Chapters Transcript Video Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia and the Myeloproliferative Neoplasms: Updates from ASH 2020 Happy New Year, everyone, let's say, how do I wear my slide? There we go. These are my disclosures. We'll be having some off label discussion that's added here. Of course, the big problem this year is getting through the pandemic. Each of us had her own approach. My wife's approach was to start baking, which did not do well from my waistline. Uh my approach I thought was a little bit more fun. I got a new puppy. So, uh and here he is, although now he's one. And of course, I hope that each of us are uh in line to get our vaccine, which will hope we put an end to this horrible situation that we found ourselves in. Well, I'm like our last presentation. I just have a lot of topics to discover and to discuss, I should say. Um and so I wanted to do more of a topical analysis. Uh, acute lymphoblastic leukemia will be the first topic. Uh and the way I think about acute lymphoblastic leukemia as I divide the world into those that are philadelphia positive in philadelphia negative. And then patients are subdivided into different age groups. Uh A. Y. A. Defined as less than 40 arbitrarily adult and an older adult. And then there's different regimens that are being used for each of these. The pediatric regiments is something that we've developed here at the DFc. I. Uh has really become now the standard of care for patients under age 40. Uh And uh and then adult regiments and lower intensity regiments for the for the older group. And of course for those patients who are philadelphia positive, the addiction of a tiki. Uh huh. In terms of uh new drugs that have been approved over the last few years, there's three drugs in A. L. L. And you'll see these incorporated into into regiments. Blenda to modify specific T. Cell engage er uh for cd 19 positive A. L. L. I know to Zermatt which is a classical antibody drug. Conjugate proceeding 22 positive A. L. L. And then to send a colossal is the only car T. Cell approved in A. L. L. But its use is limited to those patients who are under 26. So the first uh abstract is from the group in Chicago when the stocks where they took. The It has become a standard approach which is pediatric regimens uh in young patients and expanded it the older patients up to age 60. And this is a very brief abstract but I wanted to show you that you can take these regiments and and and I think they can improve outcomes. So the big key thing here was that they reduced the dose of peg elated disparage ennis. We'll come back to that in the next abstract, unregulated disparaging. This is the only a spirit Dennis uh that's approved in the United States for newly diagnosed patients. But it does have some have had a toxicity. Uh You can see here that the upper age limit here was 60. So again all of these patients are receiving a pediatric regiment. Uh And the only difference was for older patients getting a dose reduction of the regulated disparage Innis. Uh The response rates were, you know, really astoundingly high, including those patients who are able to get to an M. R. D. Negative status. And then if you look at the overall survival and event free survival uh these uh in comparison to what you would expect for standard regiments. Uh This is uh really taken off. We need larger number of patients in order to adapt this. There will be an ongoing clinical trial using a newer Aborigines preparation, very similar to this type of analysis using a pediatric regiment for older patients. And so, uh, this very well may be where the field is going just to take a step back. However, these are not without other toxicities. I mentioned that regulated disparaging causes some patio toxicity. Our site here led by Marley's lesson uh and the honest Valdez uh, super resident in our group looked at outcomes specifically looking at morbidity, bone morbidity for patients who received these pediatric regiments. Uh and again, just to set the stage. If you look at the left Kaplan Meier curves, this is the standard of care options for adult patients, uh using adult regimens uh with a five year survival of less than 50%. And then on the right hand, Kaplan Meier curves, You know, the pediatric regiments that we have a platform at the DFC. I, this was up to age 50 presentation. I just showed you was up to age 60, but you can see the market improvements, albeit non randomized studies. What we did is a retrospective analysis looking at the risk of Osteonecrosis, uh, and uh, growth plate fractures in patients who received pediatric regiments. And we looked at patients from 15 to 50. Uh, so a broad swath of patients. And you can see here that the overall incidents of osteonecrosis was about 17% with almost half of those patients requiring some surgical procedure, often a hip or knee replacement. And then again, about 12% of patients, uh, had a growth plate fracture of about a third required a surgical intervention. Uh, if you look at some of the risks for these groups of patients may be surprising that younger age was a risk for development of osteonecrosis. And here we just arbitrarily split the group between uh 15 to 30 and 30 to 50. And it was that this was the the age cut off that had the most dramatic difference. Obviously this is a ages of linear variable. So you can see an increased and there was an increase across all age groups, but it really was the younger patients who unfortunately suffered more osteonecrosis uh as opposed to our older patients. And you don't see austin of process