Total Health Oncology: Best of Heme 2025 Session 4

[00:00] Welcome and I apologize Dr. Schimale. No, no, thank you. And sorry about the change because I have the right to cash to go to the airport and we're a little bit behind schedule. So it's safer to get started with this session and then Dr. Alusi can take over. Thank you for the organizer for having me here.

[00:20] switch gears now. More interesting topic about infection, right? And it's amazing what's going on in your field and we barely can keep up with all these new drugs, all these new strategies that you're doing when it comes to infection and what to do, how to prevent, how to treat. So it's like, you know.

[00:40] try to keep up with you all. That's why we've been telling my friend and colleagues at MD Anderson, but it's been a really very exciting time for all of us, it looks like for our patient mainly, but also for us in a way that we want to do whatever it takes to keep your patient alive, to prevent infection, to treat infection, to be pre-aggressive from the beginning.

[01:00] in order for them to go ahead and continue the treatment and impact their outcome when it comes to underlying malignancy. So yeah, we change all the topics, like every speaker, there's no way I can talk about infection. In 15 minutes, it's gonna take me probably two weeks, but I can talk about it.

[01:20] about some advancement, some viral infection, and this is my area of research, and these are my disclosures, but this is what I'm going to focus on. This is where we had some headways when it come to cytomegalovirus. That's what I'm going to focus on and what we accomplished over the past two decades and what we add, especially.

[01:40] in allogenic stem cell transplant. We had also lots of work going on with the CAR T, but I don't have time to cover the topic. And at the end, I will talk a little bit about respiratory viral infection. And also I picked two viruses, which are RSV and Parainfluenza. And where do we add, and at the end give you some of my final thoughts, where are we heading?

[02:00] And for any type of patient with hematocia malignancies, but mainly transplant, that's where we focus and CMV. But looks like this doesn't happen only after allotransplant. Which is quite, if you look for it, you're gonna see it in any other patient with myelomal lymphoma, cartial or not, or other targeted.

[02:20] therapy that you may see, but what to do about it? That's what we're trying to define and to make it clear and try to collect data and see what we should do, what's best for our patient. Now, the major advances in CMV management, at least over the past three decades, we conducted so many trials, but we were lucky.

[02:40] were successful around a few years ago to have something going on and something really with improved outcome. Let me start first with the diagnostic tool that we have. As you all remember probably, probably older generation, when we used Shell Vial or when we used to use Sanveon Antigenemia, we moved away.

[03:00] But everyone moved away from that. Now we have much more sensitive tests, which are the molecular assays. But also, they're very sensitive assay. Sometimes it's not good because are we over-treating or not? Probably we are. But at least that's a good advancement. We can catch any reactivation pretty early on.

[03:20] more exciting as well as looking at these specific T cell responses. How can this guide us in order to manage this patient? Would I treat if they have low level viremia? Would I put them on prophylaxis if they don't have good T cell response or constitution after allotransplant? And many other questions that we

[03:40] We may not have answer unless we run this specific CMV, cellular mediated immunity, and we have lots of that. We publish quite a bit on it, and the statute, we may have some kind of guidance. I won't call it guidance what to do at least after allotransplant, but still, I don't have time to cover that, but this is what I like to say about it.

[04:00] Now what is more interesting is prophylaxis for CMV. As you all probably know that we have a new drug which was approved in 2017 to prevent CMV reactivation or disease after allotransplant and is supine positive, which is littoromovir. I think.

[04:20] This is big success story. I'm going to show you some data and tell you why that, at least to prevent, but also were lucky in 2021, or was successful in 2021. After multiple trials, we had another drug, which is Maribavir that can manage patients with resistant refractory.

[04:40] CMV infection. I'm talking about very serious infection and very sick patient, but the patients who get this kind of infection are pretty heavily immunosuppressed patients, heavily treated multiple line of therapy for their underlying disease, and they end up with a big problem with CMV if it was not prevented.

[05:00] So, Maribavic. So, I'm going to talk a little bit quickly about that. So, this is what's been going on in the CMV world. Many, you know, few new drugs. The Turmovir we talk about, different mechanisms of action than the regular drug that you are all familiar with, again, Syclovir, Foscarnet, or Sidovivir, very toxic drug. Does it work? Yeah.

[05:20] very toxic drug. It limits the use of this drug and they have the same kind of megas of action. At the end they inhibit the DNA polymerase of CMV. Now the new drug, the Turmovir, work on the terminus complex of CMV later on in the DNA elongation of

[05:40] the CMV, but there's no cross-resistance. And this is the one we use for prophylaxis. Maribavir, it inhibits you LNAD7, the enzyme that is needed to phosphorylate ganciclovir. That's why it's a no-no. We cannot use ganciclovir and maribavir in combination because it could be antagonistic.

[06:00] kind of different, you know, kinds of action, but there is cross-resistance between Maribavir and Ganciclovir. Specific mutation, specific codon can confer resistance to both. Another drug, Berenzydovir, that you probably heard about it many years ago,

[06:20] You know, we conducted probably at least five to six trials, were unsuccessful to bring it to the market for prevention of CMV infection after transplant. For many reasons, I'm not going to get into that. Then we tried tested in adenoviral infections. Also, we were not able to do that. Now, we're lucky enough to convince

[06:40] people who took Brinsetivir, a new company from Japan, Symbio, to test not only in Adenore, because there's still big unmet need in CMV in our patient population, but for CMV. We have a phase one B trial looking at dose escalation that almost got done with the two level.

[07:00] We have the third level and hopefully if it looks good, then we can move it into phase three trial to treat preemptively CMV infection and also to treat this and the refractory CMV infection. So this is something to stay tuned to and it may occur later on in the future. Let's talk about later move here.

[07:20] And why it was a success, a big success story. We conducted the phase two trial in early, before 2014, and those escalation we found that at 240 milligrams it will prevent CMV reactivation, what we call clinically significant CMV infection with not much of side effect, oral, and we have it also

[07:40] So an IV formulation, pretty safe. We moved to the phase III trial, which also showed that it is, it had a big impact when you compare prevention, which is a littelmovir versus placebo, which is kind of preemptive therapy. And there was big difference in outcome when you look at clinically significant CMV infection. But what

[08:00] this more interesting, we start seeing, you know, based on this first phase 3 trial, there were differences in all cause mortality. When you're on prophylaxis versus pre-emptive therapy, you have more patients dying or when they are on pre-emptive therapy and they didn't die from CMV disease.

