Chapters Transcript Video Acute Myeloid Leukemia and Myelodysplastic Syndrome well good morning everybody. I'm going to be talking about A. M. L. And M. D. S. Two topics that were extensively covered at the american Society of hematology meeting uh here in my disclosures over the past few years and I'm gonna be covering some topics in AML namely veneta clocks and inciting the new standard for older adults, not a collection other chemo together. Hyper method agent says maintenance which is a new thing in a memo. Then targeted therapy and novel therapies and mds. We'll talk about some melons of new ideas and treating high risk patients with that disease. So M. L. As you'll hear if over the next few minutes has undergone a transformation, it's not your grandfather's three plus seven anymore. We now have some other options for treating patients in the upfront setting who are chemo fit. If you happen to have uh therapy late AM. L. Or M. L. With mild dysplasia regulated changes. We can consider the use of c. p. liposome encapsulated version of donald robinson site caribbean. If you have good risk or particularly uh particularly good risk but maybe even intermediate risk carry type. We can add baptism based on a recent approval. If you have foot three mutated disease. We could admire historian if you have I. D. H. Potato disease but probably will give you three and seven no clear role yet for I. D. H. Inhibitor combining that. But maybe in the future and for all non fit patients we are using hyper medications plus Manetta Clacks and you'll hear a lot about that momentarily. So ironically in the older adult where we're not going to be using three and seven. We don't care as much at the moment about the genetics but you'll hear some controversies regarding that. So let's talk about banana clocks. The meeting did seem like the banana clacks industrial complex at times. And that's a great news because banana collapses an important drug. You've heard a lot about it in CLL from matt, but it's become a game changer, frankly in AML and it's important to recognize how it works. It binds to BCL two, which is an anti antibiotic morality, which prevents bevan back for making holes in the mitochondrial cell membrane, thereby causing apoptosis in response to set a toxic stress like chemotherapy and radiation therapy. So it's a pro chemotherapy chemotherapy enhancer drug is that's the way I look at it and uh it didn't work so well as a single agent. Uh, but when was combined with either a society or decided being an older unfair adults, the response rates were very high. This was uncontrolled data published over the last few years. You can see that basically at all some groups, if you look at senator john X. M. L. Subtype or genetic mutations, the response rate was pretty high. And uh so that was exciting. But these were uncontrolled data. So the most important trial by far that was available to us in the past year was the so called by L. A. Study which was uh again important to recognize what this was and what it wasn't. It was enrolling patients who were greater than age 75. That meant you were deemed unfit for chemotherapy on age alone. Or if you are under age 75, you could go on the trial. If you had significant comorbidities that heart failure that COPD were poor performance status, you couldn't have received, hmm before your mds. If you had mds before you turned up to have A. M. L. An important point in comparing this with the Biology c study which all briefly mentioned in a couple of minutes and so if you met one of those criteria, you could be randomized on 2-1 basis favoring the experimental arms, banana clocks, plus asia. And there was a short ramp up enough to wrap it up quite as carefully as you do in CLL versus the standard of care at the time was a society in alone. It seems like such a long time ago we were using in deciding alone for AML or older but no longer based on the results of this trial. The primary endpoint was overall survival. And here is the slide. Looking at that primary endpoint, You can see here that the median survival was 15 months for a seven In 10 months is in placebo. So that's a big difference. Most importantly the has British, it was .66, which obviously means that there was a 34% reduction in the risk of dying. If you were minimized to the experimental arm, you can see that the patients were on the treatment for eight months if you had a s event in four months if you're on placebo. Uh And so this immediately changed the standard of care for the patients who would be eligible this trial. It also brings up the issues, but maybe younger patients or other patients should receive this, but I'll come back to that in a second. The second is now, because I'm gonna tell you that all some groups benefited. When you look at the overall endpoint, the uh conference centers are always To the left of one. The one thing that's worth mentioning is if you went on this trial, because you're less than 75 didn't seem to have much of a benefit. Why is that? That's because those people were really sick from other diseases. And so unfortunately banana clips doesn't fix your heart or your lungs if they're crappy. But it does work in all some types molecularly speaking. Okay. Ml Maybe not as profoundly in P53, which is a big issue, that's the big bad guy in this disease. Still, Maybe that was profoundly and flip