interestingly and the very young in the pediatric population, but that was not studied here and then in terms of of one of the risk, in terms of therapies. Uh one of the things that has been done is we've increased the density of dexamethasone, the steroid. And we thought that that was going to be the issue. But actually it was not, it was the switch from native e. Coli asparagus depopulated disparage Dennis in the United States. You can't get Native E coli disparage nights anymore. And there's good reason for that because it's less effective. It has a shorter half life. And the peg elated form is a safer and and be you know, is more efficacious. But you can see here that it does lead to more osteonecrosis and likely due to differences in the metabolism of dexamethasone. Uh regulated disparaging. This causes a reduction in the outdoor movement, which is a drug dependent issue. And therefore it changes the farm uh kinetics and dynamics of dexamethasone, which likely affects the bone morbidity. And of course now ongoing studies to rectify this may be additional vitamin D. Calcium and orbits fascinates to try and minimize toxicity. And to moving on to some of the therapeutic studies. Uh This was one of my uh favorite studies presented by my friend Mathias Stella's from the german group. And this was an adult study uh starting at age 50 and going into older adults I included in this section here uh and the what he showed is, you know, older adult patients, as I've already shown you have a poorer survival in terms of both remission rate as well as early, higher early death as well as a lower overall survival. And one of the approaches that he took in the german A. L. L. Group was instead of starting with chemotherapy is why not take use of some of these novel biologic agents. And so I thought this was just a spectacularly interesting approach where he gave three cycles each cycles a month, three cycles of single agent in A to Z mob with some intra physical therapy to prophylaxis the central nervous system. And was able to sidle reduce before starting chemotherapy. And of course the approach that many of us have taken is the exact opposite. Start with chemo and then use the biologics later. And so this was a a reversal in that approach. Uh And this is just based on the china twosome ab portion alone. Right? So patients are just getting antibody drug conjugate which can be given as an outpatient. Uh And 100% of patients. Again small number of patients studied 30 but 100% of patients went into remission. Uh Most patients were able to complete all three cycles. And a large percentage of these patients actually had an M. R. D. Negative remission 78%. Uh And this resulted in a overall survival and event free survival here. Uh This is limited by short follow up small number of patients but I thought this was a very intriguing approach. Uh The Alliance study uh currently in the Relapse Refractory is using Itunes Man followed by another novel agent called Glinda to mob. But these type of approach is where we're were shying away from chemotherapy either early or late. And I'll show you in the next slide is the theme for acute lymphoblastic leukemia. Now that we have a lot more tools in our armamentarium. And that brings us to the next abstract from the M. D. Anderson. M. D. Anderson has piloted for almost two decades now Hypersea vod which is not a trivial chemotherapy regimen. It's intensive as it's very mild of suppressive. Uh And there are certain disadvantages specifically in patients who are older. And so what the M. D. Anderson has done Is to take the Hypersea bad and cut it off at four alternating cycles were typically it's eight alternating cycles which is very tough to get through for those of you who have used it. And then after four cycles of alternating uh C. V. A. D. Which is the calculating and three cycling portion followed by the even cycles which is the high dose methotrexate site to rabin. They administer four sequential cycles of blended to map. And this is standard dose blend into a mob four weeks of continuous infusion to man, followed by a two week break. And then patients who do not go to transplant and transplantations encouraged for high risk patients, patients then receive a year of maintenance therapy as opposed to the two years. Uh and again a small number of patients. But uh this is the patient characteristics and so patients that were adults 17-60 median age was 37. So younger than the abstract I just presented. Um there were a substantial number of patients just by happenstance that had high risk side of genetics and those are outlined in red. Having said that, however, the vast majority of patients were able to go into remission here. The remission induction rate was about 80%. Which is not any different from high perceiving because remember these patients are getting high perceive that for the first four months of therapy. Uh And then, but what is different is that the patients, a large number of patients were then able to get into an M. R. D. Negative. You can see that 70% of patients were MRG negative at the end of induction, but another, almost 30% of patients, almost the entire cohort was able to get MRT negative after the blended to map. And there was no induction mortality. And so here is the albeit short, but here is the important relapse free survival. Uh And this is uh you know, there were some induction deaths after patients deduction and some deaths for patients who went to transplant. It's hard to fault the regiment. But this is an interesting idea where you can cut off the number