[08:20] from CMV, it's all from the indirect effect of CMV. So to prevent reactivation, you may impact or cause mortality after allotransplant and recipient positive, which is very interesting. And then CIBMTR published more than 9,400 patients looking also at this outcome and they found the same thing.

[08:40] you have lower non-relapse mortality and lower all-cause mortality when you prevent viremia versus if you allow the virus to reactivate. So said okay maybe this was an exploratory endpoint in the phase III trial, maybe it's not true. So but we're interested after we start using it for many years

[09:00] Is it true in the real world use of letermovir around the world? So we put together at that time when we did this meta-analysis, we found 48 studies from all over the world. Most of them were from the US. Looking at the CMV outcome, it was true, yes, letermovir prevented CMV reactivation, clinically significant CMV use.

[09:20] infection, but also CNV and organ disease. But we were more interested to look at other outcome. What about all-cause mortality? Yes, it was true. Beyond day 200, they had less patient dying if they received a term of e versus the patient who did not. Less non-relapse mortality as well. Also, there were some

[09:40] trend or data for GVHG, but the data was not that strong, and CMV-related hospitalization. So this is the impact of Le Tourmovir over the past many years of using it in real-world data. But the other question came up actually, which is interesting. We know for years...

[10:00] years for the past 20 years any recipient positive is at disadvantage of all cause mortality or survival compared to recipient negative. By being only recipient positive from the get-go before transplant they will be they have lower overall survival than the recipient

[10:20] negative. And this is the indirect effect or the direct effect of CNV infection. So the question came up and actually we tried to answer it in our database. Did we bring, did we close the gap now with the littoromovir? If we prevented CNV and the recipient positive, do we have the same mortality compared to recipient negative?

[10:40] And this is the data that we published recently looking at more than 1,071 allotransplant patient, 940 out of this 940 some were on the termovir, some did not receive the termovir towards pre-enter therapy before the error of the termovir. Compared the control group, the D minus, R minus, and we found yes.

[11:00] Patients who were on the letermovir, they had the same all-cause mortality than the D-minus R-minus. Patients who were not on the letermovir for any reason, and they got pre-emptive therapy, they had higher mortality, all-cause mortality, compared to the D-minus, R-minus, and to the one who received letermovir. Same thing for non-relapse mortality.

[11:20] at the same time. So even we close the gap. So I think, do you know any anti-infective drug that can impact all cause mortality? I'm not talking about bacterium you treat, if you don't treat, they die from an infection or septic shock. Talking about preventing one viral infection, it impacted all cause mortality.

[11:40] And I think this is a great outcome that we accomplished over the past many years by using prophylactic regimen. Now, what about cenvial resistance? We know it's not that common after islet transplant, but it may happen. Refractory without mutations in the viral codons, you, it's much more common.

[12:00] common before the era of let her move in. Now with the term of year we showed that even is a refractory incidence went down. But still we can encounter this especially now when we have much secure patient and we can tell when we around on the stem cell transplant team on the lymphoma, myeloma, leukemia, we are dealing with more

[12:20] heavily immunosuppress patient, multiple line of therapy. Now they still, you keep them alive for long period of time to go on investigation drug before we didn't do that. They were bedad before they get to us, but you know now they are admitted because of all the complication. So we're seeing weird infection, we see

[12:40] have very heavily difficult to treat infection, not only viral, fungal infection. What we're seeing, rhinociribular, I have like three or four on my service in the form of myeloma service. You see all this weird infection now come. So we want to make sure how can we prevent, how can we do better job not to get to the stage of.

[13:00] organ disease. So for Sanvier resistant we know the commercially available drug that we had for years, very toxic drug. You're all familiar with nephrotoxicity, minor suppression, we don't want that. And we know the impact of resistant refractory if you look at an organ disease if you have refractory resistance they have higher incidence of organ disease and they have the lower

[13:20] survival as well. So it's not good to get to this point in our patient population. Big unmet need and has to do with the toxicity of the drug as well. So we need a new drug and that's why you know Maribavir, it was statused early on for prevention of CNV, it did not work, but what about treating resistant and refractive.

[13:40] We conducted the SARS trial, comparing Maribavir to investigatory Alzheimer's disease therapy, and the primary endpoint was CMV clearance on two consecutive tests after stopping the drug, which is at week 8. Compared to the investigatory Alzheimer's disease therapy,

[14:00] And what we found here, the big difference in clearing CMV viremia at week 8 if they got Maribavir versus if they got other drugs like Dansactovir, Foscaret, or even combination therapy. And we stopped at the drug. A week to a while, we had lower, we had less patient who achieved clearer

[14:20] but more than the assigned therapy in this patient population. So it was a positive trial and got approval for adult or 12 years of age and above to treat resistant or refractory CMV infection. It's an oral drug, safe drug.

[14:40] and safer than the other ones. Actually, I think I have data on side effect of this drug. When you compare both, Foscarnet is more nephrotoxicity and Valgan, cyclovangans, ciclovir, more myelosuppression. Okay, let's shift here and talk a little bit about respiratory viruses. We know huge burden of respiratory disease.

[15:00] virus. I'm not talking about only COVID-19 or SARS-CoV-2. Different story, I don't have time to cover for that. But what about RSV? What about influenza? What about para-influenza? We know it can cause, you know, it can increase mortality and patients may die from respiratory failure. And there's many specific risk factors. We look for it.

[15:20] when we treat this patient if we have something to treat this patient. And these are the one that you are familiar with from lymphopenia, hypogamagluminemia, and other risk factor as well. That's how we used to treat RSV, higher risk patient after allotransplant in our institution and many other institutions, put them in a tent, give them a resoliderable.

[15:40] of iron. We knew that it wasn't really the best strategy and we didn't know if it worked or not. There were no randomized trials all based on retrospective data or prospectively collecting data comparing ersotol of iron versus nothing and we know and you know we know that it worked but I would show you the data.

[16:00] it's not a magic drug or magic bullet, but aerosolizers are already at mid-patient, put them in the tent for 10 days to 2 weeks, it doesn't work. We don't have much going on for RSV as a treatment, a polyvizumab, a monoclonal antibody, doesn't work when you have established disease, RSV, hyperimmune.