three. Maybe I was profoundly surprisingly an NPM one because that's the chemo responsible sometimes. But as we say in boston's wickedly effective in people with A. D. H. Mutations. I'll come back to that now. Uh there were two abstracts from the head Ash, looking at that trial, the biology, a trial. We're looking at specific subgroups, uh dan paul, you're from colorado presented a some group analysis of that trial. Looking at just those who had I. D. H. One or H. Two mutations are 107. And the remission rate was much higher for those who were on the A's event compared to a placebo duration of response was quite long in the middle of a survival was quite a bit longer. If you were on his event, 25 vs six months. Uh, there wasn't any higher toxicity in the command group command uh armed for these patients, we're gonna contemplate who along with Tony Lutai is uh one of the two great scientists that are Vonetta Clark specialists if you will in the lab. But she presented a trial, the subgroup analysis and get just those 62 patients who had to fly three mutation of either the I. T. D. The more common or the less common implementation in the tires and kindness domain. Again, if you were randomised as a venue, have much higher remission rate, 65 versus 18 if you can't see ours and crH CRE which by the way is almost like cRS if you have a platelet count greater than 50K and a neutral account greater than 500 cases are really functional map which is restored. That's pretty high if you had a s event and for three mutation, the median survival those I just showed you on the forest but wasn't that dramatically better, but it was better. So the question comes and we'll come back to this in a few minutes. Should an I. D. H patient get an I. D. H. Inhibitor plus something or an idea to be alone. Should they just go ahead and get a event and the same question for the flight three patients, should they get these are keeping one ft patients, should they get Uh with the inhibitor alone for three inhibited plus a society or something else. And we'll delve into that in a second. But right now it's fair to say it's okay To just treat your older patient with seven irrespective of the sometime and remember that Vanoc lex has to be dose adjusted if you're taking a sip three A four drug namely anti fungal is all The different results have different strengths of inhibiting the ship 384 systems. So I'm gonna take that into account. We don't use as much fungal prophylaxis in the upfront setting as they do with other institutions. But it's still important to recognize this. Okay, so the valleys she trial I show for interest more than use because most people don't use low dose. Heresy is their initial therapy for older adults with AML. But because decided being in a society are not widely available in certain parts of the world such as Asia, there was an important trial of uh, comparing, but lo does have received plus banana clacks, little sarah C plus placebo. And although it wasn't as dramatic a difference if you waited long enough and looked at the letter to the mature a little bit, the hazard ratio eventually became positive in favour of, but in a class of logo sarah C and the important thing to note about this trail is you could have had received therapy for your NDS before be having AML than going on this trial. That probably accounts for the general, we less impressive outcome of 8.4 vs 4.1 Month median overall survival as opposed to the uh, what was it? 15 versus nine in the, in the valley atrial. So another subgroup, that's obviously a huge problem. Just like matt talked about with CLL, it's an even huger if that's the right word problem for if you have people from the community to AML how well does veneta klaxon decide to be work in the subgroup? And uh There's a 10 day regimen called deck 10 of 10 days decided that in a row plus financial collapse, this sort of came out of the work done by our Washington University colleagues Who published a paper uh, Dr Welch was the first author a number of years ago ineligible medicine. Looking at 10 days of decided me just that regiment alone for patients with AML specifically that people through some group and that made the new module medicine because the response rate was very high. But a huge problem with people three patients is a durability. You can see here that you can get up appreciable overall response rate With 10 days of dissent. A billion plus Mineta clacks. It's quite mild suppressive by the way. But you get a Overall response was 66%. And the T. P. For three mutant patients. Not as much as you get with the TPP. Wild type with the same regimen. Uh You got about 1/5 of the patients MRT negative by flow saitama tree. So that's pretty good. But what about the durability? Well as you can see here, The durability is not so good in the people. three million patients. It's 5.2 even with this very mild suppressive regiment. So for a while I was using what I intended to send him an infant in the class for my people, three patients. Because there wasn't anything else that worked. At least you can have a brief victory party with this stuff, but it doesn't work for very long. So I would caution you about that. Uh And the response rate again uh for uh decided being with banana clocks Is a little higher than decided being 10 day. Uh that's the so called wealth rather wealth regimen. But