This video features Asya Varshavsky-Yanovsky, MD, PhD presenting on Myelodysplastic Syndrome. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
Hello, my name is Issy and I will review updates in classification and management of M T S. Here are my disclosures addresses for today are to review the two updated M T S classifications that came out in 2022 as well as a novel risk classification model incorporating informational data. We will also review updates in management of low risk MS and high risk. MS Mao dysplastic syndromes are a group of clonal hematopoietic stem cells disorders that are characterized by morphological dyslexia, ineffective hematosis resulting in peripheral blood cell opinions as well as risk of progression of my chema. As we know clinically, it's a very heterogeneous group of conditions ranging from very indolent to very rapidly progressive. And this is related to uh the genetic heterogeneity of the Mystic syndromes. Here we see uh results of analysis of almost 3000 of M DS patient samples. Uh and we can see how many different mutations are here that can drive the disease and cytogenetic abnormalities are shown in and uh everything else is mutation. So we can see actually how much mutations matter. And this leads us to the need of uh classifications that would account for all these potential drivers. And to remind that up until very recently, we've been using the W H 0 2016 classifications that is mostly looking with morphological features of disease such as a percentage of blasts and the number of these plastic lineages. And the only group that is actually driven uh by uh molecular abnormality is M DS with deletion five Q, which as we know is indeed a very unique subtype of M DS. However, it does not account for all this wide variety of mutations that can be driving the disease of vessel. And therefore, not surprisingly, in 22 2 different group came up with two new classification systems W 0 2016 and the international consensus classification both are incorporating molecular drivers. So let's take a look at W H 0 2022. 1st, we still have morphologically defined uh subclasses um that we are familiar with MD SI B one and I B two M DS. Increased blasts are some old E one and E B two with different name. Uh There are 10, 2 new uh morphological subclasses M DS with fibrosis and increased blasts that we have always known. It's bad news and hyperplastic M DS is the one that tends to respond to immunosuppressive therapy sometimes uh no longer a number of the lines. So, but we have additional molecular subgroups. In addition to deletion five Q s of the head, we also have M DS with low blasts and sub one mutations that can overlap this MD with blasts and M DS with bili ty P 53 in activation. So, what is bio, um it really matters, uh how much functional to 53 the patient has left. And so when boils are inactivated, the prognosis tends to be much worse and how the diagnosis and activated is if we have a mutation and 17 P deletion. So when the is a is mutated, if you have two more mutations, it's trickier because they can actually happen on the same, but it clearly rises of suspicion. And then if you have a copy neutral loss of hetero and a mutation, uh so, so far, it makes a lot of sense. Uh Let's look at the second classification, which is uh uh international consensus. First of all, what is really different here is uh the new uh subclass of M DS M L overlap, which is basically M DS X plus two. So as investigators felt that uh M DS has over 10% blasts is biologically equivalent to M L. And very importantly, they recommended that these patients uh should be treated by uh this either M DS directed or M L directed therapist and also can be enrolled in clinical trials for both M DS and M L. So it can make huge difference for these patients. And they will also help us learn more about uh this subtype. Now, they also have a a van driven disease, deletion five Q. And they have um whole sub classification of uh different uh classes of tre mutated disease, including um multi heat with low blasts. And uh the scar blasts. Uh They allowed their Children just one mutated a little because of prognosis. Their health was um very poor already. Um And uh of course, as soon as the classification uh came out, um it's very important to see uh how it translates to real life, how uh biologically different uh the subgroups really are. And here comes um this presentation from it, uh recent ash with a catchy name of a product of clash of titans or the reflection of this disease biology. And the, the investigators at MORPH, it looked at over 2000 patients uh who had four emergency put in the data and also had 45 years follow up and they reclassified them according to both classifications. And here are survival cures. And first of all, we can see that some of the cures are actually very separate and very distinct. Um while others are I pretty much together, which does not mean that this classification is not meaningful because it may be two very biologically different subtypes with different targeted therapists that just happen to ultimately have a same overall survival. But what we can tell, first of all, uh the most striking finding here is that patients with a sub one mutation are doing wonderfully this overall survival of almost 10 years and also variation of P 53 driven disease uh is really bad. Uh This overall survival of 11 13, 14.5 months. Uh We can also tell us that mjs M M with than P 53 is indeed worse than MJ S with MU than T P 53. The statistically significant difference between 11 and 14 months overall survival. However, numerical is a difference probably is not very meaningful. Uh There are many other findings we can do from here such as M DS with fibrosis indeed is worse than just M DS with increased plus. And the, the number of dysplastic linear just matters based on IC C. Um So maybe um it was not very good to remove it from W H O. Uh but to summarize um both systems are great but not perfect. And maybe in the future, we will have one unified systems that takes the best out of as the best out of both. But what I know for sure is S F three B one pertains excellent prognosis. While uh bios of TB 53 pertains very poor prognosis, which we have known for a long time. And uh another question is uh we are still not sure if 10% blasts is um the most meaningful cut off to define the M DS M L subgroup or actually uh patients with 7% blasts are not that biologically different but clearly and