of cycles of chemotherapy and switch to these novel biologic agents to not only get more patients into an MRT negative status but improve the relapse free survival. Uh And this shows the improvement of overall survival, although again, uh follow up will be necessary. So what can we learn from these four abstracts? I think there's a lot of new strategies for patients with acute lymphoblastic leukemia. Uh There's been just a huge uh interest in trying to get these biologic agents that are approved in the relapse refractory setting into upfront settings. Hopefully this will improve survival. Uh Equally important if not more important, decrease the site of toxicity of the chemotherapy regiment. Uh As I've started the A. Y. A. Or pediatric regiments are associated with improved survival. I do believe these are the standard of care but but it's important to be on the on the lookout for some interesting and important toxicity specifically bone morbidity. Uh In our younger age population. Uh The next topic is our older patient population which struggled even to receive some of the basic chemotherapy. Uh This is the reduction in the overall survival based on C. L. G. B. Data but this is the data that we have and you can see the poultry data for patients who are over 60. Uh So obviously this is an unmet need. Uh Again led by the M. D. Anderson group is to take the high perceive AD Model and reduce it significantly. So all the doses of the drugs are reduced by 50%. Uh And you can see that in the next slide actually are reduced by 50%. Uh And there's no and three cycling here. So there's really no no reason that there should be an upper age limit. Uh And what is administered is an A. To Z. Map during the first four cycles. Uh This was the original design and then this has been modified uh a little bit two fraction eight. The Natuzzi map uh cut the number of cycles very similar to what I showed you in the younger group of patients to only four alternating cycles and then add blend and to map. So again this particular approach uses all of the novel agents uh china tourism ab with low dose chemotherapy initially and then uh blend into a mob to follow and then a short and maintenance of one year as opposed to the two years of maintenance. Uh These are the demographics and patients up to age 80 were included including some very high risk patient population. And p 53 was noted in a substantial proportion of patients. What's important here is almost 100% of patients were able to get remission again. Earlier use of an A. To Z. Mob as we've seen from the german group and now from the M. D. Anderson group I think is a theme that we need to take advantage of on the C. R. Rate was about 90%. And the vast majority of these patients were able to achieve a very deep remission. Looking at the M. R. D. Response at the bottom of the slide. Uh And this translated into improvements in uh Relapse free survival as well as overall survival listed here, both on the curve. The overall survival uh and red and the relapse research survival uh in blue. And if you fraction eight this by age, you can see here that patients over age 70 which are in the blue curve. I still have an issue with some of the toxicity later on. Uh And so I think the new strategies are to try and address that uh in these older age groups with further dose reduction of the chemotherapy and taking advantage of these biologic agents uh in the future. And so what we learned from the single abstract and these elderly patients is that uh new and effective strategies for older patients, you know? Similar to a colleague Shweta, I think this upper this idea of an upper age limit is being targeted and hopefully removed. Lower intensity therapy with novel biologic agents is the theme last year I presented data to you with veneta Clacks being added to low dose chemotherapy. Uh And you know these are approaches that hopefully we'll uh uh it develop into a new standard of care. So if you have an older patient with A. L. L. Please do not hesitate to refer. I just want to say a couple words on car T cells. I I think it's a little bit at a context because there are no car T cells approved for older adult patients. As I mentioned camera or to send a colossal has approved only up to age 25. Uh And part of the reason is because of toxicity. And the test cartas or Zuma three trial has not yet read out. And we're hoping that it would be a positive study and lead to the first adult L. L. Carty sale. But one of the problems with car T cells in adult patients as toxicity. Uh And this is a fast off study. The problem with car T cells in terms of the design, I didn't want to go into too much detail is that the T cells sit on the uh on the tumor cell for for minutes, 2025 minutes. Which is the which is not a physiologic. Most of your T cells uh when they're going to be stimulated by the Andijan have an on operate of about 3 to 5 seconds. And here this was engineered with a T. Cell receptor where the operator is about Uh you know, 30 seconds or so. So it's more physiologic. Not quite perfect. And as you can see here, looking at cytokine release syndrome, neuro toxicity in other toxicities is much lower than what one would have anticipated from the traditional car t cells which have been very difficult to take advantage of in the adult setting If you just break this out, CRS was seen. But it was there was virtually no Grade three crs which requires pressers ICU stay. So none of that. And all of these patients could be treated with corticosteroids are uh tuscaloosa map so easily rectified in terms of