unfortunately in this historical comparison that M. D. Anderson investigators are fond of presenting, there was no superiority or albeit small numbers for those who got decided being then vs those who got just decided me for 10 days. So disappointing unfortunately. But again brings up the issue of tempering your enthusiasm uh for initial results, the response rate me behind. But if the durability is low, is it really worth subjecting these poor folks to for long mouth suppression on their way to the ultimate. So as far as as a vendor, let's say low dose chemo and for netflix It's a new new standard of care for patients were in 75. Uh and you can use decided to invent or Lodo said happen if you don't like is it that much? Uh Again it's very effective and I distributed AML texas is manageable though. His mouth suppressive where we're going we're going to look at the younger patient populations and you'll hear toward the end of my talk. We look at this combination in MDS. And the watchword for the 2021 period is in addition to let's get a covid vaccine is triplets. So now we have your new baseline advent h. M. A. Let's come up with the foot for inhibitor on each inhibitor, blah blah blah blah blah. Some of these drugs will hear about in a minute. Okay. Uh C. P x 351 is an important and of course very expensive Version of your grandfather's 3-plus 7 which is dr Robinson side caribbean wrapped up in this cozy lamelo membrane of liposomes which releases the RSC to dR Robinson in a 5 to 1. So called fixed molar ratio. Which was a good way to kill the cell. It sort of hangs around the american department for a while. And that accounts for both its perhaps superior efficacy in certain situations and it's more profound mile suppression. So here we go. Let's combine CP extra 51 with banana clocks. This is an abstract from uh M. D. Anderson. Uh So it's a mile suppressive drug with another Mile suppressive drug. And please note these were largely patients with at least what they presented so far was largely patients with relapse refractory him although they will have a court for up front patients. And there's already a controversy for the patients who were between 60 and 75 whom c. 351 was originally tested and was superior to three and 7. Well the folks like that who have secondary AML should get. Vonetta Clark says that with cp X ray 51 That controversy there's no data yet to tell you the answer about. But anyway, even before we know that if you want to combine cps 3519 o'clock, the only point here I'm making is that they had to go backwards. So the dose level one It was about 21 days of the ah veneta clocks and they had to go down on the dose of Banana clacks # one and then they went down on the duration. And I think that's a theme we're going to see a lot of here is decreasing the duration of banana clocks. The drug is approved as it continuously does to agents. But what am l anyway. Uh I think the key point is to give it with the chemotherapy and not worry about it after the chemotherapy is done. Potentially it's chemotherapy as I said earlier, So give us a single agent. Unlike CLL doesn't seem to be that great of a deal, but we're still giving it continuously in the event situation. The response rate of these uh relapse refractory patients was fair. Uh Not much to say about that at this point. The point of the two points I want to make about this trial is number one, you're going to combine this with another mouth suppressive agent. You gotta be careful with the duration of banana clocks. And unfortunately, just like with everybody in CLL getting a you can have it her now, everybody else can AML or not everybody, but many people will be getting a banana collapse. So what's going to happen if you had banana class and now you realized you're in deep weeds, as you can see from the red curve here. So even with this model suppressive regiment, the survival were poor if you had banana clocks before. But if you had a pretty good. So, uh, just to treat our own for a little bit, we also have been combining banana clocks with three plus seven. That's the obvious question or the obvious next way to go. Maybe we can make the induction regimen better and it's a tough thing to do. Um, we have a short ramp up period And we gave a standard dose three and 7 with Banana clacks. We did define the MTD of 400 mg. If you're giving the banana class for 11 days, Starting one day before the three and 7 extending a few days after the three and 7. The good news is the uh shown on this slide the response rate was high. Uh we treated 13 patients. 11 had complete remission. The only two that didn't have a complete remission with unfortunately death. Uh one in a patient who is older than 75. 