[16:20] IVIG also at the same time. But, and there's a new monoclonal antibody not tested in immunocompromised patients. Monoclonal antibody, keep in mind for infectious reason, early, better than late. Late doesn't work usually. Early on for prevention or maybe for early infection, it may work at the same time.

[16:40] as well. But we know based on systemic review and many retrospective collected data that there is a difference in outcome when you look at progression to pneumonia, if they got erythrocytebavine or eryrocytebavine versus they don't get anything. And this is pretty old review that we did.

[17:00] but also mortality. First time to show that there is an impact on mortality as well and this is one of the largest study that we publish on RSV. Same thing, if they receive antiviral, less progress and less die from RSV and this is high risk patient as well. Now, eryosinolibovirin, we know it doesn't.

[17:20] doesn't work, you know, it works, but it's not going to occur. And then all of a sudden, in 2015, the cost went up by 300%. It used to cost maybe 3,000 to 4,000 a day, and then the whole course cost around 300,000. So I said, you know what, there's no

[17:40] way when we don't have real good data to prove that it work in our patient. So we moved to oral. Now we're using oral and we went back to see that we do a disservice of the patient with oral rivaviren. We found no, same impact on progression to pneumonia versus mortality as well. Now, so that's why it made it to the guidelines.

[18:00] published probably last year or two years ago where in high risk allotransplant they have time to define which are high risk based on a immunodeficiency scoring index that we developed at MD Anderson where patient, you know, people are using it in all centers. If patient at high risk for RSV or other respiratory viruses they may get treatment.

[18:20] or not and this is recommended, ribovine is recommended until we get better drug. We tested, we did conducted few clinical trials for fusion inhibitors, it turned out to be a negative trial but still hope it there, there's few in the pipelines. Para influenza, quick thing, also it affect outcome in leukemia patients, stem cell transplant.

[18:40] lymphoma, myeloma, more progress to pneumonia, but also mortality around 18% if they develop pneumonia from para influenzae. With good news, we have a new drug, we've been tested for the past few years. The S-181 inhaled drug, it downgrades hyaluronic acid which is needed as an anchor for

[19:00] some of the viruses, para influenzae influenzae as well. We did the phase two trial. This is the first one ever actually done for para influenzae in high risk patients, but it was a negative trial. But what we found, if you target high risk only within one year of transplant, patient with lymphopenia, you get, you see antiviral infect.

[19:20] When it comes to clinical stability and mortality, it ran. So the FDA approved a phase III trial based on different endpoints, which is return to room air. If they were on oxygen with severe para-influendine ammonia, you can put them on this drug and look at it. So we're almost done with the phase III.

[19:40] We hope it is a positive trial and then we'll see if we're going to get the first ever drug for para-influenza in high risk patients with severe pneumonia from para-influenza. It's very common, it's not uncommon, we see it quite a bit, you know, in our, around the nation and everywhere. So my final thought, low-hanging influenza.

[20:00] We have a new tool to test for severe stilterimidative immunity. This will help us to manage patients at the bedside. The S-181 for severe PIV or RTI. I didn't talk about piliatilivir, another drug, different mechanism of action than acyclovir and varacyclovir for resistant HSV infection.

[20:20] Stay tuned for vaccine, RSV, monoclonal antibody. Hopefully we have some trials going on. And there's another also modality, which is an immune modulator can elicit adaptive immunity on the lung, PUL042. We're gonna start the phase two, hopefully by this month, actually, to treat a respiratory viral infection before they progress to no further.

[20:40] pneumonia. Thank you for your attention.

[21:00] happy to have you up here. Please put the appropriate slides. Okay, well we're getting the slides up. Thank you, Dr. O'Donnell. Thank you, my friend and esteemed colleague from Andy Anderson, Dr. Tappan Kadiyeh for inviting me. A big thank you from Madison for all her great help with getting it in.

[21:20] So I promise, Tepan, I will keep this to 15 minutes and I'm going to do my best to do so if I can advance the slides. There we go. Here are my disclosures.

[21:40] So what is new in hematopoietic cell transplantation? Obviously so much to cover and so little time. We're trying to make transplant safer in all the ways shown there. We're reducing relapse or trying to and have research targeting.

[22:00] reduction and relapse through those efforts. You know, we're studying special populations, patients who have non-malignant diseases, older age transplant recipients, and looking at health disparities. So I can't cover all those topics today in 10 minutes. So I'm going to focus the area, albeit I'm not sure.

[22:20] a little bit biased towards GVHD. But the area where really some of the biggest advancements have happened in the past decade and two in terms of making transplants safer for our patients. So here we see the pivotal trial from the early 2000s looking at peripheral blood

[22:40] versus bone marrow graft source for matrim related donor transplant recipients. This was done by the BMT-CTN. It was the first trial in our network. And all patients received the standard of care, tachrolimus, a calcium-aerd inhibitor, with methotrexate. And you can see

[23:00] 50% of our patients or so developed chronic GVHD. Fast forward to the modern era and many of us believe this approach is paramount to malpractice and we can do better for our patients. So how are we doing better for our patients with regard to

[23:20] prophylaxis from GVHD. Well, there's three backbone approaches. There's the calcineurin inhibitor, tachralymis, cyclosporin in combination with short-course methotrexate. Post-transplant cyclophosamide. This is where you get cyclophosamide on the third

[23:40] and fourth day after transplant, followed by tachrolimus and with or without mycofenilate. And this was work that dates back to the 1960s in murine and dog models showing cyclophosphamide was very effective in GVH uprophylaxis. And fast forward to the 1990s and early 2000s

[24:00] colleagues at Johns Hopkins began to show that giving post-transplant cyclophosphamide followed by tachrolimis could overcome HLA disparity. And we can now do mismatch or haplodenical transplants using this backbone. So this has just taken off in the past few years and increasingly at many centers.

