Roswell Park experts Elizabeth Griffiths, Pamela Sung and Eunice Wang present updates on treatment options and recent developments for these diseases.
My name is Elizabeth Griffiths. I'm one of the leukemia faculty at Roswell Park, and, uh, I've been given the opportunity to introduce my colleagues this afternoon. So, um, the first person to speak to us is going to speak to us about CML. I'd like to introduce you to Doctor Pamela Sung, uh, one of our fantastic junior faculty here, um, who will talk to us about CML and updates from the ASH meeting. Yeah All right. Thank you so much for coming back from lunch to hear about me. I'm a little too short to actually see my slides from here, um. All right, so I'll be, um, presenting some updates from, um, this past Ash, uh, for some abstracts on MPNs and CMLs. So my disclosures. Um, so just a brief outline, I have two abstracts that I've selected for, um, both of these disease subtypes. Um, really, I get, um, 25 minutes to go through 4 different diseases. Um, and so I will try to move quickly. Um, so first up is myeloproliferative neoplasms. Um, and this first abstract that I want to, um, present is, um, this, uh, phase 3 study of Pella restive repella versus plus rexolitinib versus placebo plus rexolitinib in JAK inhibitor naive patients with myelofibrosis. Study population here was dips intermediate risk or higher, um, splenomegaly, um, platelet count over 100. Uh, and, uh, TSS scores of only, uh, greater than or equal to 10, so that's, um, a bit low in terms of, um, symptomatology, uh, and no blasts and, um, good performance status. So this was a double blind randomization 1 to 1, um, Pellaresi plus rexolitinib versus placebo plus rexolitinib, um, and the primary endpoint here was an SVR 35 response at week 24, uh, and so this data was actually reported out, uh, I think in Nature Medicine. Um, with their primary analysis, and so this is now an update that was presented at this last week, last year's Ash. Um, and so what they presented before is that the week 24, they showed some increased SVR 35 responses and then updated at 96 weeks, they showed that this, um, is an ongoing response in terms of splenic volume reduction, um, in the, um, experimental arm with beheloreib, uh, with 91.5% of patients experiencing an SVR 35 response and that these responses seem to be durable at 96 weeks. There was a trend for an improved TSS 50 response at 96 weeks. There was not much of a difference at week 24. Um, these seem to increase a bit at week 96, but the, uh, differences do cross zero, and so these were not significant, uh, which is a bit of a disappointment given the, um, amount of SVR that was seen in the experimental arms. And so, um, they were surprised to see that the, um, improvement in these symptoms was not much better. There were no substantial differences in the hemoglobin responses. There was a um numerical increase in the amount of hemoglobin in the experimental arms, but again, there was not um a difference in patients who are receiving transfusions or um who had um significant anemia. The treatment emergent AEs at week 96, uh, overall very similar. I think the only major difference that I noted on this table is that, uh, there was a, an increase in the amount of dyscusia that was seen in the Pelleressive arm, uh, and so that's probably a, uh, drug related reaction, uh, but otherwise the, um, TEAEs were very similar across both cohorts. And, um, importantly, uh, in the initial analysis, they did see some increase in um leukemic transformation which was not significant but was worrisome at the 24 week time point. Um, this did not bear out with longer term follow up and so that seemed to even out, uh, at the 96 week follow up. Uh, and so I would just point out that there does not seem to be an increased risk of leukemic transformation with the Pellebrasa versus placebo. There was potential disease modifying activity of the combination. So, when looking at bone marrow fibrosis in the pella breast arm, there was 52.5% that had improvement in their, uh, marrow fibrosis, uh, versus 27.5% with the placebo. There was a decrease in the JAC-2 vari allele frequency. Um, again, not quite significant, but there does seem to be a trend towards that, um, it later cycles for decreasing in this JJAK-2 variele frequency. Uh, also looking into the bone marrow, um, morphology, they did see, um, decrease in reticulum and fiber density, um, a decrease in the megakocyte density, and then also an increase in the CD 71, which is the erythroid progenitor cells. And so there does seem that the marrow is trying to respond, trying to become more normalized, um, with this, um, BET inhibitor. And so, from the summary of this, the addition of Pellaresi to ruxolitinib showed ongoing improvement in spleen volume reduction at 96 weeks. The early signals of possible increased leukemic transformation was not seen with longer follow-up. Uh, and the secondary endpoints of absolute change in the total symptom score and the 50% reduction. Response showed trends for improvement with the combination but did not meet um statistical significance and so because of that the FDA did not approve this drug um even though it met its primary endpoint and they're actually proposing now another manifest 3 study now another randomized phase 3 study. Enrolling patients with higher baseline TSS with spleen volume and the symptom score as co-primary endpoints, uh, and so that, um, study is hoping, hopefully gonna be opening soon at Roswell Park for RJAK inhibitor naive myelofibrosis patients. All right. The next drug that I want to talk about is this INCA 033989, which I'll just call 989. This is a novel first in class mutant calreticulin-specific monoclonal antibody in patients with ET. And so what this drug is, is a unique mechanism of action. It is, um, high affinity for this mutant CalR and TPO receptor dimerization. Uh, and so it binds only to this, um, interface where it blocks the, um, TPO receptor from dimerizing and therefore decreases its downstream signaling, uh, as the mechanism of action in, um, both ET and MF that are CAR mutated. So there are two ongoing phase one studies looking at 989 in patients with ET and myelofibrosis, and I'm only gonna be touching on the ET, um, trial that was presented this past year. Um, so these are patients with ET CR mutated, high risk, um, and documented resistance or intolerance to greater than or equal to one line of prior cytoreductive therapy, have an elevated platelet count, and a concomitant therapy with agrelide or hydroxyurea was permitted. Primary endpoints, dose-limiting toxicities and TAAs. And so these were the platelet counts on these patients. Um, you can see at the, um, at these bar graphs that, um, there is a rapid decline in the number of platelets in these patients. So usually cycle 1 day 15 you can start seeing these responses. Uh, median duration of exposure was 45 weeks and. Um, of the 34 patients who had concomitant cytoreductive therapy, um, most of them were able to discontinue and remain unsteady. And median time to discontinuation of the cytoreductive therapy was 23 days. And so it does have a rapid response in the um platelets. Both at lower doses and at the higher doses. The drug seems to be well tolerated. These are the, um, treatment emergent, um, adverse events. Um, the most common grade 3 TEAEs uh were in neutropenia, uh, and anemia, um, and they noted that, um, these patients were also on concomitant hydroxyurea. Um, the reduction in mutant CR varied allele frequency occurred in 50 out of 52 valuable patients, um, and the best reduction, uh, was in 52%. Uh, and so, it does seem to be disease modifying in that way. And so the conclusions from this, uh, 989 is well tolerated in patients with ET who are resistant, uh, to prior cytoreductive therapy. There were no DLTs observed on this phase one trial and 93% of patients remained on treatment. There was a really rapid normalization of platelets. Uh, molecular responses were, um, present, and, um, they are now expanding this in a phase three study is planned for initiation in 2026, uh, and they're also developing a subcutaneous formulation for easier administration. So just a few of the other updates and MPNs that came out this year. There was in the Journal of Press releases, um, the phase 3 independence trial of loosepatercept with concomitant JAK inhibitor in myelofibrosis associated anemia did not meet its primary endpoint of RBC transfusion independence, um, but just barely. And then secondary endpoints of clinically meaningful benefit of decreased transfusion burn and hemoglobin increase favored the loose pattern steps. So we'll wait to see what those data show. Hopefully. Either sometime this summer or next Ash, uh, we'll get some more details on this trial. There were, um, additional studies of resvertide, uh, first in class hepcitomimetic and PV that showed a durable benefit of sustained, uh, control of hematocrit and absent need of lobotomies for up to 52 weeks. Uh, the crossover patients on that study also had similar benefits. Uh, another, um, abstract in PV, um, the shore span study of, um, LSD1 inhibitor, Bamademstat, um, showed also reduction in hematocrit by week 52, lasting 12+ weeks without phlebotomy. Um, this is additionally being tested in a phase 3, in previously treated ET which we are enrolling at Roswell as well. And then this phase to enable study, um, this is a, um, phase 2 study that was run by the Italian groups looking at deccitabine and venetalax and blast phase MPNs, uh, notably, MPN's prior history of MPN was excluded in the BLEA study that, um, you know, got the approval of HMA and vetalax. And so, uh, this prospective study is now confirming that this is a, um, a viable treatment option for our blast phase MPN population. Uh, and so many of these patients were successfully bridged to transplant, and it compared compared favorably to historical controls. And as we expected, the results and the adverse events were comparable to older patients with de novo AML. And so this is just confirming what a lot of us do anyway, um, and then a pending study at Roswell, which will be run by Doctor Green is a phase one trial of HMA venatoclax with picritinib, and accelerated and blast phase MPN, and so we'll look forward to that study. All right, Switching to chronic myeloid leukemia. So, this is data from the uh As for first study looking at a simonib