1 of the young patient Who unfortunately was given the 600 mg dose which were no longer giving of these uh 11 Crs nine had their M. R. D. Measured seven or M. R. D. Negative. Which is probably very very very small numbers but double what you might expect. So what about combining banana clocks with other stuff beside inside the medical uh decided being and uh low dose ever say well you can do it if you're careful not showing the uh M. D. Anderson abstract where they combined in a class with flag, extremely mild, surprising regimen, shockingly they were able to with some tweaks. Yeah banana klaxon and get a very high response rate even in real option Factory patients. So flag out event is now being used by some people in the relapse refractory setting. They also combined with the letter B. Inside caribbean which I won't go into now but we really need randomized trials and and the hopefully the U. S. Uh cancer therapy evaluation program. In other words the N. C. I. Is about to sponsor some important trials. We should be asking some questions like should you get C. P. X. 351 or as event if you have tabulated them at least adverse risk aml etcetera. So a much more to come on this in future years. But banana clacks isn't important came up potential later. There's no doubt about that. And we have our own may his soul rest in peace. Stand course Meyer started this field. And now dr litai who's uh doing some great work along with other colleagues at D. F. C. I. On making banana collapse and other similar pro empathetic agents. A reality in AML and other diseases including L. L. As dan mentioned obviously Cll and maybe MDS is I'll say in a few minutes. But as a society in the backbone chemotherapy agent is given intravenously or subcutaneous lee two patients down for M. D. S. And M. L. But there is an oral formulation of that uh made by Celgene. Now brought up by bristol. Myers Squibb called uh I won't even say the trade name because I was stupid but I always forget anyway. Uh C. C. 486 was developmental name but this slide is meant to remind us that how this might work. It's supposed to be a hyper method in agent and cause differentiation, but it also causes are in a disruption a Potosi's so it's a complicated molecule. And another point of the slide is to remind us that this oral decided being should not be uh combined or a sub student for uh I. Ve. Or something uh society and routinely in fact never at the moment. Uh the approval of oral decided being comes in a specific situation which is both interesting from the oral decided being stand or is a sighting standpoint and from the maintenance and ml standpoint. So as I think most people know, we routinely use maintenance which means low dose therapy after all, the high dose therapy is done ferrelli, prolonged period of time in kids and adults with L. L. There were a few older trials uh in which maintenance therapy didn't seem to help in AML. So this trial which has just published a new original medicine like recently uh is giving us new thoughts about maintenance therapy. But again, the devil's in the details. We have to know the patient population. And that is uh that uh you have to be number one grand age 55. Uh You can have the no vote or secondary ml but you have to be treated with standard induction chemotherapy and then go on to receive period of consolidation therapy. So again Age 55 with Aml. That's a patient population that we tend to transplant a lot. Uh And uh we're so a lot of these patients, the game today in a farmer would get transplant and he couldn't get a transplant and go in the study. This is the people who were trying to keep these older folks, we're trying to quote cure or at least prolong their survival with chemotherapy. But the point was when they were done with their induction chemotherapy uh and got and that consolidation chemotherapy, It would then be randomized to 14 days of oral is every month or 14 days of placebo every month uh for a bunch of cycles. Uh If they this is important, if they sort of started to relapse, uh they could go on to they could still stay on their insight in placebo. If they really relapse, they had to stop treatment. So let's see what happened. Uh So the what happened here? Okay, A little trouble would be a singles try that. There we go. So uh the uh what happened was that the survival was markedly improved, not quite doubled in the median survival uh with a good hazard ratio with a significant p value, both overall relapse for survival. So this led to the approval of this drug. But again, just within the context of patients, it would have been eligible for this trial. We see, we don't want to see it overused, that would be inappropriate. Uh Dr donor and my colleague from home Germany presented a subgroup analysis of that, a major study, the quasar study that was published in a little message as I mentioned, which was um looking at patients who were in that category of people who had those early return of blasts And they can continue to receive the study drug ongoing for 21 days rather than 14 days at the investigator's discretion, Which I would have thought was a ridiculous thing. How could this possibly work once you had 5-15% blast? You know, you give all the oral lease in the world you want. It wouldn't help well wrong again. Uh the even in this so called escalated dose in court, it was a benefit compared to the placebo of receiving your escalated uh, world isn't. So that's interesting. So in summary we take all this uh maintenance stuff together. Um As I said, we should not yet substitute the world is a for ivy or sub to asia and Mds or other areas, but it's certainly going to give us some food and some ammunition to do future trials. Uh And of course obviously you're probably saying to yourself, well, we're going to have all oral therapy for AML soon. We can combine this stuff. CC 46 with Banana Klaxon have a good outcome just like we did with society banana class. That may be true. We have to prove it. And you many of you may know about the oral decided