[24:20] include my own. We are now using post-transplant cyclophosphamide not just in the haplo setting but in match-related and unrelated donors and in fact that's our standard of care at our center. Some retrospective single center reports have raised questions about possible toxicity with this approach. You know cardiac

[24:40] toxicity from cyclophosphamide. There's some retrospective single center analyses that suggest maybe you have weaker graph function and problem with counts when you use cyclophosphamide in this fashion. Some data to suggest maybe higher infection rates. And so there is still some

[25:00] concerns about toxicity with this approach. Finally, the third backbone is graft manipulation. So we know that it's the mature T cells in the graft that results in graft-versus-host disease. And so in the 1990s, depleting the graft of these T cells or

[25:20] selecting for the CD34 stem cell component was adopted. This requires some expertise and it's very costly. Some centers, notably Memorial Salon Kettering, was a really big pioneers in graft manipulation with CD34 selection.

[25:40] But those T cells are also needed for the GVL effect and so there's concerns with this approach as regard to maybe higher relapse. And then those T cells are also vitally important for early immune reconstitution in our transplant recipients and so these patients are profoundly immune deficient and we see

[26:00] numerous, numerous opportunistic infections. So how can we improve upon this in 2024? Well, using the TAC methotrexate backbone, you can add a third drug. Commonly, especially in Europe, in vivo T-cell depletion with ATG is used.

[26:20] More recently, Abatosept, a costimilation blockade, CTL4 agonist, was studied, added to a backbone of tachmethotrexate. And in fact, Abatosept is the only FDA-only agent FDA-approved for the prevention of GVHD, and this came to be through the

[26:40] Aba2 trial, where this was a randomized trial and match donor recipients. They've received either placebo or four doses of abatosept in combination with calcium eryninhibitor and methotrexate. And in randomized trial, this reduced the day 100.

[27:00] cumulative incidence of grade 2 to 4 acute GVHD, but importantly, it had no impact on grade 3 to 4 severe acute GVHD, no impact on chronic GVHD, didn't lower non-relapse mortality, and it didn't improve survival, and because of that, this really, this

[27:20] Despite being FDA approved, this has not really been broadly applied across centers. People are looking at extending a beta-septosing to mitigate against chronic TBHD. They're looking at giving a beta-sept with post-transplant cyclophosphamide, and that is ongoing research that hopefully will have answers.

[27:40] to in the next upcoming years. Okay, turning to post-transplant cyclophosamide, is this the standard of care? Well, certainly in the reduced-intensity conditioned recipients, there's good evidence to suggest it may be. This is the results of our

[28:00] our 1703 trial. This was a randomized multicenter phase 3 trial comparing tachrolimus methotrexate versus post-transplant cyclophosamide followed by tachro and mycophenolate. In patients who receive reduced intensity conditioned allotransplants from peripheral blood, stem cell, sore.

[28:20] The primary endpoint for this trial was GVHD-free, relapse-free survival. So to meet this endpoint, you cannot experience grade 3 to 4 acute GVHD, cannot have chronic GVHD-eating treatment, relapse, and of course, you had to be alive. And the trial

[28:40] was positive for this primary endpoint, much more likely to have griface when you received post-transplendent cyclophosphamide than tachymatotrexate. And this largely was because it was successful in reducing grade 3 to 4 acute GVHD, bringing it down from 15% to 6%.

[29:00] a less chronic GVHD, a third of the patients down to 20%. It did not do this at the detriment of relapse. There was no difference in relapse rates between the arms. And there was a non-statistical trend for improvement in survival, 77 versus 72.

[29:20] So at this past ASH, knowing that this was a trial mainly done in older patients who are appropriate for reduced intensity, the question was raised whether, you know, maybe, you know, since a quarter of the patients roughly were over the age of

[29:40] If cyclophosphamide is too toxic, we would see it in that population. And the hypothesis was that maybe in that population, post-sci is not the right answer. And here's the results of that trial. And it was quite surprising, or the results of that analysis. So in patients 70 years and.

[30:00] older consistent with the primary results, Griffiths was better in those patients than those who received post-sci versus tachmetlotrexate. But more importantly, and this is this is outstanding, overall survival was better in those patients 70 years and older who got post-transplant cyclophosphate.

[30:20] I mean it's crazy to think that at the overall survival rate at one year in patients who got post-sigh who are 70 years and older was 90%. I mean when I started in a transplant 22 years ago, you couldn't imagine getting a 70 year old patient, you know with that type of overall survival.

[30:40] And it was statistically better than those who got tachymatotrexate. This was because TRM was markedly low with post-transplant cy. And there was no indication that cy increased infections, nor increased cardiac toxicity.

[31:00] Really if you're going to see toxicity with the cyclophosphamide, certainly you would see it in patients 70 years and older. So what did we know from this analysis presented at ASH? Well post-I should be considered the standard care in patients 70 years and older. And this high survival rate.

[31:20] with post-transplant cyclophosphamide should really encourage greater consideration for L-transplant in this older age population with hematologic cancers. So what other strategies are being done to see if we can tweak post-saw and even get better results? Some are looking at

[31:40] The feasibility of giving lower doses of cyclophosphamide. At Mass General, across the board, they instead of giving 50, they give 30 times 2. Some data suggests that may have improved outcomes. In Europe, they give ATG in combination with cyclophosphamide. Some data suggests it may be

[32:00] chronic GVHD rates are even lower. The addition of the JAK12 inhibitor, ruxalitnib, has been given as additional prophylaxis following post-sci and has some really encouraging results. I'll show an abstract of that in a second, and it's actually shown here.

[32:20] So this was results from a trial conducted at Medical College of Wisconsin. My friend and colleague, Mehdi Hamadani, was a PI in this trial. And in this trial, they reduced the dose of cyclophosphamide from the traditional 50 times 2 to 25 times 2. So cut it in half.

[32:40] and they then gave microphenolate and tachrolimis and started ruxalitnib 5 milligrams twice daily once the patient engrafted and gave it for a year. Now, the results of this trial are premature. Their follow-up has been short and not all the patients have been enrolled, but there is very much

[33:00] very, very low rates of acute GVHD and severe acute GVHD really can't comment on chronic GVHD with a degree of follow-up at this time, but encouraging results. Alright, finally, in the last few moments, what about how can we improve upon graft manipulation? What do we know about historical CD34 depleted trans-

[33:20] transplants. Well, this was results of another BMTCTN trial. It was a three-arm trial and one of the arms was CD34 selection or T-cell depletion. And this is very effective at reducing graft-versus-host disease, both acute and chronic.

