So altogether, it's about 85% response rate and the P 53 mutated subtype, it's about 60% and these um are sustainable. Again, Latin curves are good, but you can clearly see the blue is wild, wild 10 patients about 80% response rate and you can't compare studies. Um Eventually this, this is currently in a phase three, like I said, but if you were to compare it to a s, then you've got about a 15% benefit with the addition of this drug. And this is the highlight um the importance of transplant if you are able to attain AC R in patients of this subset. Uh the caveat being though that in this study, you were able to move on to a transplant if you had did attain AC R. So you're probably selecting out the patients that would do better overall, regardless if they got a transplant or not. But if you didn't get a transplant, no one is alive after nine months. And if you did, uh six of the eight are alive, impressive is that five out of eight patients actually attain an MD negativity. Um I do think that if you do transplant patients, P 53 this is pretty much really important to see if you're gonna get a benefit out of it and a drug out there that can help you attain that. And P 53 T M um is, is, is very important, the conclusions of this study. And I'll, I'll focus on the last pitch, which I think is important later is that it was safe. No one died in the frontline setting. Uh It was like eight weeks and you saw a 60% 63 response percent response rate in 2 53 mutated patient, which is far better than any other uh combination that we've used in the past. And the wild type 88% get uh fantastic outcomes with um no one dying. Still a problem in the relapse of factory setting. And then the patients that received the claques but still on 11%. It's not bad. But the patients that didn't see that 50% respon a very important side effect is that CD 47 is on um dying red blood cells. And because of that, it can cause a hemolytic anemia quite abruptly, very shortly after the infusion. And because of that careful monitoring needs to be done, um all patients should be admitted and are will be admitted on a clinical trial that we have over here. Um You have to have a blood bank that's able to do genotyping because once it's kind of like there are two that uh it can throw off the type of swing of um blood needed. And this reaction only tends to happen for the first infusion. So after the second infusion, 3rd, 4th infusion doesn't seem to be a problem. But during that first infusion, you have to make sure that the person's hemoglobin is above nine and it's done in an inpatient setting. You can appropriately respond to people that can have transfusion reactions or uh things with hemo aia. It usually just responds to transfusion support and no further problems occur. It is an infusion drug that's given about uh date 14, I believe, uh 15 and 18 and then further on is only given twice a month with a, like I said, the study is now open in Fox Chase. So if you have patients with AM L and you feel are not fit for intensive chemotherapy, please refer to our center. It is a very important study that we hope to approve very quickly. Like I said this compound a approved within a year and I and I it's pretty encouraging that the data that it showing in a very difficult subset of patients with AM L to highlight what I spoke about today. Uh I just wanted to show outcome long term outcomes of A of an which is now considered the standard care uh for patients with AM L I wanted to highlight that moving forward, what might happen to the patients moving forward is adding a targeted agent to this backbone of a of an or perhaps adding that the patients still attain an M R V negative state. And one of these targeted agents already available being guilt written report three inhibitors. The other targeted agents I wanted to discuss and highlighted were met inhibitors used to target about uh about 40% of the subset of A MLS that we'll see. Now it's a phase two data as a monotherapy for the relapse of for a patient Um And I also wanted to highlight um the difficulties that we've had in the past of treating patients with T 53 mutations and the promise that comes with this new targeted agent, the and other CD 47 inhibits that will be coming on the market and also have a transplanter. So I want to highlight the importance that right now the only creative options for poor risk a amount and is transplant. Thank you for having me as a part of this conference.