being centered in the emanates inhibitor combined pill, which all mentioned briefly later in the MDS stock. If we can combine that with Panetta Clacks and do oral therapy as well for AML. Well again, I wouldn't do that now. I still, we're still sort of stuck with the, have you decided to the sub cure ivy is a side named cluster in the class but things could change in the future. So let's move on to targeted therapy. Everybody knows about flip three being mutated. About 30% of AML patients, mostly in the uh, just a memorandum man, sometimes in the candy store man. And we want to inhibit flip three because it's an activating mutation With either type one or Type two kindnesses. Uh, and as you can see from these diagrams, the kindness inhibitors, Well, the flight crew members have different degrees of specificity, 1 to the other. Right now, there are two approved flitter inhibitors in AML. What is my historian up front use based on the ratified trial and the other is guilty retina, which is a more potent and specific inhibitor than is my historian. It's approved in the real upsetting based on this trial. Led by Sasha PERL from penn comparing guilty with him to chemotherapy and the real upsetting and the good news was that it was better than chemotherapy. The bad news is not all that effective in the launch of the people you want to relapse. Uh, if you have flip three disease or any type of AML for that matter. So can we bring Flight three inhibitors upfront beyond The three and 7 situation. And this is the last one trial which was presented in small part by Eunice juan from buffalo Roosevelt park. It was a three armed comparison in the so called chemo unfit population of the same type of population that would have been eligible for the by L. A. Trial is a newly diagnosed in a little pretentious chemo. They could get guilt ridden them alone or guilty. And plus Asia or is it alone? Which was than the standard of care? Of course this trial is now a little bit outdated because there was no is a van or you don't have that benefit. Uh But uh Dr wang presented the early safety data for the guilt of an amazing group. But uh a press release. This is how we get a lot of our information now. Came out a few weeks ago after Ash where the Asia versus Asia guilt. Part of this trial did not meet its primary endpoint of overall survival. That was armed A. C versus upside down below. So what does that mean? We don't know because we haven't seen the data but if it's really not better than Asia and we know that as a van is better than Asia. We're still kind of stuck with a cement for for three patients until we can get a triplet. But there's more to the story than that and that is this really need study by doctors diver from M. D. Anderson and Pearl from uh Pen who looked at banana clacks and guilt ridden him again. All oral therapy. This is truly all oral therapy today. This is mutated uh for three ml relapsed refractory. So the same time the pages that would have gone on the admiral trial which was killed versus team. Oh now it's just Vanessa. I'm sorry Van guilt. Uh and you can see the design here. There was a a wrap up more complex ramp up in the early phase part of the trial to make sure it was safe. And then there was a less complicated ramp up in the just expansion, just over three days, which is what we do now uh the year's event. So. Okay, so it's just it's not a controlled trial. It's just been And guilt oral therapy. Relapse refractory AM L. Uh and you had to have a white count that was not too high to start. Okay, So uh just look at the dose expansion. It has been 400 Plus Guilt 1 20, which is the full dose of both agents. You can do that and again, I'll go uncontrolled, you know? But the response rate was nearly 100%. Uh And uh in in this uh population, even in patients Who had prior foot three inhibitor exposure because Remember nowadays since uh three and 7 plus my story is a standard care for upfront patients. Your average patient here is who's relapse refractory is gonna have seen a TK islands and they just is a man or something like that. So will these response rates be durable when we don't know yet. But over the short follow up that we've seen the overall survival and uh the I. T. D. Group, which is a more common group is high, ridiculously high for real after Frederick patients. But remember The median follow up is 3.5 months but still exciting, you know, and some of us have already started using them going back to the upfront setting three and seven of my history as a standard care. What historians uh maybe not the best foot three inhibitor in the world. How about guilty right now, which is the best for for three of them are in the world that we have available right now. There may be some other ones coming down the pike, but keith prats who is also from Penn Uh presented this phase one study of guilt ridden them with induction consolidation. And again, it's just a Phase one study. Not just but it's a Phase one study with various, you're allowed to get IDa heresy or donald heresy which we used on or around here, but anyway, not too important just to say they were combined. Um I can't say much of the Phase one study. Overall survival is not yet reached. Uh It can be given safely, that's the main point she irate um was okay but the duration response again, just like I showed you with the then guilt, guilt