neuro toxicity. Again, there was subtle neuro toxicity seen upgrade to And in one Grade 3 but again it was easily reversible. Uh and it was the site of penas uh and uh and whatnot. So I think that this represents a potentially less toxic approach and this is a trial that is ongoing at the DFC. I uh in spite of reducing the toxicity uh the efficacy did not seem to be abrogated. Patients were able to get into remission, patients were able to get into an M. R. D. Negative remission. And durability was seen here by by looking at the patients who were still in remission with the arrow. Uh It was fright to show a Kaplan Meier curves short follow up and here's the Kaplan Meier curves for this study which was very impressive. And one last thing is off the shelf card. You know, one of the problems with car T cells which I'm sure others will bring up is that you need a harvested T cells and it takes 2 to 4 weeks to make the cars. Uh It would be nice to have something in the freezer. And so this is an off the shelf car directed against cd 22. Uh This is an allergenic car. So basically a patient comes in with relapse. If their cd 22 positive you saw the car you give some immune suppressive immune limbo depleting chemotherapy and on you go, there's no need for bridging therapy. And this is a very early look in an al Akhar directed against Cd 22. This is a dose expansion. It was safe. There was one patient who actually entered a remission uh and this is a dose expansion uh as well as playing with the conditioning regimen is ongoing in this trial is also open at the DFC. I. Uh and this is just always nice to show you're responding patients. But we haven't had a huge amount of success in a low cars in general. And it's nice to show uh you know, the really remarkable success in this particular patient. Aloe cars are not durable and it's really viewed as a bridge to transplant. But this is very exciting to see such a wonderful outcome. So, in conclusion in this section, uh you know, careful attention to bone morbidity for R. A. Y. A. Patient's specifically with a vascular necrosis. Uh Monoclonal antibodies for relapse to L. L. Are now being incorporated into upfront regiments, specifically in a twosome have been blended to um have less uh intensive strategies seem to be effective in older patients and maybe can abrogate the need for long term side uh side of reductive chemotherapy and shorten the duration of chemotherapy. And then car T cells are currently being developed in our adult patients with the L. L. Uh We do have a myriad of active open trials at the farmer. So again, think about referring anybody with A. L. L. Uh to us moving on to the next topic, chronic myeloid leukemia, maybe a little bit more akin to uh for most of you who see this in in the outpatient world, there was actually a lot of interest in CML and I think uh two particular areas that are going to be disease changing. So this is the current landscape. 2021. We have four drugs that are FDA approved for up front, imatinib relative, this attentive and pursuit neve. There are three drugs that are approved for suboptimal or refractory or intolerance, relative disadvantage and pursuit nev Banana has approved 3rd line Uh in the United States or after uh utilization of other agents or in the setting of T315 I transplant is left uh maybe wrongly but it's left for those patients who really have no other options. And almost Cytisine is another agent that has has approved that we won't discuss. So out comes from the optic so pinatton if it has an interesting history. This was approved for patients who had previously received two or more TK ice or had a T 315 I because none of the first or second generation agents hit the T 315 I. And this was a drug that was approved. Then it was halted because of the incidents of of uh thrombosis and cardiovascular toxicity. Then it was reapproved uh With some modifications in the label and and those of us who use this agent a lot really struggle with what is the right starting dose. The initial dose was 45 mg per day. Is that really the right dose to start? And so this is a study that really try to address the question patients randomised to three starting 45 mg, 30 mg or 15 mg. And then there was a protocol specific reduction in the dose. Once a patient achieved remission, which was defined here as a VCR able one transcript level of less than 1%. So whenever you hit that transcript level, the dose of Panatta was reduced. Now what I have been doing uh and you'll see wrongly. So in my chronic phase chronic patients just starting at 30 which can abrogate much of the toxicity. But there's no data until now showing whether that was a right move or not. Uh There was lots of data presented. I'm trying to show you the money slides and this is that one. So here looking at the rate by 12 months in order to achieve a level of less than 1%. Whether you started at 15 30 or 45. And this was split up based on the response to the last tiki. I whether you had a response to the last tiki, I then switched or you were refractory to the last tiki. Which is always uh a poor prognosis. But regardless of whether you're in the red box or the black box, you can see that the higher dose was associated with the better overall response. And if you look at the prior number of TikiS s again less than two, more than two. And you can see the different graphs here again. The 45 mg starting dose, which was then reduced to 15 was associated with the better overall response. And if you add up all the different subgroups and there were more subgroups depending on