in frontline um CML chronic phase. Um, and so they asked for first study. This is just, um, the trial design, and this was presented, um, you know, in the New England Journal, uh, in 2024 and led to the approval of aiminib in the, in the frontline setting, uh, randomizing patients to either aiminib in the front line or into investigator choice of TKI, which, uh, was a matnib and for some patients and then. Uh, 2nd generation TKI and others, uh, and so the primary endpoints were, um, MMR at 48 weeks versus all of the investigator, uh, selected TKIs and then MMR at 48 weeks, um, against a maib. Uh, and so, um, I believe last year Doctor Green, uh, mentioned about how ASXL one, positivity, um, is a poor prognostic feature of chronic phase CML, and so this is now being prospectively looked at on this ask for first study, um, and so they did, um, next gen sequencing. On patients enrolled into this study and they um identified the prevalence of um additional genomic alterations or AGAs from the diagnostic blood samples of these patients, um, several of them were not included because of their location, uh, and they, um, grouped them into four different categories. There were people who never had an ASXO1 mutation. There are patients who eradicated their ASXO1, so it had it at baseline, but then at a later time point then cleared it. Patients who had persistent ASXO1 from diagnosis and up to week 96, and then those who had emergent ASXO1, so negative at baseline, but then developed it at a later time point. And so then they compared all of these cohorts, um, across their treatments with TKIs. And so this was presented by Doctor Branford at IHA showing the um prevalence of these mutations in these uh uh new diagnosis of CMLs and so ASXL1 mutation was the most prevalent at 11.4%, um, followed um thereafter by DNMT3A and TET2 and, uh, several other common myeloid mutations, uh, overall detected in 21% of all patients at baseline. So this is the rates of uh major molecular response and deep molecular responses by ASXO1 positivity at baseline, uh, comparing assiminib versus your investigator uh selected TKIs and so you can see in the ASXO1 negative populations asiminib um outperformed the, uh, the investigators selected TKIs, uh, both for MMR and for deep molecular responses. Although these are at small numbers, ASX01 positive patients overall did worse than their ASXO1 negative counterparts, um, but they did not, uh, meet statistical significance in this low, uh, small patient population, uh, and so it could not be confirmed as a negative prognostic risk factor, um, with the short follow-up as well. What they did see is the longitudinal changes of mutant ASXO1. And so, in patients who were able to eradicate their ASXO1 mutation, um, those patients did quite well. Many of them went into MMR. Very few went into treatment failure, and very few of those, uh, had a BCR-ABL, um, mutation, uh, that developed into resistance. However, those who had persistent ASXO1. Uh, very low rates of, um, MMR, high rates of treatment failure, and high rates of BCR-ABL1 mutations. And for those who developed ASXL ones on treatment, uh, many of them went into MMR, um, but also treatment failures and BCR-ABL mutations. And when they looked further into those, uh, with MMR, those were actually, um, ascribed to chip mutations that, uh, arose from the bone marrow and probably a, a different, you know, myeloid clone that developed, uh, that is separate from their CML. And so, overall, BCR-ABL-1 mutations were acquired more frequently in patients with persistent or emergent ASXO1 compared with patients who eradicated ASX0150 versus 3.4%. These are the Kaplan-Meyer curves of, um, treatment failure-free survival by ASXO1 status. Uh, as you can see, the simonib in patients with ASXO1 negative disease, uh, did better than all of the other cohorts. Um, those with, um, investigator selected TKIs and a lot of these patients were receiving imatinib, um, did very similarly whether or not they had an ASXO1 mutation. Um, and then the patients with, with, uh, um, ASXO1 mutations that were treated with Asiminib did very similar to the, um, investigators selected ASXO1, uh, investigators selected TKIs, and so for patients with no ASXO1 variants at any time, failure rate was considerably lower with aiminib, and then patients with ASXO1 positive at any time, treatment failure rate was comparable between aiminib and the investigators selected TKIs. And so, uh, the conclusions, patients in the overall study, uh, improved, had improved outcomes with aiminib, lower rates of treatment failure, and higher rates of MMR and deep molecular response with the strongest improvements observed in the ASXO1 negative patients. And while it's relatively uncommon, um, the ASXO1 mutation resulted in comparable outcomes between patients receiving aiminib and the investigators selected TKIs. Um, this exploratory analysis, uh, further confirm confirm ASXO one variants as a risk factor, but do not predict a superior treatment choice. And so I think that that is still an area of investigation. Um, and monitoring ASXO1 variants together with the molecular response may help to identify patients with chronic phase CML who have persistent or emergent mutations and are at increased risk of treatment failure. And so, um, hopefully we'll be getting larger cohorts of this, um, study as more and more of us are using Assiminib. All right. And the last study that I wanna present, uh, is about management and outcomes of patients diagnosed with CML and blast phase. This is a, a consortium analysis, uh, retrospective study. And so when patients go into blast phase, they have the, um, you know, unfortunate event of either being myeloid blast phase, lymphoid blast phase, or sometimes mixed, and the, there's no standardized approach for, for how people treat these patients, um, when they turn into blast phase. And so they, uh, looked at patients who received only TKI TKI plus chemo or chemo alone and then looked at the different, um, TKIs that were used. Uh, different chemotherapies and whether or not they want to transplant. So these are just the baseline numbers that they had. Uh, median follow-up of 46 months. Overall survival was 19.7 months and the 5 year overall survival rate was 38%. Comparing across the types of treatment, patients with TKI plus chemo seem to do better than, uh, than either chemo alone or TKI plus chemo, uh, in terms of overall survival and event-free survival. Uh, looking at either 1st gen, 2nd gen, or 3rd gen TKIs, there seemed to be no difference across, uh, which TKI was chosen as long as the patient was on some TKI. And, um, overall survival and event-free survival by phenotype, myeloid patients tended to do worse, whereas lymphoid and mixed, uh, patients, um, fared better. Uh, in a landmark analysis for overall survival, uh, for patients who underwent an allo transplant within 6 months, these patients did significantly better than those did not, uh, with, um. 127.95 versus 15.95 months um after transplant. On multivariate analysis, here are the findings. So patients who were younger did better, uh, patients who got some TKI did better, um, and the myeloid patients did worse. So I think I just talked about that that in the generation of TKI did not have a significant impact on overall survival or event-free survival and on multivariate analysis, addition of chemotherapy did not make significant differences in overall survival and, uh, further diff further studies are needed to confirm these analyses and using a TKI followed by an AI transplant is an accepted standard um management practice for patients with CML and blast phase, and I think this is confirming what we already do. Uh, and so some other updates in CML. There was another, um, look at ASXO1 mutations in frontline imatini patients. Um, these patients who with this mutation had a worse five year failure-free survival compared to patients with other variants and no variants. There are two novel stamp inhibitors, so stamp, uh, inhibitors target the miostoy pocket similarly to a siminib. Um, so, uh, turns 701 has promising efficacy in, uh, patients previously treated with aiminib and or pannatinib. They are now, uh, enrolling in their dose expansion. Uh, and then the other inhibitor, TGRX 678, uh, in chronic or accelerated phase with T315I, promising efficacy across dose levels, and, um, we're targeting lower dose levels to mitigate toxicity. We do have this trial at uh Roswell, but it unfortunately has been suspended due to some contracting issues because it is, um, sponsored by a company based in China, uh, and, uh, with the current governmental rules we're not allowed to, uh, participate in that study anymore, um, and then the current and pending studies that we do have open, uh, aiminib as initial therapy for chronic ACML, of course it is already approved, but, uh, this is being tested, uh, in a consortium level, uh, with additional, um, modifications. And then, um, treatment-free remission with Asiminib after a prior attempt at TKI discontinuation. And so this is a potential opportunity for people to try to get off TKIs if they have previously failed. And that's it. All right, thank you very much, um. Elizabeth Gross, I'll be giving the 2nd talk. This is an update on, um. Myelodysplasia and clonal hematopoiesis from this year's ASH meeting. Um, These are the efforts that we'll hopefully cover during this talk. Um, I just want to remind everyone that in order to make the diagnosis of MDS, you require persistent cytopenias that are relatively stable over a period of 3 months, uh, with these lower levels of counts and exclusion of other causes, um, we still see a fair number of patients who get referred who have, uh, AML and evolution, um, and are told that they have MDS or who have other causes of cytopenias. And so that in combination with the major criteria demonstrating clonality, dysplasia, and increased blasts. Um, in 2022, we had two pathological, uh, staging systems or scoring systems, um, which are currently still, uh, competing for prominence. Um, I'm part of a large group that is trying to unify these pathological staging, uh, schemas, and, um, in, in order to do that, we've used a cohort of more than 7000 patients, and we've been able to really definitively identify three distinct groups that are defined genomically. Those with bioelic inactivation of TP53, those with MDS and