three and seven good duration of response represent patient. Uh 30 and 60, immortality Was zero, which is nice. Uh So uh where is this going? Well. It's going to be compared to uh three and seven gil will be compared to three and seven plus minus story. And uh you know in the relapse refractory patients yield plus ven plus is there will be looked at as well as in the upfront patients killed plus men plus as a will be looked at. So we need to again concentrate on triplets in the future. Maybe if they can be given but triples are not going to be benign because it can be combining a bunch of other suppressive drugs. Let's move on to I. D. A. Tradition. Uh It's really needs story. Of course I. D. H. Mutations Lead to the production of Annie amorphous reaction product called two hydroxy include a rate which photo copies the epigenetic changes you get with a tattoo mutation. It's this mysterious combination of ah uncle metabolic with junko genetics and as you know in single agent use of these drugs. I have assigned it for I. D. H. One mutant patients. An ascendant variety of communications. The response rate was about 40 half being crs roughly you get a differentiation syndrome and so what you have to watch out for and give steroids, you can keep the patients on the drug. But what about combining these these pretty well tolerated drugs With more familiar drugs like three and 7, which I'm not going to talk about today. Well with the saturday. When veneta Clacks. Well there's been some initial trials done with all of them. This is a bit complicated slides to tell us that what happens if you give me deciding alone little complete remission rate or uh in a city where I'm assigned him alone, you get the lower complete remission rate. Once the trials that have combined, there's with Van, this group has already showed you earlier on. Very good remission rate. Because the idea of an emitter with this idea permission, it doesn't seem to be higher than what you get with this event. So this goes back to his event. Should be used as event first and then move on to uh nine th inhibitor when they fail as a man. Or should we combine this specific drug? Uh upfront in these I. D. H. B. Patients, we don't know but Denise him and who who worked with us for a while now in MD Anderson. A Canadian, a Canadian uh fellow. Uh Well it is true that if you start with, if you look on the left and you start with an I. D. H. Ph based regimen, you can salvage patients if you moved to bent later. If you start with uh Mhm. A and then you move to and and uh your ideas you know better down the road. Uh You can get a lot of salvage rate. What this means is totally unclear when I still use a s event uh upfront and save the ideation emitter even though the response rates not as high uh for later. So this is where we are with the I. D. H. Story again triple to being uh worked on. And we have an AIDS event ibo trial at Dana Farber. For up front. I th one mutant patients of Dr. is leaving. We'll move on to some novel stuff. The most interesting novel stuff is the Uh stuff for P 53 mutant patients. Uh there's a uh a. p. Which is so called P 53 re folding agents. I'll talk about that with regard to MTs in a second. I won't say anything about us. Into some of the thing in the middle here. Anti 67. We're supposed to promote immunological degradation of cell. But I will say a bunch of stuff about anti City 47 specifically Macchiarola bob. And of course this drug is all the rage now Because it is # one of the mechanism action. Uh Number two, it seems to work in P 53 mutant AML. Mhm. So uh yeah, Gorilla Man is this anti city 47? And it's a fun thing to say. It covers up the do not eat me. Say no. That is manifest by CD 47 expression on AML cells and other cancer cells. Ah 7:47 also on um red cells. So it does cause anemia. And you have to give it a sort of wrapped up fashion to get a so called priming dose to get away from the on target anemia. But that's not that big a deal nowadays. So basically this is the study of macro plus A Visa and A. M. L. And N. B. S. Notes. It's not my gro plus event. It's macro pluses. This is the amL expression cord and a really high response rate. Uh Even in P 53 mutant AML. So this is not a P 53 targeted agent like a P. R. 246 Well I killed her name is for Flight three. This is a drug that works in P 33 Ml. Perhaps because it works by a completely different mechanism action that doesn't require maybe a Potosi's and the functioning mitochondria as much who knows? But the response rate is 70% is pretty good. Uh Not that many patients yet. And obviously we'll have to see if Magara is it Or perhaps Magara is event is better than a event for this difficult patient population. And as far as durability I showed you the lousy durability for this uh 53 million population with said they decided me but seems to be appreciable although not curative. Uh uh the people of three population compared to the other stuff that I showed earlier. So stay tuned. And the last thing in the mm I'm gonna say it's about this interesting drug or class of drugs called men and inhibitors. Again this is research done by scott Armstrong largely I was at a pediatrics indiana farmer who showed that men in which is a component of this transcription aly promoting complex which has got a lot of proteins in it Is important for us turning on this developmental pathway