[33:40] to the single digits for both. But despite that reduction, overall survival is worse with CD34-selected transplants. And mainly this is because of infections and it's because of toxicity associated with that approach. You need to get very intensive conditioning regimens to get the graft in.

[34:00] and outcomes as shown in this randomized trial was worse with that approach. So how can we improve upon that? Well, ORCA-T has been the strategy of late to do this. This was work done by Robert Negron and colleagues at Stanford and they commercialized this into our company.

[34:20] company, where they said, okay, T cell depletion, CD34 selection doesn't work, but how about further manipulation of the graft? So with Orca T, you collect the graft from the donor and that graft are the progenitor cells and stem cells, of course. There's conventional T cells, regulatory

[34:40] T cells, NK cells, dendritic cells, et cetera. And with the Orca T approach, they do a CD34 selection and collect that and set it aside. They separate out the T cells and they collect the tolerizing regulatory T cells and then the conventional T cells.

[35:00] And with this approach, following ablative condition transplants, and it should be pointed out the donor is collected two or three days before the transplant, the cells are sent to a central manufacturing facility at the company's site, and in two days you get the cells back.

[35:20] cells are, the stem cell graft is infused on day zero along with the component of the regulatory T cells. And then two days later you infuse the conventional T cells. And this approach has been done. Patients go on to receive tachrolimis. It was studied first in a single center.

[35:40] at Stanford and then in a multicenter phase one trial. And it showed really encouraging results, low rates of acute GVHD, 4% severe, low rates of chronic GVHD, just 5%. Unlike traditional T-cell depletion, serious infections were very uncommon.

[36:00] And there is really low non-relapse mortality, 4% at one year, and no evidence of higher relapse. So this is currently being tested in a randomized phase III trial. Standard of care arm is receiving the traditional attack methotrexate following a blade of matched donor transplant.

[36:20] So, some have said, okay, well, the conventional, the standard care arm in that randomized trial is tachmetotrexate. We believe this to be inferior. How would outcomes compare when you compare it to post-Sci? And so at this last year's ASH, that question was answered, comparing it to

[36:40] orchitin, the patients enrolled on the multicenter phase 1B trial compared to the registry. The details that they presented were not that granular, but overall survival seemed favorable with the orchitin compared to registry patients who are matched.

[37:00] And just some hints that maybe Orchatea can even outperform post-transmod cyclophosphamide. Just in the last few seconds, not getting away from GVHE prophylaxis, there was a great abstract presentation looking at multicentered.

[37:20] analysis of looking at socioeconomic factors as predictors for patients who will get transplant, who gets a transplant, as well as outcomes, and it was fascinating to see that the socioeconomic factors highly predicted for likelihood of getting a transplant.

[37:40] But when patients got a transplant, the outcomes were comparable. So really interesting work. There was another trial results from the CHARM trial. This was looking at predictive models in patients who are older age getting an allogeneic transplant. And this trial showed that a there was a

[38:00] for a tool looking at composite factors could predict for disability in older age patients get on an allogeneic transplant. This is important because while we of course all fear death and complication, fatal complications following transplants, what older age patients often fear.

[38:20] is being disabled and being a burden to their family. Finally, a transplant-looking, abstract-looking at reducing relapse with maintenance chemotherapy post-transplant. This was work done at the Farber, where they did, looked at two dose levels.

[38:40] levels of Incoviz, either given days 1 through 3 or 1, 3, and 5 in combination with vin had o'clax, 400 mg daily for 14 days in every 42-day cycle. Eight cycles were given. In general, the therapy was very well tolerated. Most patients completed the eight

[39:00] cycles, although it was not uncommon for dose modifications to be needed due to cytopenias. With that, I think I'm very close to being on time. I thank you for your attention and

[39:20] That was really wonderful. And now we are going to change, as we've talked about the order of events just a little bit, and welcome Beth Faiman up, and she is going to do not one but two talks for us today, covering patient conversations, navigating complex cases, followed by addressing health disparities and hematologic oncology.

[39:40] Thank you very much. Thank you so much. Thank you, all of you who stayed, and even if you have to leave, that's okay too because it's a long day. I'm Beth Faiman from the Cleveland Clinic, and in the next 20 minutes, we'll cover two topics, first navigating complex cases and then we'll dive into some disparities in hematologic cancer. So, communicating with people is a very important thing.

[40:00] Patient is definitely challenging, especially if you're managing multiple conditions. Here I have a case example of somebody I saw in a clinic recently. This is a 48-year-old healthy male who worked full-time, no significant past medical history, went to the PCTP because he was feeling tired, had a hemoglobin of 10.

[40:20] went through colonoscopy, anemia studies, B studies, couldn't find anything. So he was referred to me for an IgA-CAPA paraprotein small M spike of 0.18. Felt fine, just tired. Thought he was tired because he had three kids under the age of 8 and was working full time. We reviewed the diagnosis.

[40:40] of MGUS, what that entailed, and the plan to identify the underlying cause of his anemia. These are his labs notable for CBC diff showed some anemia. He had a Kappa-free serum of 15,000. So when they screened for MGUS with an S-PEP, this was not captured.

[41:00] Notice at the bottom he had 12% peripheral plasma cells. Remarkably his serum creatinine was 1.8 okay, calcium and albumin were surprisingly normal in this healthy guy, but he has now plasma cell leukemia. So now rapidly this conversation changed. It was you have EMGUS, it's very common, low level.

[41:20] but let's try to find out what's causing your anemia too. Now you need an immediate treatment for your blood cancer. And we all know in this room that there's this long and winding road of blood cancers, whether you have a pre-leukemia, CLL, or an MGUS predisposing you to possibly multiple myeloma. You can go through a series of reminiscence.

[41:40] patients in relapses, unfortunately you might ultimately be for refractory to whatever treatment you're given. Survivorship concerns are very critical to address at diagnosis and beyond. One of the strategies that many of us employ in our practice is shared decision making. You saw this mentioned throughout the slides. We have bispecific antibodies, CAR T cell therapies.

[42:00] of different drugs available and how do you arrive that decision. So as providers we try to say this is what I think is best for you, but really involving that patient in on the discussion is super important. There's four essential elements that include two participants, the healthcare team and the patient caregiver. Both parties share mutual information, they take steps to

[42:20] to build a consensus, and then ultimately, a mutual agreement is hopefully achieved. And numerous studies have identified that this leads to less decisional regret, increased provider trust, and increased adherence. Empathetic communication is another strategy when you're managing difficult patient cases, and that's defined as both responding to emotions.