deletion 5Q, and those with mutated SF3B1, the remainder of patients still are defined based on their, um, their, um, appearance under the microscope and based on their blast percentage. Um, Our algorithm allowed us to say, OK, morphological classification can improve class, um, our algorithm can improve over morphic classification. These morphological MDSs remain quite molecularly heterogeneous, and we can probably Say that there are 3 specific mutational events that probably should be AML irrespective of blast percentage, and this is sort of analogous to what we see in the core binding factor, leukemias. Those with NPM1 mutations, those with CABP alpha mutations, and those with core binding factor, these should be AML irrespective of blasts. And then finally, in patients who have a high blast percentage, unfortunately, we still don't have a unifying, uh, characteristic of those people. I also want to remind people that most of the clinical trial data that we're seeing read out now are still based on older classification schemas. Mostly, they enrolled patients based on either IPSS, the original classification schema from 1998, or the IPSSR. Remember that IPSSR Included prognostication based on blast percentage, cytogenetics, and cytopenia. And you can see here on the left that for those people with higher risk disease, overall survival is pretty poor, and freedom from evolution is pretty poor. But there are still people in the lower risk categories who, who fare pretty poorly. And so one of the things that we had more recently was the development and the widespread adoption of the molecularly based international prognostic system. And I want to remind you that in the IPSSM, which you can get, you can assess for your patients using an online calculator, uh, scores are based on hemoglobin, platelets, bone marrow blasts, as well as cytogenetic and molecular features. And lower-risk patients are defined as those with a, a score less than 0. And you can see here that this, this scoring system is, is substantially better at defining outcome with median survival for those very low-risk patients of 10.5 years and low-risk patients of 6 years. So, it gives you a better way to identify patients who are less likely to need aggressive therapy. I want to remind you that in general, the IPSS risk score compared with the IPSSR or the IPSSM, uh, IPSS and the IPSSR actually upstages patients. OK? So this data is, was presented by Valeria C Santini, uh, now several years ago to Ash and then the manuscript finalized, um. In 2023, but they looked at the Saatolumab study groups, and they recharacterized those patients using the IPSS scoring system, the IPSSR and the IPSSM. And you can see that overall, mostly what these novel scoring systems do is they change people from lower risk disease to higher risk disease to give us a better sense of those who are going to do poorly. We have made some progress in the therapy for patients with MDS. I would say probably not at all the same level of progress that our colleagues in the myeloma field have had and, and somewhat less progress than we've had in the field of AML. But you can see here that a lot of our progress has been in better classification and characterization of disease biology. Um, more recently, since 2019, we've had several agents that are newly approved, um, with the caveat that doccitabine cetazuridine, which is really a better mousetrap, a better way to give IV doccitabine, um, the majority of the approvals that we've had are for lower-risk patients, including loosepatercept, uh, ivocitinib, and, and now arguably enaccitinib, the targeted therapies for IDH1 and two mutated MDS patients, and then Emetalstat, which was FDA approved in 2024. Um The treatment algorithm for patients with low-risk MDS has therefore evolved. Um, most of the patients with low-risk disease will present with symptoms from anemia, and when you see these patients, the first cut is whether or not the patient has a presence of a deletion 5Q. And for those patients, lenalidomide with or without growth factor support remains kind of the standard upfront approach. For those people with anemia who do not have MDS with the deletion 5Q, the next cut point is really, does the patient have the presence of ringsideoblasts? Remember, ringsiderooblastic disease commonly coexists with the mutation in SF3B1, and, um, these patients in general, historically were very resistant to ESAs. So now we have therapy for these people that's quite effective. For those people with low EPO levels, loosepatercept is really frontline, and indeed, loosepatercept is FDA approved for all patients with, uh, transfusion-dependent anemia. Um, It's pretty clear from looking at later data, and I'll cover that in some moments, that those people with higher EPO levels actually respond less well to loosepatercept. Um, for those patients, we may be thinking about using this newer approved drug Emetalstat. We'll talk about that in a minute. And then for those people who do not have ring etcoblasts, again, our plan is to use this EPO level as a discrimination to use ESA or loosepatercept for those patients with lower EPO levels and, um, for those with really high EPO levels above 500 to use this novel drug, a metalstat. I want to remind you that for people who are transfusion dependent with quote unquote, lower risk MDS, actually outcomes are pretty poor, with many patients suffering and dying from complications related to their disease. And so in this population, it is not unreasonable, those who have failed these therapies to consider use of allogeneic stem cell transplant as a curative therapy. So, this year, um, we have follow up from the command study. The command study was the large phase 3 randomized loose patercept versus erythropoietin alpha study that enrolled patients in 1 to 1 fashion to LUSPA versus EPO. Remember, these patients were enrolled based on IPSSR categories, low, very low and intermediate disease. They were largely ringsideroblastic patients. The primary endpoint was transfusion independence for 12 weeks, and I mean hemoglobin increase of 1.5 g. Um, a majority of the patients enrolled in this trial had SF3B1 mutated disease. Um, those with serum EO greater than 500 were, were, um, not enrolled on this study. The current dosing indication for loose patercept is to start people at 1 mg per kilogram, and then dose escalate them if they have not achieved that end point of transfusion independence. And so the question becomes, how can we maximize the efficacy of this agent? Um, could we use it for non, for symptomatic non-transfusion dependent patients? Um, there's a study currently enrolling called the Element MDS study. Does starting the loose patercept earlier potentially impact overall survival? We have some data from the from the command study that was presented this year at ASH. And could we forego this dose escalation paradigm and instead just start at the maximum dose in order to figure out which 40% of patients are actually going to benefit and then be able to offer them something else. Uh, and that is going to be addressed by the Maxis study. And then could we salvage responses for those people who become cytopenic if they've already seen an ESA? OK, so, E MDS is a randomized phase 3 clinical trial in non-transfusion dependent symptomatic patients with low risk MDS. This study is currently open and enrolling and is screening patients and randomizing them 1 to 1 to conventional loose patercept dosing at the 1 mg per kilo with plan for dose escalation versus EPO. Um, we expect to see these data in the next year or two. Follow-up of the commands data presented this past year at the AS meeting show overall survival after more than 2.5 years of follow-up. Again, you can see that the, the median overall survival was not reached for loose loose patercept and was 46 months for the Epo alpha group. Um, this was not statistically significantly better, but certainly suggests that it doesn't cause disease progression. Um, Next, we're looking at the, uh, potential for starting patients at a higher dose. Remember, the plan for patients currently who get loose patercept, you start at 1 mg per kilo, you give two doses, and then after that six-week period, you have the opportunity to dose escalate if the patient continues to be transfusion dependent. Um, many of us would actually use a hemoglobin goal as an alternative approach in that population. In our practice, we actually use a goal above 11, 11.5 to consider redosing. Um, but the Maxus study said, well, instead of dose escalating, since we know that this agent now is relatively safe, could we just start people at the maximum dose? And this was a, a phase 3B open label, non-randomized study that had two cohorts, people who had previously seen ESAs and those. Who are ESA naive and then these people were followed for weeks 1 to 24 and then they had the potential to continue therapy for up to 2 years, um, to look at outcomes including AML progressions, secondary malignancies, worsening MDS, um, or overall survival. Um, this study was presented in preliminary fashion at this year's AS meeting. You can see here that these were reasonably similar cohorts. age was around mid-70s. Um, there was a male predominance in sex. Um, most of these people were relatively lower transfusion burden. Um, baseline hemoglobins were lower, obviously in the relapse refractory cohort. Um, most of these patients had EPO levels less than 500, and they had lower risk disease. And you can see here that this study met its primary endpoint, um. Strongly showing uh in the ESA naive court almost 73% of patients, 74% of patients responded, um, responses were less dramatic in the people who had higher EPO levels in the upfront cohort, um. This was the data from the ESA relapse refractory or intolerant cohort. You can see here they, this too met its primary endpoint of 65% transfusion independence for more than 8 weeks, um, somewhat less active in those with rings that are less negative disease and in those with higher EPO levels. So in, in summary, the Maxus study has met its primary endpoint with reasonable rates of transfusion dependence for 8 weeks and improvements in hemoglobin by at least 1 g. Secondary endpoints were also, um, favorable, and this did not have any unexpected toxicities. Um, we have additional data coming to us from Europe with the Part A of the Kambala study. This