called the Hawks Me one Pathway which is important in MLL rearranged M. L. Or L. L. For that matter. Which is your 11 Q. Abnormalities. And it's also important M. P. M. one a.m. L. Which is a pretty common subtype. So uh scott and his postdoc, you've done work with a fed. I'm an inhibited and mice with an M. L. L. F. Nine rearranged model leukemia. As you can see her eating this stuff in their chow led them to survive and if they didn't eat if they were dead. So it works in uh M. L. L. N. N. P. M. One. So uh we're doing a trial with the syntax company that wasn't presented Ash. But it does have uh that drug does have activity the trial that was presented. And Ash was uh a small snippet of the uh trial with a drug called from cura oncology. Um and There were six responding patients showed here on this line. And what was interesting was I guess uh patient uh the 100 mg patient, the second face from the top who had no And the low rearrangement or npm one mutation and who had a complete remission. So this is uh weird but it caused a big stir because maybe then inhibitors have activity beyond there uh predicted some types of response NPM one ml rearrangement. So we've got a whole bunch of new drugs in A. M. L. A lot to play with. Makes it feel a lot more complicated, A lot happier than it was just a few years ago. So the last 10 minutes I'll just talk about Mds and I'll talk about CML is some type of Mds. Early in Mds uh M. P. An overlap syndrome. This is when you have M. D. S. But you have greater than 1000 model sites in the peripheral blood. And uh background of this trial was the fact that we don't have much to use in CML. Sometimes use a hyper method of agent. Sometimes we use hydroxyurea and the proliferation some type of AML. This is a trial that was done years ago. Show that directs here Ria It was better than the world. It's a facade. But the trial that was President Ash by Raphael. Its extent of France, it was decided being versus hydra first, a randomized trial and cinema will invest disease. And unfortunately uh if you look at an end point of ah either being dead or converted to html, the decided being versus hydra were completely super imposible. So you may have, you wanna make, you may want to reach for decided me but uh you can still get away with hydra if you need to lower the white count. Supermodel, it's just as good about has decided me. Uh And then dr Garcia, our wonderful faculty member uh dana Farber presented this drug company sponsored trial of phase one B. Study of a deciding plus banana klaxon. Mds. I risk Mds, especially the same uh uh protocol that was used in AML now is a pledge of Mds, but be careful now, these are people with lower blast counts. Older folks, they may be uh they had a little trouble getting a safe dose with these two drugs together, But ultimately they did show that you can give the banana clacks for for 21 days in 28, give the usual asia. These were patients who are of any age who had higher risk mds. And uh the response rate, Well you normally expect a response rate of no more than 40%. Uh With these alone was 80%. So the real question before the jury is whether we should be using is event, which we're now using routinely in older adults with uh mls I showed you earlier. Well this should we should we use it in Mds? And I would say no, it is much more mild suppression. Mr President and the drug company is going to mount uh and dr Garcia will be the national lead of your same is V. L. A. It's going to be easy versus is abandoned. High risk and be at higher risk Mds. So I think still I still think that trial should be done and hopefully we won't have trouble accruing to it. Uh This is looking at the uh patients who received either event at the recommended face. Who knows who received them at a lower dose and not bad for high risk MBS Again, median survival is not good to look at, but it's looks like it's going to be north of a couple of years and that would be nice. We'll see uh if that really makes a difference. Have an interstate was presented by our old friend Mikhail Sekeras is now in Miami plus a society and permanent stat uh is uh interesting drug from the Takeda former uh Takeda company which is a net activating enzyme inhibitor. That's a mouthful. But basically the one short of it is it causes the degradation proteins you probably don't want if you want to kill the cast yourself and permanent said it's easier to give with deciding than is veneta class. So this is often talked about his kindler general therapy that is event for MDS. And this was a large trial in high risk Mds high risk. Um El Lobo last can am L the kale presented just the high risk of the escort and try to make the case that the overall response rate was higher. And uh have a Visa that it wasn't a visa. Okay, that's good. So what the median time to first permission was four months, which is about the same as it was in a society. And it's a slow onset of permission Unlike the a. seven, which is a much quicker commission uh achievement. Was it better in terms of event free or overall survival? Well kind disorder. It wasn't really power to see this, but there was a trend in favor of over event free survival. I mean, statistically significant improvement in then for survival in a trend towards improvement overall survival. So whether a larger trial would have shown up differences unclear. So