[42:40] patients and actively appreciate another's point of view. There are many different cultural and other factors that play into whatever patients want for them in terms of treatment or not treatment. Some people, like my patient, he says, can I just think about it or go home and take some herbs? You know, that was his first response when we started the discussion.

[43:00] answer is that's probably not what's best for you, but let's circle back and talk about the diagnosis, et cetera. And we'll get to how we approach that topic in a moment. But empathy is not what you say, it's how you say it. And patients will always remember how you relate to how you describe the diagnosis to them in the next

[43:20] And it's a way for us to remain patient-centric. So my favorite strategy throughout the years, and I've been over 25 years in the myeloma space, is to use this ask, hell, ask nurse strategy for empathetic communication. So again, the nurse stands for naming, understanding, respecting

[43:40] supporting and exploring the emotion or the response to whatever you're telling them. But I first start with like ask, tell, ask. So for example, when we start our consults, I ask them, what do you know about why you're here today and why am I seeing you? You tell the patient the plain language, what's important information to digest in small amounts, this is the basic information.

[44:00] and then ask the patient what they are absorbing. Of course, in my patient example with this young guy who had some mild anemia and fatigue, we had to go through this whole nurse whole thing, naming the emotion that we're observing. He was a shell-shocked. It was like the pathologist calls me 12% perfoplasmic cells. He's on his way home.

[44:20] lives an hour and a half away, has lots of work to do when he gets home. So we had to go through that. And using words like I see that you're surprised by the diagnosis, and I am too. So unexpected news can be overwhelming and just trying to recognize what he might be going through. Understanding what they might need, such as a little more information might be helpful. I'm not going to get into it.

[44:40] go into everything today, but let's just talk about what we need to talk about today. Additional staging information, additional scanning that might be required for us to get the right treatment for you to make you feel better. Respecting the patient, maybe they need a few minutes, maybe they need something to drink or a cool glass of water, you know, making sure that you're respecting them in their day.

[45:00] space and then supporting the patient. My patient was by himself and his wife was at home with the kids. So do we need to FaceTime somebody? Bring them in on the discussion and then can I get the social worker to come meet with you as well? And of course, exploring the concerns. In my patient example, you know, young, healthy guy, now he has a very serious condition.

[45:20] condition that we need to learn more about in terms of the bone marrow biopsy findings and imaging. But exploring their concerns. Like we've discussed a lot today and what are your concerns about next steps and really just letting them absorb everything. Now, my scenario is more focused on a new diagnosis, but end of life

[45:40] conversations in the patient communication space can be very, very difficult. In hematologic cancers, it's hard when they don't have symptoms and they have chronic leukemia or CLL to bring in the palliative care intervention early, but multiple studies and numerous different conditions have shown that early palliative care intervention can actually improve

[46:00] outcomes at end of life. And so I think just starting the conversation about what you know about that prognosis and bringing in the palliative team, they might meet with them once or twice, not see them for a year or two or three, but we talked about that winding road and there might be critical periods to introduce them to palliative care at other points such as relapse etc.

[46:20] This is just a conceptual model I threw in there about the multiple conversations over time. This was published in New England Journal of Medicine last year, but it just is really talking about how you have these cycling conversations over time. Hopefully, with an early palliative intervention, you can have increased quality of life, decreased psychosyptics.

[46:40] social stress and improved facilitation of end-of-life decision making. Now in the interest of time I won't go through these communication strategies. I'm biased of the ask-tell-ask nurse method because I've been using it for years, but this is just some communication strategies regarding prognostic awareness which were highlighted in the New England Journal of Medicine paper.

[47:00] last year.

[47:20] my chart messaging him, by the way, you have cancer. I hear that all the time. Or you need to see hematology, oncology, because you have a condition I'm worried about. Trying to talk face to face with them is really, I think critical to successes and building trust down the road. I think I already went through this whole ask, tell, ask.

[47:40] Ask him if he wants to connect with somebody, what do you think you understand about what is going on here, and then telling them just the basic information. One of the things that I think is of critical importance is the multidisciplinary team. I have a PhD and I'm a nurse practitioner. That's my role in the team. So I also have physicians.

[48:00] pharmacists, social workers, financial counselors. I am fortunate to have all that support system. So why not bring them into the discussion? So in this particular example, I knew he was my 1 o'clock consult, we got labs in by 3 o'clock, he needed to come back and we had that face-to-face discussion. And I told my nurse and my pharmacist and

[48:20] my physician that I work with, I work with 12 of them, but the one that was in the work room with me, and I said, can we all work together to get this patient what we need? Because I had a full clinic, I still had lots of patients to see. So bringing in your team is really important. We implemented shared decision making. You might not have a lot of options. We know four drugs that

[48:40] front for myeloma, anti-CD38, immunomodulatory drug, proteasome inhibitor, and corticosteroid is probably what most of us would recommend for this guy, but we still needed bone biopsy information imaging as well. And he might not have a lot of options, but is it inpatient versus outpatient? And we are at

[49:00] talked about empathy and how important that is as well. These are our key takeaways. Many hematologic cancers are not curable but highly treatable. Patients will go through a series of remissions and relapses, but hopefully if we can keep patient-centered, empathetic communication up front that will establish trust, decrease decisional rigorization.

[49:20] and enhance adherence. I shared with you my Ask Tel Ask nurse communication strategies and just want to put a plug in for discussions about prognostic awareness to start at the beginning and then interject them throughout the disease trajectory. And of course, don't forget to document all of these discussions in the middle.

[49:40] medical chart. So thank you for that. And since now I'm doing back-to-back presentations so I can get to the airport, we're going to talk about disparities in hematologic oncology. Sure is dry in here. Maybe it's the alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-alpha-

[50:00] My voice is shaky because of the trinest. Anyhow, I don't think I need to tell this audience about how prevalent hematologic cancers are. The 2025 new estimated cases show that lymphoma is, surprise, the most common hematologic cancer.