is for people who've previously seen an ESA and who've lost response to that therapy. These patients are being Uh, evaluated to see if the addition of loose patercept on top of the ESA might improve outcome. In the initial data, which was published last year at the Ash meeting in 2024, uh, this was initially presented by Doctor Lionel Ais from the French group. Um, they had about a 30% overall response rate and the recommended phase two dose was identified as 1.75 and 60,000 units a week. Um, they presented some, um, the, these. They're now entering the randomized portion of the study where lower-risk patients who do not have ringsideroblasts and no adult 5Q who failed an ESA are randomized 1 to 1 to the combination of LUSPA with ESA or to just LUSPA alone. And so far they've enrolled 40 patients, and that study is ongoing. Um, the next agent that is, uh, quite active in this space is this drug Emetalstat, which is a first in class inhibitor of telomerase. The hypothesis is that this, this drug targets the malignant stem cell clones, which are more sensitive to inhibition of telomerase and thereby allows healthy residual hematopoietic stem cell clones to, uh, regrow. Um, the Emerge phase 3 randomized controlled trial was published by Doctor Plotzbecker in 2024. This study randomized patients 2 to 1, lower-risk patients, 2 to 1. Again, this was IPSS randomization. Um, To receive either a metalstat or placebo. These patients were excluded if they had had prior therapy with lenalidomide, loosepatercept, or an HMA. And the primary endpoint here was 8-week transfusion independence or and secondary endpoints, 24 week transfusion independence. This study met its primary endpoint. You can see here a metalstat in blue and placebo in orange, and you can see here a marked superiority for the ametalstat therapy group over the placebo group with improvements in hemoglobin on the order of 3.5 g. This is a pretty substantial improvement in hemoglobin for our patients. You remember the end points for LUSA is 1 g of improvement. Um, and so questions remain. This, this agent is now FDA approved and we use it in our practice. Um, There's a hypothesis that this drug might actually be disease modifying and might be selectively killing these uh myelodysplasia clones. And so, um, the question is, should we start this drug earlier? Should we go to it earlier? And then, one of the things that was dramatic about this drug is that there are quite a few treatment emergent cytopenias, especially during the first cycles of therapy. And so, what do those cytopenias mean? And, and to this end, we have some data from Doctor Amar Zaidan presented this year at the AS meeting. So, this is long term overall survival for the Emerge intention to treat population with 48, 45 months of median follow up. You can see here overall survival in these two groups of patients receiving either ametalstat or placebo were not different. So, this is reassuring. This drug is not changing the natural history of disease or making things worse. Um, and then Doctor Dyan used the Emerge, uh, study group to actually ask questions about the in the, the identification of early cytopenias in this patient population because this was really our biggest concern about this drug. To do, to answer this question, he collected patients who were treated on the phase 2 single arm study, the phase 3 double brand randomized study, and then the, the rollover study, and then the QTC substudy of the phase 3 I merge study, and, and this allowed him to look at a cohort of 226 patients who had all received a mental stat at the conventional dose of 7.1 million. Milligrams per kilo for the first two cycles. And what he found was that in those patients who demonstrated significant falls in platelets and ANC in the first couple of cycles, you could see that those people were actually the ones who demonstrated the best response to therapy with improvements in hemoglobin and decreases in the VAF of the SF3B1 clones. You can see here that these patients also ended up with better long-term transfusion independence rates with 24 week transfusion independence higher, about 32% versus 7% in those people who saw maximum platelet decrease above 70, above 50%, and, uh, 32 versus 7% in those with either, with the combination of platelet decrease greater than 50% or maximum neutrophil decrease in 75%. I think this is analogous to what we have seen in the past with lenalidomide, where the patients who respond often will, will show significant cytopenias in the first cycles of therapy that then are improved over time with treatment, suggesting that they maybe are changing the, the dominance of the clonal production, the clonal cells that are making red cells, white cells, and platelets. So, for higher risk disease, where are we now? Uh, this is an algorithm to kind of identify what we do with our high-risk patients. I think I want to just remind you that we now recognize that patients with DDX41 are probably 5% of our population. And so it's important to consider germline testing for patients who have two primary malignancies or those who have, um, this disease and they're in age less than 50. Um, the first cut of these patients is really, are they or are they not allogeneic stem cell transplant eligible? For those who are eligible for transplant, um, if they have low burden disease, then we think about considering those patients for upper allogeneic stem cell transplant. And, and if they're not ready to go right now or they don't have a donor, um, we would use some kind of bridging therapy. Usually in my practice, single agent hypomethyting agent, whether it's parenteral or oral. Um, touched briefly on the idea of using combination studies, combination drugs for this cohort of patients with HMA venetoclax. Um, and then for patients after transplant, consideration of a maintenance approach, particularly if those patients have TP53 mutant disease. For those people who are not candidates for transplant, if they have the presence of a TP53, uh, mutation, I would strongly favor single agent hypomethylene agents for as long as they're working, followed by clinical trials. And then if they are not TP53 mutant, you could consider combination therapies versus single agent. I, I generally would favor single agent. Um, the best data we have for this disease is really still the ASA 001 study now published many years ago in 2009 by Doctor, uh, Fenno. Um, this is the only study to have shown a significant survival benefit for higher risk disease. Um To that end, we are now trying to develop an oral version of this best available therapy. Uh, we've had open for this study, the ASTX 030 phase two study. This is actually a phase 1 to 3 program, um, that is open in, in a single, um, protocol. This was presented by Doctor Garcia Monaro. This study confirms, is aimed to confirm the recommended phase two dose of oral ASTX 030, a combination of azacytidine oral with cetazuridine. Uh, this study, uh, phase 2 enrolled 30 patients, and people were randomized to receive the oral agent in cycle 1 or the subcutaneous agent in cycle one, and then could cross over to receive the sub would cross over to receive the subcutaneous in cycle 2 if they'd received oral and the opposite. And this allows every single patient to act as their own. Control for the pharmacokinetic studies, which are really the basis for this trial to demonstrate pharmacokinetic equivalence of the two agents. The primary endpoints here are the geometric mean of of AA total cycle exposure, and the secondary endpoints are clinical responses and changes in uh methylation. Um, best overall responses, um, in this cohort of patients were, um, 45% commensurate with what we would expect to see with single agent, uh, subcutaneous or, uh, intravenous azocytidine. Um, CRs were 27% of patients, um, with hematologic improvement as you would expect. Um, you can see here that the AUC exposure was equivalent for the oral versus the, the subQ, um, treatment exposure. So this allowed us to move ahead with the phase 3 study, which is now completing enrollment. Um, we have some follow up for ASTX 727 and MDSMP and overlaps. Um, you may all remember that, um, some years ago, the French group performed a clinical trial called the Dakota study where they compared hydroxyurea against decitabine IV, and that study failed to meet its primary endpoint. And so for many years now for these patients with MDSMPN overlaps, hydroxyurea upfront has been considered the standard of care. Um, the group in England that was led by Doctor Dan Wiseman, uh, performed this study using ASTX oral decitabine cetazuridine in combination for MDSMPN patients. Um, and these patients were randomized either to receive ASTX 030727 for, for 5 days or to receive hydroxycarbamide, also known as hydroxyurea. Um, they presented this data, this study, uh, way outpaced its enrollment targets and did very well. You can see here the overall survival for the ASTX 727 cohort versus the, um, hydroxycarbamide cohort, strongly favoring the ASTX 727. So I think for me, this, um, affirms my tendency to use, um, hypomethylating agent for this population of patients, and I would favor using oral doccitabine cetazuridine here. Um, I want to remind everyone that for patients who have received a hypomethylating agent, um, once they fail, outcomes are really pretty dismal in the absence of allergenic stem cell transplant. On the left of the slide here, you can see a median overall survival in real-world data, uh, led by Doctor Zaidan, um, really showing overall survival 11 months in higher-risk patients. Overall, the same for docytabine or, or azacytidine. And median overall survival for higher risk patients of all ages in the clinical Research consortium, median overall median and overall 5 cycles, median overall survival 17 months. And once you fail HMA overall survival, something like 6 months. So, we should prevent patients from developing failure of HMA. So how can we do that? Uh, could we potentially optimize these patients by offering them combinations? Well, I'll cut to the chase here. We all know that Verona did not meet its primary endpoint. I think there is some role still for combinations with targeted therapeutics, including IDH inhibitors and maybe with me inhibitors if you have the right target. Uh, but I think we're still unhappy. We have many dead doublets in this disease state, unfortunately, you