obviously, more blasts uh is worse. So now that leads us to the need um in a better prognostic score system because uh we've been using I DS S R as uh our standard and best uh prognostication system and, and it's good. Uh but it's only taking into account cytogenetics and uh cyto opinion and the percentage of lasts. And again, we know that some patients may really be mis stratified, some of a patient um presenting with still discos and not very many blasts, but by 50 still loss. And the knows that this patient is going pro progress very rapidly. However, by IP S S A, they may actually fall into intermediate risk and this will not reflect the true prognosis. So we need to uh we need the new systems that would incorporate mutations and here comes I S S M that uh looked at all almost 3000 patients um in the International Working Group Court. And um they came up with um some factors um that uh uh are more uh significant in terms of prognosis. And so ultimately, Mark is a model uh that accounts for all those factors. And here as a result, uh the patients are stratified from very low risk to very high risk and survival groups are very significantly separated for the subgroups. And uh when we are looking at the patients classified by IP S S R and reclassified by IP S S M, we can see that many patients were upstage and very few patients were downstage. And again, it's not surprising that because uh this will be all these typically three mutated patients. And uh as a report prognos prognosis mutations such as the one that just happened to be in intermediate or maybe high risk by the whole classification. So this is a no calculator. Um It's really very user friendly. Um and I'm using it now uh for all my new patients. And of course, um when the system came out, the Real world validation immediately came out and was presented at a and uh without spending much time on it, we can see that uh in this uh large real world cohort of patients treated according to the standard of care, the survival curs are very consistent with the original ones. OK. So more than going to the updates in management uh and let's start with lower risk and, and uh also updates that I'm gonna mention uh the potential to management of engineer. Uh And I want to go over two very well known to us drugs and one very promising investigational drug me. So limit, limit and low risk M DS. Um This deletion five Q uh is a very well established standard of care. Uh So the study M DS 004 was published in 2011. And patients who are uh this um uh deletion five Q M DS who are transfusion dependent. We randomized the two doses of raid versus placebo. And as the primary end point of six months, trans independence uh was met in 56% of patients treated with 10 mg of raid and almost none in the placebo group. There were also cytogenetic responses and based on the study was approved specifically in this integration. Uh there was another study that extended it to non deletion, five Q patients. Uh and there were some responses but much more modest. So this is currently our preferred treatment for this population. But uh what about patients who are not transfusion dependent? So, um imagine this your patient uh with uh low risk with deletion five Q and they have these counts, maybe a little bit of neutropenia and their hemoglobin is 10.5. So, what are we normally gonna do with these patients? Observe because they do not have indications for therapist. They are doing well. They're not needing transfusions. We know they are gonna need transfusions in the near future. That's a biological disease. But standard of care of these patients is not to expose them to potentially toxic treatments and observe. And so here comes the center study um that is randomizing patients with deletion five Q who are not transfusion dependent with medium hemoglobin of 10, including criteria less than 12. And it gives this patients either limit five mg uh continuously for two years or placebo and primary point is time to transfusion dependence. And let's look. So this to me is very striking. Uh patients who were treated with essentially uh most of them did not get the transfusion depend. It was very long follow up of five years. Patients who did not have uh who who were treated with uh had me attempt the transfusion dependence of 11 months. Now, that is very exciting. But they do have concerns at that point because uh can potentially cause secondary malign is that the cancer that the more aggressive clone, it may accelerate time tele chemical pollution, the reticular. So they looked at that, let's see. Um So our biggest concern in this context would be T P F the patients and they did have 20% of typical patient in both uh groups and actually variantly frequency for the 53 1 was decreased uh in the rev group compared to placebo. Also, they have very deep cytogenetic responses. 87% of patients have complete cytogenetic response and most of them had decrease in variant frequency. So I think this data can potentially become a practice changing because uh from the results, um they may think that this potentially may be um disease modifying therapy. Uh toxicities were minimal and as expected from W MA mild eye and the skin toxicities. So that's our first bit of date. Now, um let's move to the second track that we also know about about the spider set. So that is at the inhibitor that releases a block on late stage maturation of er precursors in um Cibro blast, uh M DS. And it was approved in 20 for the patient with um M DS with ring blast who have failed erin stimulating based on status. It showed a 30% 38% rate of transfusion independence uh of eight weeks longer patients. Um So, it's recommended by N C C for this patients group. Um There was also MD studies that um enrolled uh also non cro blast patients and they also derived some benefit but it's not approved at that time. Uh So let's look at the updates from the studies that were presented at recent ash me study was not specifically powered to assess P F S or OS, but they still looked. And what we see here is these four curves. Uh So the uh dark red cure is patients who uh have responded to those. And the orange cure is those patients who were nonresponder. And the great cure is patients who were randomized to placebo. And this uh great cure is uh placed responders so called. So basically patients who uh were not treated with the spider but still were considered independent. And that's a very, very tiny group of patients. And