[50:20] But if you tease out all of the different subtypes, actually, multiple myelomas are number one. And that's why I do it. But anyhow, the deaths are from primarily leukemia as well. Unfortunately, we heard today about all of the advances in leukemias, lymphomas, myelomas that have been enjoyed

[50:40] the last few years particularly, but those successes have not all been recognized by all different groups. So there are obviously biological, environmental, sociological, and cultural factors which interplay into whether or not people will have successful outcomes. So just

[51:00] going through the top three, myeloma, lymphoma, and leukemia cancers. Myeloma is one of the hemolyganes with the greatest disparity in incidence, prevalence, and outcomes between African Americans, Hispanic, and white Americans. It's the most common blood cancer in African Americans, and the genome-wide is

[51:20] association studies have identified some germline genetic variations with increased risk in African compared to the European ancestry. Interestingly, some studies show that the differences in myeloma in African-Americans may lead to lower risk disease, such as translocation of 1114 and some other 14, 20, 14, 15, 15, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 25, 26, 27, 28, 29, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25, 25

[51:40] with many subtypes involving those translocation differences. Hispanic patients unfortunately are younger at diagnosis and have more advanced disease. This is just a slide again highlighting the disparities in the diagnosis treatment and outcomes. Two times more likely African Americans are to have myeloid.

[52:00] than the white counterparts, delayed diagnosis, less likely to undergo stem cell transplant, and are underrepresented in clinical trials, both African-Americans and Hispanics. Slower gains in overall survival improvements. Again, we have this vast improvement in overall survival. And you'd think because they have better disease, they would recognize that.

[52:20] Unfortunately, that's not true. So I stole this from my friend and colleague, Dr. Joe McHale. African-Americans are less likely to receive the four T's, transplant, triplets, cartons, and trials. So being aware of this is a thing. When you see these patients in clinic, please try to offer them equal access to therapy.

[52:40] Now there are disparities in lymphoma and outcomes as well. Non-Hodgkin's and Hodgson's lymphoma are again similar to myeloma. The black's Hispanic populations predominantly do not get the same care. We also saw the different somatic mutations and driver genes that are listed here that are more common in patients with asthma.

[53:00] compared to European ancestry. In terms of leukemia, surprise disparities exist there as well, higher in men versus women, and although overall survival outcomes seem to be improving, especially in acute myelogenous leukemia in the last several years, especially with all these great new drug developments, the different racial and

[53:20] ethnic groups do not get that benefit in some studies. So this is just a conceptual model that highlights the disparities in survival in the context of hemagogical malignancies. This is from a meta-analysis that was recently published, I think in 2023, Blood Advances, that looked at the different education, access and quality, neighborhood, healthcare,

[53:40] access, social community, et cetera, pretty much the social determinants of health. And this was in all hematologic cancers. And consistent with many other studies, this meta-analysis looked at and identified that lack of health insurance or having Medicare or Medicaid, receiving cancer treatment at a non-academic facility.

[54:00] low household income, low educational level, and being unmarried were big drivers to treatment outcomes. So additional drivers that were also highlighted in other areas, the health care system, systemic racism, we talked about the social to hermitous health as well, implicit and explicit biases.

[54:20] I think of that in regards to clinical trials where you see somebody in clinic and you're like, they're not gonna be a good clinical trial candidate because they never call when they need anything or they miss appointments. But having a conversation, establishing trust, opening the lines of communication is one major way that we can impact and hopefully overcome the lack of clinical trial representation.

[54:40] representation, I always say just ask. So don't have your biases of who's going to do good or not, just ask. So what are some barriers and recommended treatments for patients with hematologic cancers? I think of it in four buckets, trust, awareness, clinical trial opportunities, and access to care. And you can pretty much read here on this

[55:00] slide. Trust is definitely a big barrier. It can be cultural, it can be social, and a fear of mistreatment, historical stigmas, and not trusting the provider. And so that's where trying to establish trust. People just might want to have a little bit more time to communicate with you, asking questions and feel comfortable.

[55:20] comfortable in the encounter. Awareness of the disease, the risk, language fluency, these are all things that can be barriers to acceptable treatment in patients with disparities. Clinical trial opportunities, like I said, just ask. Don't assume that your patient might not want to participate in clinical trials. Try to explain.

[55:40] to them the benefits, how it might be helping them, might be helping others. There also can be a bridge for the financial burden that they might be experiencing. For example, they might live 60 miles away and you think, oh, they're not going to want to participate in a clinical trial, but a very well-designed clinical trial that might be sponsored by pharmaceuticals.

[56:00] or another company, then they can get travel assistance, reimbursement for parking and other expenses, not coercing them, but giving them that opportunity to participate in that clinical trial. And then access to quality of care might be a barrier, too, that we need to overcome. So some solutions are highlighted here for the Trust Awareness Clinic.

[56:20] clinical trial and access to care, you can read these as well. But again, just really trying to communicate and access and establish trust, giving time for the patient and the caregiver to answer questions, explain to them why you think that this treatment is superior to other treatments out there, and having that conversation. Again, making sure that there's culturally appropriate.

[56:40] communication in their language. That's one of the problems with the clinical trial participation is there might not be a consent form in their native language. So making sure that you're translating those consent forms if you have a high Hispanic population or other Asian-speaking population is important. Accessing to social workers, financial

[57:00] counselors. Partnering with them in the communities is also important as well. Innovative ways to assess the medical costs of transportation back and forth. The appointments can be happen. Like a lot of insurances will have a benefit for Uber or Lyft services. Like in Ohio we have about 60 rides per year. Some of the insurances

[57:20] are allowing. And then our hospital does also have a patient fund based on benefactors where they can have transportation assistance as well. So in conclusion, disparities in blood cancer exist and hopefully we as healthcare providers can help bridge and overcome those barriers and gaps in care.

[57:40] identify and intervene with some innovative strategies as well. Thank you. Can I get us back on time? You did. Dr. Famen, fantastic job and thank you. Marathon, marathon. Great round of applause. Okay so we're going to move on now to our next speaker.

[58:00] to be Dr. William Dale from the City of Hope, talking about a very important topic for all of us as we treat our patients and in our aging population. It's hematology and aging, tailoring treatment for older adults. Dr. Dale, thank you. Thanks. For those of you who are hanging out, thank you for making it to the bitter end.