can see them listed here. The question is, is azacytidine and venetoclax dead in MDS? The phase 3 Verona study, um, Presented data here. This was the follow up from presented by Doctor Garcia Monaro. This was the long awaited study randomizing patients to receive either Vennetalax for 14 days plus AZA versus placebo plus ASA, um, looking at overall survival. And unfortunately, this study also failed to meet its primary endpoint of overall survival. I can see here these are the long term follow up. There may yet be a role for this agent in combination with azoytidine. Um, particularly, some groups benefited. That is to say, the TP53 unmutated cohort did benefit, uh, in terms of overall survival. People with higher blast percentage, I want to remind you, the Verona study only said that you had to have high risk disease, didn't say you had to have a high blast percentage. So they actually had quite a large cohort of patients with blasts, less than 5%, and I would argue this is a blast killing therapy. So I, I think that was possibly a mistake in terms of the study design. The bone marrow blast percentage is higher, seem to do better with this combination, and certainly de novo as opposed to patients with secondary MDS did, did better. And I think, um, the safety was as you would expect, right? We've seen this before. Doctor, um, Doctor Gar um, Doctor Jackie Garcia has presented previously phase 1B and phase 2 data showing this side effects. We know this is a cytopenia inducing regimen, causes low blood counts, uh, but they weren't different, um. There may be a benefit for this combination among those people who, in whom you think a stem cell transplant might be the right choice. You can see here, this is the phase 1B follow-up data for patients, uh, treated in Doctor Garcia's study, uh, published in Blood last year, um, or this year rather. Um, you can see your long-term overall survival superior for those patients, um, who went to transplants versus those who did not. And, um, so I think that that brings us to the final portion of this stu of this talk, which is really to focus on the fact that since our patients with MDS if they fail HMAs are very unlikely to do well, we should strongly think about implementing this potentially curative approach in our patients, remembering that we can now do transplants up to significantly higher ages and we have no limitations in terms of who can get a transplant based on donor availability. This is the BMTCTN study published now some years ago, um, which demonstrated overall survival of almost 50% versus less than 30% for people who got allogeneic stem cell transplant and for, um, Upfront. And with this data, we think allogeneic stem cell transplant should certainly be offered to high-risk patients, um, even older patients. But I think it is also important to remember that perhaps transplant should be offered to low-risk patients as well. And I would say that any patient you're following who has low-risk disease who demonstrates clonal progression, or somebody who has a a younger patient who actually has higher risk disease by these novel molecular staging systems, or those with profound cytopenias that are unresponsive, who remain heavily transfusion dependent, the Canadian group has shown us that the people who are continuing to receive transfusions actually end up with very poor survival. And then progression of symptoms out of proportion to cytopenias uh should be evaluated. Um, and any patient who develops a secondary mutation that's suggestive of disease transformation. So in summary, I think, I, I hope I've shown you that loosepatercept is really working, working well for our patients with transfusion, with MDS with, um, with lower risk disease, especially those who are lower transfusion burden. The duration of response can be quite long. Um, a metalstat is really a very active drug, especially for those with higher transfusion burden and, and seeming to show a trend towards overall survival benefit. We have, uh, oral decytamine cetazuridine, and an FDA approved agent, which should be used for CMML. And unfortunately, we should be really selective about who uses, uh, the combination of this of HMA plus venetoclax for MDS and then strongly consider sending your patients for allot transplant. Thank you very much. And now And now I, I, it's my pleasure to introduce, uh, Doctor Eunice Wang, my chief of service and friend for the last 17 years, I mean, 20 years, forever. Thank you very much. Um, I was hoping to give this talk a little bit earlier because now you all have a very important choice of what you're gonna do with your time right now. You could either listen to me give updates on acute myeloid leukemia, um, from the ASH meeting and from 2025, or you could. Watch this hockey game that's being broadcast, something about playoffs, sabers starting at 2 p.m. So just if anyone wants to do that, feel free. I'm just giving you the option that you have a really important choice in front of you. OK, for those of you who are just to save my, you know, my pride are gonna listen to my talk. I'm just gonna talk today about clinical practice updates for acute myeloid leukemia. Is there like a timer? OK, great, no timer. Great, I can talk forever. So the, um, so I'm gonna talk for the entire duration of the Sabres game. No, just kidding. So what I'm gonna talk to you today about is about some really important updates for the treatment of acute myeloid leukemia, which I know most of you don't treat, but I think it's a. It's a disease that we've really made significant advances. 14 new drugs approved since 2017, many of them here just selfishly, um, tested and, uh, utilized by patients at Roswell Park prior to their approval. So one of the major topics of this year's ASH meeting was the paradigm study, which I'll talk a little bit about which actually offers the possibility of an alternative to 7 + 3 also developed at Roswell Park in the 1970s for our younger fit patients with newly diagnosed disease. We also wanna talk, uh, I also wanna talk a little bit about some newer prognostic, um, tools we all use ELN 2020. To, are there other things on the horizon giving the changing therapeutic landscape for acute myeloid leukemia and then just some emerging data, triplet therapies, incorporation of targeted therapies in the upfront setting, and a couple of really cool agents in development for relapse refractory leukemias. So just as a preview, um, everybody knows acute myeloid leukemia is a disease of older adults. We mean by older adults they. Median age of presentation is the age of 70. And why is that? Because the incidence and frequency of secondary AMLs is actually on the rise. That secondary AMLs meaning AMLs are rising from prior myeloid diseases like MDS or MPN. Or from therapy related, because of the success of our solid tumor and lymphoma colleagues is rising and now makes up about 20 to 25% of all newly diagnosed acute myeloid leukemias, we can see that the age as this occurs is going to continue to advance. What is the current diagnostic workup for patients with newly diagnosed AML? So this is what we do, Elizabeth and Pam and myself on a weekly basis. We are trying to determine, does the patient have acute myeloid leukemia. So we look at morphology and flow, which at our institute can generally turn around in 24 hours. Conventional cytogenetics and Fish, Maryland municipal chemistry, apologies, should be 2 to 7 days in recognition of my cytogenetic colleagues who on weekdays can get this back in as little as 48 hours. And then at 3 to 5 days due to my molecular diagnostic colleagues is the turnaround time for next gen sequencing and for PCR assays and listed here are all. Of the mutations with the NCCN deems as required, ideally to turn around in 3 to 5 days. And those are recommended within the first month of therapy. And this list is going to grow. And why is this? Because we are now and now looking more closely at this data before initiating therapy. And why is that? That is because AML is not one disease. It's zillions of little diseases. So shown here is a pie graph that illustrates how complex and biologically heterogeneous this disease is. This was published by the ELN in 2022, and you can see all of the diverse, uh, cytogenetics. About half of patients are going to have normalcytogenetics. The other half are going to have like an array of different cytogenetic. Abnormalities and you can have mutations from 9 or 12 different biological categories and you can have co-mutations. So what does this tell us? This tells us that we, um, when we are trying to predict the outcome of our patients, this is our risk ratification and I would ask any of you to memorize this, um, categories, and you can see broken down. Um, why is this important? Well, you can see that if you have a favorable risk AML per this ELN 2022 category, you could have an overall survival where 2/3 of people are cured with conventional chemotherapy cured, 60 to 70%. That's a good prognosis, cancer. I don't care what you have. Or if you have P53 or complex mutant disease, it doesn't matter when you treat younger, fit patients with intensive chemotherapy, they do horribly. So this is what is our standard for younger fit patients is intensive chemotherapy, but these are primarily people under the age of 60. So we actually have a whole algorithm now based on how people are fit. Here's your diagnosis. I just talked to you. You made this all of this stuff done. You have a diagnosis of AML. OK, you have the patient, you have a fit patient, OK? ECOG, age, functionality, comorbidities. You're going to give them intense chemotherapy with 7 + 3, cytarabine and anthracycline and a. Training analog whatever a liposomal component if you are unfit, meaning that you have comorbidities, your performance status is poor, or you're above equal to or above the age of 75, then you will get a less intensive regimen and we just saw data on Friday from our colleagues that the one disease group that treats the most. Patients above the age of 80 years old at Roswell Park is the leukemia service, and we are routinely giving chemotherapy to our patients 80 and above. And our less intensive regimen is a Vennatoclax-based regimen combined with the less intensive chemotherapy, and we can safely do this in people in their 80s. Imagine that. Um, the question is, what are we doing in the current era? Given the