whether you had a T. 315 I or no T 315 I. Or whether you had any other mutations. Or as I just showed you whether you're responsive to the last Tiki I or whether you had two or more prior Tiki I. So it was a large different group of patients. But however you sliced and diced it overall, the benefit was seen that it was more efficacious to start at 45 high And then reduced to 15. And the interesting thing here is that although starting at 15 clearly clearly resulted in no cardio cardiovascular toxicity are very little. The difference between starting at 30 and starting at 45 was insignificant. So The approach that I had been taken was wrong. Patients should be started at 45 and then dose reduced to 15 once they achieve a molecular remission, which is defined in this particular protocol of 1% based on quantitative PCR. And this led to a change in the label back in December. So again, this is an important label changing. This is really uh this is going to be adapted and incorporated to the FCC and guidelines of course. Uh so this is the way that penetrative should now be used for chronic phase CML inappropriate patients. Is that the starting dose is 45. Regardless if the patient has a T 315 I've regardless of whether the patient has to prior tiki s or three or more prior tks, whether the patient was resistant or intolerant and then dose reduction to 1 to 15 once the patient gets below 1%. So practice changing the next drug is not FDA approved yet, but will be likely by the third or fourth quarter. Uh This is a synonym formerly known as a bl 001 That was published. The Phase One study was published for patients with chronic phase CML about a year and a half ago in the new England Journal. And this is a for those of you who may not have heard this. This is a very novel agent. This is an agent that inhibits a mirror installation site. All of the FDA approved uh, tyrosine kinase inhibitors are ATP mimetic. And so it's not surprising that they may have similar toxicities. Mirror installation site is a negative regulator that is removed. And you can see that in the middle cartoon here is removed by the translocation. Bc. Are able therefore this negative modulation is no longer there, but a small molecule inhibitor in this case s imminent. IB. Is able to recapitulate this and bind to the merced elation site and deactivate the Kinect. So this is how this drug works. So it's very different than the other A TPM, a medic agents that we have all known that have changed the standard of care. So there's two abstracts they wanted to present. The first is a subset of patients. These are patients only harboring the T 315 I. Uh These patients uh uh There was about 50 patients that were enrolled. They got single agent as primitive. Uh There was a large range of doses, but the dose that's probably going to go to dose is going to be 200 mg twice a day. Uh And you can see here uh this is stratified based on whether the patients had previously seen punitive or whether they were punitive, naive. Uh and you can see if you haven't seen Panetta uh response rate is better. But regardless, I think this is a significant uh You know, practice changing because oftentimes when patients have a T. 315 I and if Panetta name is effective, that's great. But a pattern of platinum is not effective. There's just nothing else to administer. Or if a patient has some cardiovascular toxicity for which you do not want to administer punitive, you have now or potentially will have uh alternative option. And these are the four log and 4.5 log rates on single agent as primitive, showing that patients can even get into a very deep permission. And so again this will be submitted for FDA approval for the T 315 indication. Uh Probably more practice changing. Was this late breaking abstract from Andres Hothouse on behalf of the assembled group. This was a 3rd line study comparing as definitive to pursuit. Here is the uh study criterion. Study design. These are patients who have had two prior tiki s important to note that all patients uh no patient I should say could have a 315 I mutation or V 299 L. As both of these mutations are resistant to pursuit in it. And then patients were randomized to receive either 40 mg twice a day of SM Initiative or 500 mg once daily of the pseudonym. And I'll come back to that later. Uh The study endpoints was a two year major molecular response or a B. C. Are able level is less than 0.1%. Obviously important to show that the baseline characteristics were well stratified between the two groups. It was a 2 to 1 randomization and the money slide. This is the primary endpoint 24 I'm sorry, 24 weeks, not 24 months, 24 week mmr rate. I've asked some tentative versus Basu tip. And you can see that there was a significant improvement of 12%. Almost a doubling of the rate of MMr at 24 weeks in the assessment, NMR versus Basu DEV, which was statistically significant. And if you look at the cumulative incidence of MMR, the line shows that 24 week primary appointment you can see the cumulative incidence uh the curves continue to expand. Um And so here in third line that is patients who have had two prior Tks and have not responded uh than uh the use of SM initiative is better than pursuit nip. If you look at deeper responses, this is uh the saddle genetic remission rate which was a secondary endpoint again in favor of the Osama native arm. Statistically significant. If you look at the four log and 4.5 log remissions again, this is an early look. You'd expect this to happen a little bit later. Both were in favor of a synonym. And then very important the toxicity profile was in favor of assam in it. If you had more toxicity in the pursuit of art. And so I like to come back to that because you know this was the although this is the FDA approved dose of the pseudonym Uh those of you who know me and referred patients, I never start a patient in 500 mg of pursuit. Uh You can tolerate the son of a lot better if you started a lower dose of two or 300 then every couple of weeks you increase the dose of 400 typically is my max dose or 500. 