in summary was uh Mds, what can we do now? Uh uh We have actually two recently approved agents which are worth mentioning uh they weren't new to ask this year, but still pretty new uh for lower risk disease. We're still using that a little mite alone in five Q minus. We have, we're stuck with erythropoietin. Maybe you were three potent plus a little little man. Uh Unapproved for low risk Mds. We have low dose fundamentally agent therapy. three days. Three days have decided me every month. We can use uh and loose pet Herceptin sF three B one mutant of those with links to the blast. We often have an S. F. Three B one year. It is quite potent in that subgroup does have a side effect of fatigue in some patients. So we've made some strides and low risk disease, high risk disease. We're still using H. M. A. Is the standard of care. The hmm can be our old friends decided me in order, uh, deciding. But it can also be the oral decide to be inserted into the emanates inhibitor, Which was called s. t. x. 7- seven. Uh uh and I won't say the trade name, although I will say it has a. Q. And it is not followed by you. So it's interesting english I think uh we still try to transplant these votes if possible. Especially based on the first trial you heard about today, which was presented by color. Uh this is uh donor versus no donor in high risk mds. There was a big improvement in a three year old war survival. If you were randomized. If you had a donor and could get a transplant, I will say that who knows what's gonna happen. Uh now that we have is event or we'll have a live event that's going to improve the outcome in the so called no donor patients. We don't know that yet In the P 53 mutant mds. Uh there was another press release that followed Ash. Looking at the Phase three trial of is a plus a pr 246 at P. V. Three re folding agent I mentioned. Unfortunately, the primary endpoint of improved response rate was not met in that trial. So, our initial enthusiasm for a P. R. 246 plus is having a high response rate was dimmed. Unfortunately. By this press release, we have some interesting new drugs on the horizon. Uh Anti city 47 like mackerel amount I showed you for Ml could certainly be used in MDS as being used in Mds. And the pen is that net activating enzyme inhibitor that I showed you is also being tested in uh, MDS. So I hope you've had your interest piqued by this. Talk about AML M. D. S. We got a lot of new ideas, A lot of new drugs need to learn how to combine them more effectively. I'd like to thank uh all the nice folks across the world. Uh many of them were friends who who said slide so I can do this talk. And I would particularly like to thank my colleagues, especially dan and all the other people who work so hard on with our patients. And I lied Golinski whose name I won't mention so I won't get hurt later in the day. Uh and of course our wonderful scientists uh ah who do some amazing work at Dana Farber and people throughout the world work with us on these things. So thank you very much. Please ask questions or contact me anytime. Thanks a lot. Thanks Rich. That was a great talk. And really remarkable evolution of therapy over the past few years in in these diseases. Um a couple of questions regarding banana clacks and this is certainly something we see when these patients are admitted to the hospital was significant milo suppression. How do you manage that when you're using it during induction or? Um And the question also comes up about antifungal prophylaxis. I think he said we don't generally do it. But um if you could discuss that the antifungal prophylaxis but you know I at least talking to our I. D. Colleagues uh they don't feel strongly about using easels in the upfront setting. At least at our place. We don't see a lot of uh initial infections in people who get this regimen. So I don't use it. But if you are going to use a is all objections to it. You need to reduce the dose of banana clacks according to the scheme. And I showed it doesn't seem to compromise the advocacy. So it's just a from a pharmacologic thing. You're just going to pay attention to it. I mean I will tell you that if the venue clerks doses level is higher, I'm not sure that's necessarily a bad, you know, terribly bad. But because we were using 800 mg of banana clocks and the phase one trials without too many problems anyway. The more important question though is the mouse suppression question and it is more mile suppressive. So the first thing I'll say is you should do a bone marrow. If you give me an older adult ace event, you should do a bone marrow about 3-3 and a half weeks after you start. Just like we do a day 14 mayor with three and 7 because the low counts they get at that point could be due to the failure to respond. In which case you keep them on the vent and give them more iza. Or it could be due to mild suppression, in which case you stopped the van and wait till they recover before you give the next cycle. Uh And that's really the most important thing. As far as growth factors. Uh You know, I think other institutions are more comfortable than we are giving them, but certainly I would have no problem giving them in subsequent cycles. Help patients get to the next is a dose. Great thank you. Um I think uh for the sake of time we're probably going to move on. But thanks again for outstanding talk. Published Created by