success of these lower intensity therapy therapy and targeted therapies, how are we treating patients in 2026? So here's a case study. I really like case studies because they allow us to kind of grasp what we've been listening to and apply it to an actual patient. So this is, uh, Sam. Sam is a 53 year old gentleman initially discovered to have isolated neutropenia on blood work, otherwise. Feels fine, asymptomatic, has his blood work come back? White count is 1.2, ANC 0.1, platelets 120, 25% less. Uh oh, this is not good. You might have acute leukemia. He gets admitted, we treat him, we do the diagnostic workup. We confirmed that he has acute myeloid leukemia. We do our next gen sequencing. He has an SRSF2, a STA-2, and a DMNT3A mutation. So he is 53 years old. So what are you going to give this gentleman? Well, per our algorithm I just saw, I showed you, we should give this gentleman intensive chemotherapy, and we can argue whether he should get 7 and 3, he should get a liposomal 7 and 3. He doesn't seem to have a secondary disease, no other prior history. Should we give him HMA? Well, you know, he's not 75, he's not elderly, he's not unfit. What would we give this? So this is actually the question. So this is a study that was published last year, much less fanfare for this study as opposed to paradigm, and this was done in China. And what the Chinese investigators did is they took everybody between the ages of 18 and 59, no extramedullary disease, no prior HMA, regardless of whatever their cytogenetics or mutations were, and they randomized them to receive either Ven to cytabine. Or intensive chemotherapy with cytarabine and idorubicin and their primary endpoint was to look at CR, how many patients had ablation of their marrow, less than 5% blasts with or without count recovery, and how did they do safety wise. And so shown here on the right hand side, all there was no difference in all patients, all comers, all 188 patients, no difference in CRCRI. Rate, but when you look at carrier type, there's no difference in patients really between favorable risk or intermediate risk. They got a then HMA based regimen versus intensive chemotherapy until you get to adverse risk. There's a huge difference, see, between the blue and the red when you look at patients with adverse poor risk. I mean, this is a huge difference. This is like a 50% difference in complete remission rate. But obviously when you look at toxicities, 7 and 3 is much more toxic and so all the red bars are higher for toxicity in this study. So what is the paradigm study? The paradigm study was a study that looked at very similar outcomes. Patients above the age of 18, newly diagnosed AML, but in this study, being in the US, we're very ethical. We excluded everybody that had favorable risk disease. Anybody that had, uh, uh, uh, CB, uh, alterations, anybody that could get a FLIT 3 inhibitor because they had a FLIT 3 mutant disease, anybody that had an NPM1 mutation that could have benefited from 73, all excluded from this trial, OK, um, so we only really wanted to look at patients with intermediate risk and adverse risk because we didn't want the patients 60-70% outcomes to get not to get the standard of care. So what were the, uh, what were the endpoints? The end points are not CRCRI or event-free survival, and I just wanted to step back for one second if I can do so. You were randomized. You either got 7 and 3 or liposomal 7 and 3. You got a society named Venetoclax. The end point was to achieve a CR and to go to transplant. You are not supposed to get this therapy forever. The randomization was only for induction. So if you got randomized to 7 and 3 and you did not respond, you know what happened? You got Vannaa. If you had Vasa up front, you're randomized to Vasa, you were refractory or you're relapsed, you got 7 and 3. Guess what? OK, if you achieved a CR at any time on any arm, you could go to transplant. So this was a study that was. Looking at the event was either relapse or going to transplant. OK? All right, so we're looking at these studies. What are the patients? And so I'm just gonna highlight there were about 86 patients in each arm. They were not randomized or controlled for different cytogenetics and different mutations. The number of patients was too small to go and randomize for that. I also want to point out there are 188 patients were randomized. They screened 432 patients. So my question to the investigators, we did not participate in this. Why are so many patients screened out? And they claimed they were screened out because they had all those cytogenetics. But you wonder whether some attendings or some physicians were like, you know what? I don't really want to randomize my patient Elizabeth to Van Asa. I want her to get 73. So anyway, there's a big screen failure rate. When you look at the patients, they are somewhat different. There was no randomization for different mutations, so they're all about 65 years old. They're, um. Um, you can see here E.OG was all good in all these patients. Very some favorable risk patients leaked in that despite the fact that they tried not to do this, uh, 15% were intermediate risk. 70% of patients on this trial were adverse risk patients, adverse risk, OK, adverse risk. You can see that there's a slight difference, uh, in different mutations. You can see, let's see, P53 is a. Bad mutation to have P53. 18% of patients getting intensive chemotherapy got were P53, OK, as opposed to 10% in patients getting Venasa NMP1 IDH1 IDH2 generally considered good prognostic good response factors, much more common in the Vasa group versus the intensive therapy group. So some sort of imbalance, although they, they said this was not statistically significant. Adverse events. OK, clearly infection and bleeding is going to be higher with 7 and 3 based therapies. 16 more mortality, much higher with 7 and 3 based therapies than Menvenatoclaxazocytidine. Response rates were also different. CR, CR with full count recovery was the same. But, uh, responses without full recovery were better in the patients that got azocytidine venolax, and when we look at the primary endpoint here on the left event free survival, statistically significant improvement when we gave V Aza as opposed to intensive chemotherapy, but. The overall survival was the same. Why was the overall survival the same? We don't know, but I can might be the crossover that was allowed at the time of relapse. Transplantation rates higher in Van Asa. So again, why was the overall survival the same? That was not a primary endpoint, but definitely this data suggested. That then AA improves event-free survival over intensive chemotherapy and primarily adverse risk patients leads to higher rates of overall response, CCR, higher number of patients going to transplant, less mortality, less less symptoms, less time in the hospital, improved quality of. Life all favoring the nanolexazocytidine for these patients. They also said these would favor intermediate risk patients. There are 15 patients with intermediate risk disease in each of these categories. So I am personally I'm not changing my practice for intermediate risk AML based on 15 patients in this group and 15 patients in that group. So what does this mean for us? So if we are going to now give VASA for all patients, we cannot reply on ELN 2022, which is based on intensive chemotherapy. So do we need another prognostic category to predict how our patients with VASer are going to do? So we have this 4 gene classifier which was proposed by the ELN, but there is a proposal here at AS saying that there is a new model. It's called the PRISM model, the prognostic risk integration for survival modeling. And what it did is it took 3 different data sets. It looked at an initial pilot set of patients all treated with then ASA based regimens. Then they did a validation cohort. Then they did an external validation cohort, and they looked at numerous factors. They picked up all these factors that they thought would impact on outcomes with V AA. They incorporated into this model, and they demonstrated that their model was much better at fine tuning the predictions of. Patients treated with NASAH regimens than the prior regimens and this is available online similar to the IPSSM you can plug in the age, the genetics, and you can come up with a prognostic. What we see is that this actually clarifies which patients do better and which do worse. So the majority of the benefit is that in the other classifications, half, more than 50% of patients were favorable. We've moved those patients potentially into intermediate risk. So this particular patient. If you plug him into the prismM model, if he gets a Vasa, he is considered a very, um, low risk with about a, a median survival of 25 months with Vasa-based therapy. If you use the conventional other RISM system, it says that he has maybe like a 17 month. So this might be where we're going in terms of prognostication. What about the truly old patient? OK, now we have this is much more typical 79 year old gentleman comes in. Hypertension, hyperlipidemia, DVDs, aortic aneurysm, presents, uh, with nausea, vomiting, abdominal pain, elevated white count of 42,000, 59% blasts, and he has a profile that's different NPM1, FLT 3 DMNT3A mutations. These are very common mutations in the elderly patient population. He is 79, so I would argue that most of us would give him Ben Asa. Right. Based on what I just said, but because he has these targetable mutations, would you add a targeted therapy? What about a FLIT 3 inhibitor? He's FLIT 3 mutant. What about amennin inhibitor? Menin inhibitors like Menon party now at Ash, right? Multiple mennin inhibitor parties. So what are we doing for these patients? OK, so in the older patient population, neither FLIT 3. Inhibitors nor menin inhibitors are approved for upfront therapy, OK? They're only approved for relapse and refractory disease, but the question is, why not use them for newly diagnosed patients, particularly in older patients that cannot get other chemotherapy agents. So I'm gonna talk to you about a couple of studies, all of which these studies are all available here at Roswell Park if you're interested. Um, this, uh, just looking at some of what we call these triplet therapies, adding a third drug to VAabase regimen. So this is the first study of Viceroy. So the addition of guilterritinib, a FLIT 3 inhibitor, to the clocks