400 is the FDA approved dose in newly diagnosed patients 500 relapse refractory. Very few patients are able to tolerate that due to diarrhea and liver function abnormalities you can see here. So I think the toxicity platform was was destined to be a negative study based on the study design, but the efficacy is the important issue. And there's no doubt that as diminutive is not only better tolerated, but it's more efficacious in this third line setting. Uh there are and there were very rare arterial exclusive events. And it's interesting that these events were predominantly seen in patients who had had prior to the lot number Panatta. Uh and that was higher in the estimate of although numerically one patient versus zero, these are very rare events. And We did not see a huge our signal in the Phase one study. But it's just something to be aware of. And lastly for this study, I just want to show there are new mutations, right? Nature is smarter than we are. So we always think about the kinds domain mutations in our 80 paramedics. And uh what we're seeing with the assimilated are these more installation mutations. So another site and obviously when this drug or if this drug gets FDA approved, which we expect in the third or fourth quarter for third or greater line of therapy, that this will be another area that will have to think about in terms of sequencing for patients who are resistant to estimate in a very briefly there is another drug as if we needed another drug for CML. But there is another drug of No batting. Um This is a pan tyrosine kinase that's being developed both in the United States and elsewhere. DR court has presented to face one data. It looks like the MTD is either 1 74 204 uh and just very briefly both in panettone. Um naive seen here and Panetta nib previously treated seen here. Uh we see durable responses. And so this may be another yet another agent that's being tested in the United States on ongoing clinical trials for patients who are intolerant or resistant to punitive. So again, more tools in the armamentarium for our chronic phase CML patients. So in conclusion CML uh optimal dose of Connecticut is now 45 mg per day. Uh And you are instructed to decrease this to 15 once a patient achieves A. B. C. Are able one transcript level of less than 1%. Uh This is a new FDA label as imaginative new mechanism of action. It's active in t. i albeit at a high dose The randomized study and 3rd line it was superior to the pseudonym uh awaiting FDA approval. And then a Battle bat Nab is another novel agent uh that is being developed for banana refractory patients. So on to the last topic that I've been assigned uh is uh milo proliferate disorders. Uh those of you who know me, I've I've spent the last 15 years looking at patients with systemic Moscow psychosis and just a couple of words uh we looked at are just looking at the bone marrow response. This is a complicated disease. Uh This is a drug, have a print in it, which is selective kit inhibitor. And you can see here some of the waterfall plots in terms of response in a representative patient who was on the study that we've treated. This is a very active drug. It's very tricky in terms of establishing response. It includes uh you know, both laboratory studies uh bone marrow studies. It includes radiographic studies as well as the reversal of organ damage. And so you can have, it can be very tricky in terms of defining remission. What we did in this presentation at Ash is a very simple look, just like we would lymphoma or leukemia. It just looking at the pathology and whether a patient is in remission or not. In this particular study, which I didn't include in the slide, 80% of patients are responders, 50% achieved a cr CR H and another 30% a partial remission. And you can see here that the Kaplan meier curves for outcome is dramatic. Of course responders always do better than non responders, but the degree of response is profound. And and the important thing is when you're defining a new a new way of defining response is that your definition of a responding patients make sense. And so we're hoping that this will make this a much more easily achievable criteria for adjudicating response and then open it up to patients, even those patients without c findings. Uh One last abstract on Moscow psychosis Before moving on to milo fibrosis was the pioneer study. This was a randomized phase to an indolent systemic masto psychosis uh and we presented last year and again updated this year That in this randomized Phase two study that three different dose levels in the first panel all showed response as compared to placebo. And the two other panels. These are called spider plots. Where you're looking at patients symptom symptoms scored. The goal of this study was to reduce the symptoms and you can see that the 25 mg dose, reduce the symptoms all across the board uh in patients as compared to placebo. Interestingly, there was no placebo effect in this particular study. And if you look at the quantifiable uh markers of objective markers of mass cell proliferation that we