what we can see from here is uh first four patients who responded to those cept um lived longer compared to those who didn't respond to those. And we can think of it as uh probably it was selection of ba risk patients, the one who responded. However, there is also significant overall survival difference between patients who were treated and responded to the spa uh compared to patients who were randomized to placebo. So we can conclude uh that there is a subgroup of patients who actually get survival benefit from treatment as the and they think it is very encouraging because they are using this drug. So I just want to briefly mention uh this uh not yet approved investigation drug. Uh It's a Telemar inhibitor. And uh the study looked at patients with uh low risk and who were very transfusion dependent. Uh these high requirements and it was a very small study. But important finding is um overall 42 patients achieved some response. But the majority of patients who achieved transfusion independence with this drug maintained for a very, very long time and 29% maintained for over one year. And that is very promising and likely will become uh an option for our patients soon. So the component for anem management in low risk can uh consider starting glow dose five mg, early five patients. It can actually be practice changing and maybe this is modified potential survival benefit is a spider and low risk patients with cera blast is androgen and we are waiting for more data on email. So moving on for the high risk patients. Uh and honestly, there are not many of these because we are waiting for the readout for uh from the three major randomized studies. Uh But uh let's focus on some uh on what we have now and what we are looking for. So, let's talk about oral and uh this drug was approved in 2020 based on the results of a certain stam uh the the is it's rapidly metabolized uh when taken orally by uh Sagen Dana. And so it's coupled with as an inhibitor of this enzyme. And uh in this form, the drug has excellent bi availability. And the original certain study actually had intra partial comparison of uh exposure and P K and the ventilation pattern. And it was identical with the I V and oral formulation. Uh overall response rate of 60% and 21%. They are are favorably compared to what our expectations are from uh simulation, hyper and high, high risk and death. Uh So it, it's a good drug. Uh But let's look at the update from recent ash. They did subgroup analysis specifically for T P 50 discriminated patients. And one of the reason it's important is because it again demonstrates uh how important is to um stratify the typical to stimulate the patients into biel and monolith. Uh because the outcomes were very different for these two groups of patients. Uh patients with monoliths were quite close to the vial type patients and patients with bi mutations had much poorer outcome. But overall uh survival in all three subgroups. Uh again, quite favorably compares to historical controls with a H MA s. And so it just uh confirms that the oral B is an effective drug and it's very convenient compared to the I V administration. So we should really be encouraged to use this drug. Couple of words um about Vaneta Clocks. Um So Vaneta Clocks um is not actually approved for M DS, but they did receive breakthrough designation uh for high risk MJ S M combination by D A and is supported by C C N guidelines. And these days, it's actually approved by most insurance companies. Uh in this education breakthrough designation was based on the phase one B uh study in treatment naive high risk families, patients who received a standard schedule of days and 14 days schedule of a class and the overall response rate was 80% which clearly is higher from uh higher than what we see. The single version Hyper is 40% C R. Then it's a deep response and the responses were seen as early as psycho one, which is a huge difference um from normal dynamics of response uh the singular Hyper and it is similar to what we see in Malpas data with. And that makes it a really great option for uh patients who are being breached for our genetic transplant when we wanted to bug them and we want to do it rapidly. However, er it's still a phase one B study and uh it's still a breakthrough designation. And we're waiting for the results of a phase three randomized trial. And hopefully we will find out soon two more drugs that are not yet approved. Uh But uh there is some promise. Uh First drug I want to mention, I'm personally very excited about is my problem. And that is Mafi checkpoint inhibitor. It's an antibiotic to uh CD 47 checkpoint molecules that transmit do not eat me signal to mas. Uh Again, we have a phase one B study uh that looks very promising response to certain and causing them to stimulate the population. It does have uh an interesting on target toxicity. Uh C 47 is also expressed on red cells and therefore there is a risk of hemolysis. Uh But luckily, it only happens with first couple of doses and prime do. Is it so very promising? Waiting for the first three randomized study called enhanced readout that will happen soon. Um And the last drug I want to mention is another checkpoint inhibitor, this very interesting mechanism of activity. Um So it's an antibiotic to Tim, which is an immunomodulator expressed on immune system cells, but also leukemic stem cells. So this uh may have dual activities, checkpoint inhibitor but also direct the antibody cytotoxic. However, as promising as it looked, uh the first results from the randomized phase to study the stimulus and did not show a difference in P S uh between um and place in combination with ma uh so one potential encourage finding from this study is for those patients who have achieved C R duration of C R was much longer. Uh The sub compare compared to placebo, which makes a sense that maybe our expectations from immunotherapy in my malignancy should be different. And maybe the main role of these drugs would be to help maintain reunion, which is also very meaningful endpoint. So to summarize uh high risk contest uh or, or is an effective and convening treatment option, the nela in combination with a induces deep and fast responses and therefore excellent option for a transplant. But we are awaiting survival with the and uh we will be looking for is a final readout of the and sub or maybe find a place for immunotherapy drugs uh in these settings. And that's all I wanted to review for today. Thank you.