of cytidine was piloted in a phase 2 study at MD Anderson showing excellent response rates and some prolonged cytopenias, but only at this one site. So the question is, could we replicate the MD Anderson data in, in real life, like not just in Houston, Texas, but also like in. Buffalo, New York, or in Tampa, Florida, or in, you know, Arizona or, or in other places and so this was a site that was done across the world. It was done at 15 medical centers where we combined a FLIT 3 inhibitor guilterritinib with venaplaxazocytidine for newly diagnosed patients, elderly unfit with FLIT 3 mutant disease. We noticed that there were no significant dose limiting toxicities when we looked at different doses of ananalax, and we found that we were able to replicate the very positive results that we're seeing at MD Anderson. Then ASA has an overall response rate in FLIT 3 mutant patients, about a 60% response rate. Here we saw a CRI rate about 86 to 90%. The median overall survival of Van AA and a FLIT 3 ITD patient population is about 13 to 15 months. Here, the median overall survival was not reached. We think it's somewhere in the range of 20 months, 19 to 20 months. So definitely both of those are significant improvements. And if we can get our 90% of patients into CR, we might actually be able to do some of these transplants on patients. And so this shows us. That this is a very tolerable regimen and supports bringing that FLIT 3 inhibitor combination to the upfront setting. So a phase 3 study obviously is planned with this in the near future that we will be participating in. What about mennin inhibitors? Menin inhibitorzifto Mein is now approved for patients with relapse and refractory NPM1 mutant disease. NPM1 mutations are found in up to 1/3 of newly diagnosed patients. Why can't we use it in the up. Front setting, can we combine amennin inhibitor with Vasa to improve outcomes for NMP1 mutant patients? And this is the results of a phase one study where we did the same thing. We did Vasa. We added the Mennin inhibitor ziptomanin, which is 600 mg taken once a day starting on day eight of the neliate cytidine. Now there are some side effects with venin inhibitors. You'll hear about differentiation syndrome. You hear about myelosuppression. You hear about QTC prolongation. None of these were really a problem when we added the ziomeum. Actually, the incidence of differentiation syndrome dropped from 15 to 20% to 3%. No real significant QTC prolongation was seen with this combination, and the myelosuppression was really also not a problem. And you can see again, overall response rates 89%. Didn't matter if you were com-mutated with IDH1 or. At 3, 80 to 90% CR follow up of half a year, everybody was still alive. OK? So again, starting to see that particular combination moving forward in the upfront setting in a randomized phase 3 trial, which is also now open here at Roswell Park. Um, we also have the trial that incorporates the addition of Ziomeum plus intensive chemotherapy for younger fit patients here. What about patients that don't have mutations? What else can we target? We can target proteins on the surface of these patients. So CD 123 is a marker that is overexpressed in almost 100% of patients with that is regardless of mutation types. If you don't have a mutation, you could have this surface protein, and we have an antibody drug conjugate, meaning an antibody against CD 123, plus a chemotherapy drug attached together infused in addition to vetoclaxazocytidine. We did a study. In older unfit people, as well as younger unfit people, combining this triplet in the upfront setting. And you can see here again, suggestions that this might improve efficacy. Since this is mutation, not specific, it may also work, we think, in patients with that dreaded P53 mutant disease. You can see here overall response rates improved a little bit over standard chemotherapy. Again, you're getting overall response rates in the 80, 90% range. You're getting prolonged survival. Even P53 mutant patients may be getting a benefit, maybe living seven or eight months as opposed to 5. So this is something that's mutation agnostic. So that is something that we really probably do need to do for our patients that don't have NPM1 or KMT2A or FLIT 3 or IDH1 or IDH2. Back to, uh, Greg P. He got treated with Van Aza guilt, um, and he relapsed, got a response, relapsed. What do we do? Well, now he can get menin inhibitor, right, because he's relapse disease he gets treated with ziomein or Revvimentin. But is there something better? So there's newer generation mennin inhibitors out there. If you can make something, you can make it better, and this is a new menin inhibitor, enzomein, which you can see is a different chemical structure and different pharmacodynamics. It goes in, binds the mennin, and falls off really quickly. So it's a twice a day drug, but it doesn't go in and irreversibly bind, but it goes in, binds and falls off. So why is that important? It might decrease the side effects, and it is an extremely potent selected agent. So you can see here that Revumene and ziomene have response rates, CR rates about 23% overall response rates maybe in the 30%, 40% range. Enzomeneb, this new novel menin inhibitor. Starting to hit 50 or 60%, OK, in very, very small numbers of patients. And so could this be a way to better treat patients in the relapse refractory setting? Could you combine this with Vanna that we are looking at all of these things in clinical trials here at Roswell Park. You can see median and overall survival getting to be greater than 6 months, a little bit in our patients. What about immunotherapy for our patients? We're always talking about CAR T. Bites. OK. All day yesterday, bites by specifics, carts. Why don't we have this for myeloid disease? They didn't say anything, my colleagues here about immunotherapy. So we may starting by starting to change that. We have uh, an antibody now, antibody, a bi-specific antibody called CLN 049. It binds to wild type FLIT 3, which is a surface protein found in many patients with AML regardless of whether they have the FLIT 3 mutation. And it's combined with the CD3 epitope so it can activate the immune system. OK? So what about this drug? This drug might work again in patients regardless of mutations. We do see evidence of cytokine release, which is good. That means the CD3 component is working, we're activating the system. So they did have an initial studies cytokine released in 100% of patients, so they modified the step up dosing now, so we only see it in about a third of patients and at higher doses we're starting to see actual CRCRIs, OK, in patients treated with a bi-specific antibody. For acute myeloid leukemia and in patients with, again, that dreaded P53 mutation, this does not reply upon apoptosis. It doesn't rely upon DNA damaging or cell death pathways that are P53 dependent. This is an immune response. And so 4 out of 6 patients that had um. AML relapse refractory setting that had P53 disease appeared to have some response and durable responses up to 4 months with this bite antibody which we also have in clinical trial here at Roswell Park. So that's a lot of information. I don't know how the sabers are doing. Hopefully they're doing better than I am. Um, and justice is a very exciting time for AML therapy, improvement in outcomes, changing of the standard of care, incorporation of low dose therapies, moving towards a light chemotherapy backbone and targeted therapy, and maybe hope for newer targeted therapies and immunotherapy. So thank you very much. All right, thank you for your attention. Um, we're now happy to take a few questions. I think we have a question and answer session for a few minutes. Any burning questions? Yes. You got that mutation for AFL. Lost come back. She left me So in many of our patients it's the presence of the mutation, for example, in P53 mutant AML versus MDS. It doesn't matter how many blasts you have, you do poorly. So there's many people that think that, um, that sometimes the presence of the mutation is more important than the actual blast count. Yes, obviously if your blasts are 90% versus 20%, we're more concerned. But a lot of times it's the underlying biology that dictates how well patients respond as opposed to the blast count per se. So for diagnosis now it's changed for 20% plus. So yeah, so in the um there has been some newer classifications. So the standard has been less than 5% your normal, greater than 20% your acute leukemia, between 5 and 19% your MDS. The uh ICC classification has said between 10 and 19. percent you're this entity AML slash MDS so you're, you can be both and I think that was because when we write clinical trials sometimes it's really artificial whether a patient can go on study if they have 21% plus versus 19%+. So if we introduce a category where essentially those are the same, right? Then you. Might be able to expand eligibility for some of these novel agents to um to technically MDS patients. So I'd actually do think that very high risk MDS, um, as well as AML right around that 20% range is exactly the same disease. It really just matters where you put your needle in when you do your aspirate. And we are starting to see, as you can see from the Verona trial, that patients with very high blast count MDS respond similarly with benefit as patients with AML. So if you have a blast count of 7% with MDS, probably I wouldn't treat that as AML, but if you have 18% versus 21%, as the Verona showed, you're still getting benefit from Benaza as long as you don't have a TP53 mutation, right, as long as you don't have a TP53 mutation. Doctor Evan, first for Doctor Sung, what's your standard now for doing NGS and CML? Do you just do ASXL one, or do you have a battery of other things that you look at? Do you only look at the marrow, or is the blood sufficient? Uh, I think we're still supposed to look at the bone marrow, um, regardless of, you know, what we think it's, um, chronic phase versus, you know, potentially accelerated phase. But I think the number of patients that are upstaged based on having low percentage of blasts in the peripheral blood is quite small. And so, I think people are moving a little bit away from doing those bone marrows at baseline. I think according to the NCCN you are still supposed to, so we do. Um, as far as additional sequencing, we sequence everybody just because we can. Um, and