saw reductions in Mastel at the at the treatment dose as compared to those patients treated placebo. And this randomized Phase two trial is now Uh enrolling uh to large trial of about 250 patients. And this is opened at the d. f. c. i. So next and finally our milo fibrosis patients. These are patients that are very difficult to treat. As you all know. These are older patients. These are patients who suffer from disease, risk of disease progression to leukemia proliferation and both the spleen and other organs, which can lead to severe cachexia and anorexia. Uh It was a lovely study uh which is another study that we have open using a brahmin domain inhibitor in combination with rocks, aluminium. Uh and this is a study uh in treatment naive. There's many arms to this study. This was one arm of the study and treatment naive and I just wanted to show you a couple of hallmarks. Of course the waterfall plots in terms of patients who had a splenic response are there. But this is a little bit higher than you would have expected from single agent russell in um uh but again, this is a single arm studies so there's no comparator or uh here is the total symptoms score again very, very responsive most patients and improvements in their symptoms. But this is the slide I wanted to show you is that with time there is improvement in the hemoglobin. A one of the problems with rocks. Aluminum is the on target jak inhibition of erythropoietin sis that leads to anemia and actually can take a patient who is not transfusion dependent and make them transfusion dependent. And here we can see the abrogation of that with this particular agent in a subset of patients. And so uh phase three study of comparing Russell Latina plus C. P I versus russell, let alone will be ongoing shortly. Another Jak inhibitor mama listen, um uh this is a drug that was tested in two studies presented and published. Now simplify one and simplified to both were turned down by the FDA. The FDA does now have a kinder gentler approach to the development of drugs. Mom aluminum has this interesting a modification of reception that can lead to improvement and hemoglobin. And so if you look at the simplify one, which was the randomized trial of Rocks versus a crossover, you can see that splenic response and duration of spleen response was slightly or at least non inferior in the more militant farm. Uh but this is important here is the duration of transfusion independence in mama little with superior. And again, this is looking at all patients have crossed over to mama lighten up. Those patients who are on mama linda or those patients who were treated initially with Rocks and the treatment duration or the transfusion independent duration is very important here. So this is obviously an interesting subset for patients that we all see who are very transfusion dependent. And this may be an alternative if the FDA is kind. And this is looking at those patients who had previously received rucks and now have crossed over to uh chamomile it nip this is the simplifies to study again showing the transfusion independence with single agent, Mom Melinda. Another agent will tell set this was presented both an M. D. S. I'm not sure if Dr stone is going to present that data, but this was the data presented in milo fibrosis. It has a novel mechanism of action. It actually inhibits uh telomere uh function. So it's a telomerase inhibitor. two doses were tested in Milo Fibrosis. You can't compare because it's not howard to look at the comparison, but you're able to see here the overall survival uh In patients with relapsed refractory milo fibrosis to prior Jak inhibitor, I just wanted to really show this one slide uh and that there were some patients. Again it's not power to show that, but there were some patients where there was reversal of the fibrosis, which obviously we're always thinking about in all of our patients. Because what we want to do is try to have a more of a disease modifying agent than just having the patients feel better and shrink their spleen. And so if this is real, which will take a larger study and there is a Phase three study that will be started. This could be a practice changing event. So, I just wanted to bring your attention to that. Uh these are two ongoing phase three studies the emetel set uh as well as in Jak inhibitor refractory as well as the addition of CP I plus rucks uh in newly diagnosed patients. So it's some important things. And so in conclusion for this part, in the last part of my talk is a bit pregnant, which is a very potent inhibitor shows a very high response rate for patients in advanced systemic massive psychosis. We await FDA approval for this agent. There is ongoing clinical trials in an indolent systemic masters of psychosis. You guys have any questions or this is a rare entity. But if you think of of patients, please let me know russell. It remains the standard of care for patients with intermediate to in high risk or for patients with symptomatic intermediate one basically spleen symptoms. The dragnet was FDA approved about two years ago. There's another JAK inhibitor was very similar issues. It's it's one pearl is that there's no dose reductions for patients with the low platelet count. So this is I used to draw primarily for patients where the platelet count is less than 100 because you do not require a dose reduction. There is no agent approved when the platelets are less than 50. We await the FDA review of Crit Nib specifically and thrown beside of panic patients. MaMA lit niB showed you the data and then there's the two novel