so our, um, Panheme genetics panel has, I think, 500 genes on it. Um, most likely we're all we're going to pick up is ASXO1 because it's the most common, um, but I don't know of any stand-alone ASXO1 mutant panels, uh, and so I think broad NGS is what we're going to have to do. Got. And next for Doctor Griffiths, so both um in uh metalstat and also um the other drug have immunologic underpinnings, and it seems in early stage MDS that all these mutations give a competitive advantage because of the inflammatory environment that they outcompete. The normal clone for so is the fundamental issue here really in terms of disease modification improving the inflammatory competition, so decreasing the inflammation so that the normal clone outgrows, and should we be looking at drugs that do that more than these drugs that, you know, are maybe affecting the clone specifically? Well, I mean, I think loose patercept is an, an, an, a differentiation agent that allows cells to overcome the inhibitory hump and, and complete erythroid differentiation, um. I think a metalstat is theoretically a drug that is selectively killing the mutant clones in a manner that's somewhat analogous to what we saw with with lenalidomide. Um, we have known for many years that the inflammatory, that the microenvironment in low risk MDS is particularly inflammatory, as you say, and there's certainly approaches to, to address that. Um, unfortunately, these, uh, IL-6 inhibitory therapies, early studies have. Not shown substantial disease modification or improvements. Now those were later stage, those were studied in later stages of the disease. Um, there's certainly enthusiasm for IAC 46 as an inhibitory molecule in these patients, which theoretically also would be inhibiting the inflammatory environment. I, I think the answer is we don't know yet. Got you. And then finally for Doctor Wang, a couple questions. The emergence of interest in hereditary defects that lead to acute myeloid leukemia has now been acute up to into the 50s and even early 60s for some patients, rarely. What is your practice in screening for those in AML patients currently? OK, so I'm gonna turn that over to Doctor Griffiths, and that's been one of her areas of research. Sure. So, um, you know, within the context of the NCCN, we now recommend that any patient with AML or MDS presenting at an age younger than 50 undergo evaluation and genetic counseling and, and screening. Our, uh, our current next generation sequencing panel includes a variety of different inherited predisposition genes including anchor D26, uh, DDX 41, um, some of these genes, um. That are um that are also on there that are that are not reported but are there for us to see and we, so, uh, within the context of NCCN we recommend testing for any person presenting MDS and AML less than age 50. We recommend um any person with a personal history of two cancers. So if you have a secondary malignancy, a secondary hematologic malignancy, um, about 25% of those patients, if you look at various case theories, uh, will actually have a germline predisposition event in repeated things that we look at. I mean, BRCA mutant patients for sure, DNA repair patients with FAND, um, many of these. Things that we actually didn't think of, um, um, AFP, familiar familial, uh, colon cancer during genome repair, these, these are all associated with increased risk for clonal hematopoiesis and increased risk for the development of, uh, secondary myeloid malignancies. And so these people are all recommended to undergo genetic testing. So in our practice, we refer patients to our genetic counseling service, um, and depending on the circumstance, we normally would send a skin biopsy for expansion of fibroblasts, which are not contaminated with blood samples, with blood and with blood elements in order to assess the germline. Does that answer your question? I think so. It's your own panel. So we use our own next generation sequencing panel. Uh, for all of our patients at diagnosis on their malignant sample, so their peripheral blood or their bone marrow, and then those people in whom we identify a putatively germline event or who have this family history, personal history, uh, are referred to our genetics group, and they undergo skin biopsy testing and they, right now, that sample is sent out usually to Ambry Genetics. Um, or depending on the patient's insurance to the specific place that's recommended, um, but we are actively working on developing an in-house next generation sequencing panel for that. But Amber is who you use as your baseline guy. And then the final question is, uh, what, uh, doctor, uh, do you do for the P53, the double mutants that have been now open, and how many are you actively sending to aloe transplant when we don't have really good evidence that aloe transplant really makes. The difference in this cohort. So what else does clearly should have watched the Sabres game instead of listening to my lecture. So, um, yeah, that's, uh, that's the challenge that we have. So for our P53 mutant patients at diagnosis, the recommendation, the recommendation. Of many national organizations is those patients need to be referred up front for clinical trials. So right now if they have a P53 mutant patients, we're putting them, um, upfront therapies. Um, we, um, the data suggests that VenASA does not result in improved overall survival over ASA alone in patients with P53 mutant disease. So depending on the patient's ability to undergo. Myelogenetic stem cell transplantation for elderly unfit patients that are not able to do that, we may recommend even just ASA alone with no addition of ananalax, and that allows the patient to be out of the hospital, have fewer cytopenias, fewer complications, and potentially better quality of life. Patients who are transplant candidates, we're continuing to upfront enroll them on clinical trials or as a backup, give them Vasa. In the hope that they may clear their blasts as in the Verona trial quicker to bridge to a transplant, we still refer our patients who are able to go to a transplant. That is the only modality that's been shown to lead to any prolonged overall survival in these patients. But do you require them to clear their P53 before transplant team? Our transplant team requires them to clear their blasts before transplant, not necessarily the P53. They would love it if we cleared the P53, but in these patients, um, we are able to clear blasts. The problem, and this is a common problem, is that it doesn't last. So it's really important in those patients to identify up front if they're candidates for a clinical trial versus Vennea versus ASA. If they're candidates for allo transplant, then the goal would be to use whatever modality you can to safely clear the blast as soon as. As possible and to transplant them up front. So as you know, our transplant team has now dramatically over the last year decreased the time to aloe as opposed to in the past and that I think is an important parameter when we're thinking about particularly these P53 immunant patients getting them to transplant within 46 or 8 weeks. And what about post-transplant then? What do they and post-transplant we're using post-transplant maintenance, so we don't have good data with that. Um, there's, that's been a struggle. We are using, um, low dose HMA and growth factor support and actively anticipating the results of, um, clinical trials to see whether oral HMAs might represent a new standard in that setting. Thank you. 11 quick question, um, for the panel. Um, doing a more targeted therapy in ML patients. Are you seeing more CNS relapse with AML these days, or I mean. So that's a really interesting question. So the question is, are we seeing more relapse? I think that with the downgrading of many patients from intensive chemotherapy regimens such as cytarabine-based regimens, we are potentially, and the fact that we are prolonging survival in patients with Vasa who otherwise would not have gotten therapy, we are seeing more extramedullary disease progress as a result of our success, both our adaptation. Of therapy for many people and the lack of high dose cytarabine containing consolidation for many of our younger patients, um, so that is something that, um, we are having a little bit of a struggle with. We have started to see extramedullary relapse. We've seen patients who have aggressive extramedullary relapse on Vasa, um, that require that to be addressed. So that's a, that's a great question. We also know that with again. At the adoption of Vasa, Vasa doesn't necessarily go into the CNS, and it is an area of concern. So for patients that have, um, FLIT 3 mutant disease, patients that have very, very high white counts who have monocytic phenotype, we are now for all of those patients doing an upfront LP, um, sort of at the time of last clearance specifically to rule out the possibility of CNS disease in those patients. I, I just wanna comment. That that Chinese study with Aza that you mentioned, they consolidated all those patients with intermediate dose cytarabine, and their outcomes did not demonstrate increased risk of CNS disease, but, but I think that's because they were using intermediate dose cytarabine consolidation, and that study was really only looking at CRCRI and toxicities and so they, the consolidation was used for everybody, um, but that is, uh, similarly, uh, a different end point than was used for paradigm. OK, OK, wait. One other quick question, sorry, I brought up this CD7 transplant for AML patients again who had CD7 on the surface. I'd like to know your thoughts about that. So CD7 is expressed in a certain percentage of patients with AML, I would say probably like 30 or 40%, and. And it's actually been a very interesting target because we've used it for TALLs, but there is emerging data that CD7 can be an active target for a subset of patients with AML, and there's some early data from the Chinese investigators showing that CD7 T cells actually have shown impressive results as a, so that may be a novel immunotherapeutic target. So I think we're gonna have to wait and see, but it is a very intriguing target that kind of came out of the blue. Um, that we're starting to see, I mean, I, I think the data with CAR T CD7 CARTs and AML is actually looking kind of interesting. So thank you for that question. Thank you. Thank you.
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