agents and we'll tell SAT and the C. P. I. Agent that very well uh may have some practice changing our approach and phase three studies are in the plans and initiated. And obviously we still need some novel strategies for our advanced patients, specifically those who are Jack Refractory. So that's my presentation today. I know we've covered a lot of topics. I do want to thank my uh leukemia team. That's hard at work. I want to thank the investigators for sending me the slides and obviously the patients uh and their families for participating on these clinical trials. Because without participation we can't move the field forward. Uh These are my after a year, the puppy is no longer a puppy. Uh and uh and if you have any questions or if you need any help, please reach out to me. Thank you very much extend. Uh That was really a fantastic talk with a lot of really exciting data. We have a few questions. There was one general question uh about making PDFs available or information after this talk and we'll be sending out information to the participants as well as the recording so you can take a second look. Um Sure anybody of course. So dan for older and frail patients with A. L. L. Um Is it reasonable to think about using biologic agents only without chemo? How do you sort of see that evolving? Yeah. You know so so there is a strategy at the alliance you know Rich is the is the chair for the leukemia approach. It's it's still in its infancy. We're looking at cider reduction with china to sin mob and then following that up with blended to map it's now in the relapse refractory. We're just getting experience with that and then move in then we'll move it forward. Uh I think it's an interesting strategy. I think that you know the german strategy is just it's just incredibly interesting. And the question that I asked uh Matthias is is you've got such a great response. Why do you need to then hit the patients with chemo? The details from that presentation? Is the toxicity was in the chemo part, not the in a twosome. Apart, the approach that we've been taking is very low dose, very low dose chemotherapy and either augmenting it with china to sin mob or veneta clacks. And uh, and the question is, do you really need the chemotherapy? I mean, those are questions I think we're going to need to try and sort out, but you can see where the field is going. Market reduction in chemo uh, with addition of biologics or just no chemo and just using biologics. Uh, I think it's going to take a little while to sort that out. Rich may have some other comments later dan. Uh, in terms of your on the other age and of the, you know, the the outcomes are so much better with these pediatric inspired regimens. How do you see the incorporation of these novel agents for that patient population? Another phenomenal questions. So the trial that I'm leaving right now, again through the alliance is is the same pediatric trials that we've been using. Uh, and then uh, it's a randomized study, patients are randomized to receive an autism or not. You know, one of the difficult things that we do have is that although most patients get in remission 90% 90 95% of patients we get into remission. And I'm talking about pediatric patients now, is there still about 20% of patients who are MRT positive? 20 to 30% of patients who are MRT positive in spite of consolidation therapy. So about half the patients MRT positive at the end of induction, and then you can improve that after consolidation. And and those are patients who are destined to relapse. And those are patients who we target for transplant. But if you could add a biologic agent uh So I need to use a map in the relapse refractory setting has an 80% 80 80% remission rate and an 80% of those patients who go into remission get MRT negative. I'm talking about relapse refractory. If you can add that on to those patients who are M. R. D. Positive at the end of induction, for example, maybe you don't need transplant. And so the idea of taking, you know, this group of patients who are young, many of them haven't had their Children yet and be able to potentially affect a cure without the need for transplant is something that I would be thrilled to be a part of. And so that's where I think these biologic agents and I showed you studies where anna twosome as being included or Belinda Tomb as being included in uh you know the details have to be worked out with these studies. But these are ongoing large studies. And then maybe one last question. We had a couple of questions regarding um secondary mile of fibrosis and the role of Rexel IT nev. And some of these novel agents in that setting. So secondary meaning post PV or post et. Yeah. Those are all included. That's a phenomenal question. I should have been clearer and I'm sorry I wasn't. So in uh these strategies and although the presentations are suddenly different, they all included both primary as well as post policy, systemic and post essential thrombosis. Ischemic patients. So all three were included uh in all of these studies. And that's that's important. And we see responses across across the spectrum. And it's not just your Jack to it's jack to cal articulate and nipple. Uh It's the same pathway. The difficulty in treating patients in milo fibrosis, or those 5 to 10% that are triple negative uh motel set, interestingly, there was a separate presentation that may specifically target this very difficult to treat triple negative MF, but all three were included in those studies. I showed great, well, thank you so much for a great talk. Published Created by