[58:20] glad you're all here. Some of the earlier talks I think are a nice setup and I always remind myself in these circumstances that Lincoln did the Gettysburg Address in two minutes and we still remember that one so. These are my disclosures which I don't have any. I really like older people. The woman on your

[58:40] Our right over here was 112 years old when I took care of her. These last week I had a 101 year old who had two cancers that were treating at City of Hope and a 104 year old were also treating with surgery. So for those of you who were looking for places to treat these older patients, we're doing that at City of Hope.

[59:00] These are just a reminder. So I'm just gonna give you some basic tools. So the way to take care of older patients, as we saw, there's all these barriers to care. All of what you just heard about with all the different groups that you described, you don't have access.

[59:20] Most of them are older. When you look at clinical trials and you see who's enrolled in clinical trials, most of them are younger. The patients you have to treat in clinic, the majority of them are older. So your typical patient is an older patient who you're trying to treat with data from people who are younger, many of whom have had a lot of access barriers to get them.

[59:40] there. So what do you do with these patients is what I often get asked and some version of a geriatric assessment is what you do. I'm not just going to tell you that. I'm going to show you the two large trials that just change the treatment guidelines that are making this basically the standard of care and I would encourage you to use the tools which we're trying to make available. So the essential

[01:00:00] The essential tool is all those domains we just heard about that prevent people from having good outcomes is what's in these assessments. And we've spent a number of us, many, many years trying to come up with the most concise, simple way to assess performance, function, cognition, psychology.

[01:00:20] nutrition, social support, all those things that are essential to treat patients that we basically don't assess very much at all in our clinics these days. So what does this look like? These are all in hematological illnesses. When you do screenings for patients who show up in any of our hematological

[01:00:40] clinics. These are the percentages that you will find who have deficits that are significant in these domains. You may be surprised. I know my colleagues often are to see that a quarter of their patients will have cognitive issues that are unidentified. Patients that have 50% of them don't have social support that makes it possible for them.

[01:01:00] to go through treatments. So when they get to us, they do very well, but getting to us is often the problem. So just, this is like the super fast primer on this. So we have a chemotherapy toxicity risk assessment tool available online at the MyCarg website that allows you to predict in advance of receiving.

[01:01:20] chemotherapy grade 3 to 5 toxicities. If you use KPS to do this, you might as well just eyeball them because that's about how good KPS is at identifying those who are going to have toxicities after treatments. If we use this risk score with 12 factors in a scale from 0 to 19,

[01:01:40] can give patients the pre-treatment likelihood of toxicities from 25 to close to 90%. I also showed the form at the MyCard website. You can go there, log in, it's free to the public. This is a real quick timeline, which you can see in the slides, of the two randomized trials in the ASCO update.

[01:02:00] how to take care of older adults with cancer, which we led from City of Hoh. This is one of those trials called the GAIN trial, which reduced chemotherapy toxicity, increased advanced directives, completion significantly, and what was done was a geriatric assessment was done.

[01:02:20] prior to the trial, randomization, supportive care interventions were put in place afterwards, and both heme and non-heme toxicities were significantly reduced. This is the GAP trial published in Lancet. This is the exact same geriatric assessment that's

[01:02:40] on the website in which chemotherapy toxicity was lowered over 20%, falls were reduced, medications were adjusted mostly to be decreased and polypharmacy went down. The chance of getting reduced dose intensity went up and the chance that your survival change

[01:03:00] was not at all. So all you got was chemo, reductions in chemotherapy, toxicities, less dosing of toxic medications, and the same amount of survival. And I would suggest that's a good intervention and it would be a nice drug. It's not a drug. You just have to do the actions required.

[01:03:20] This is the framework we just heard about decision making for older adults. This is also published in a JCO article in which you determine vulnerability using the geriatric assessment, then you can predict toxicity risks, life expectancy, and targeted intervention.

[01:03:40] Then you can use that to tell people about their risks, overall benefits and risks, and guide your therapy appropriately to maximize according to their preferences, balancing quantity and quality of life. What are the barriers to GA use? So we did a big survey.

[01:04:00] of about 1,200 oncologists and asked why is this something that's so hard to do. On the left is what they told us in that study. On the right is one for transplant. And essentially people say these tools are great, we believe they work, but we don't know how to use them. We haven't been trained in how to use them.

[01:04:20] them and we don't have the support to administer them in clinic. So our task has been to create for people an online available tool. This is the action chart from the ASCO guidelines that tells you exactly what the tools are, which have been boiled down into about a 10-minute assessment. The items that you should

[01:04:40] act on what the cutoffs are and what the intervention actions you should take would be. In a way to make this as straightforward and simple, but also bring this powerful tool to clinic. Most of this can be done not by oncologists. This can be done prior to clinic by other personnel in the clinic.

[01:05:00] We do it with online assessments, two small tests in the clinic with our medical assistants, which is then given in a digested form to our oncologists so they can add it into their discussion with patients. Now shifting real quickly to heme malignancies.

[01:05:20] Age is associated with almost all of the hemolyganes in terms of a risk factor. As people get older, the chances that you'll have a hemolyganacy go up. What is really helpful is as we expand these therapeutic options, as we heard about earlier, age is where that expansion is going to occur.

[01:05:40] There's a new tool. This is the tool specifically for transplant patients who are being considered. We saw the encouraging data about those over 70 with the availability of transplant possibilities or CAR T. The CHARM study was just completed by the network.

[01:06:00] These are the factors that ended up in the model for the CHARM tool. This paper has not yet been published, but has been presented at ASH. So there are lab tools, albumin and creatinine clearance, CRP, comorbidity index,

[01:06:20] drugs, cognition tool, age, weight loss, and KPS were all entered into this charm model. What came out of this is that non-relapse mortality at one year was predicted by sorting using the charm tool, and overall survival at one year was also

[01:06:40] able to be sorted through use of the charm tool. It's available online but you have to have the permission so far and they're about to make it more publicly available. I just wanted to remind people so they can reach out and you'll be able to simply put in these values and it'll tell you exactly what the non-relapse mortality estimate is at one year.

[01:07:00] for patients over the age of 65. Very quickly, I wanted to just show you that we have a multidisciplinary clinic at City of Hope that uses geriatric assessment prior to stem cell transplantation for patients referred to us by our colleagues who are over the age of 60.

[01:07:20] I won't walk you through all of the details, but what I just described for you, we're able to put into our clinic with minimal disruption of the clinic flow in close collaboration with our colleagues. It allows us to sort patients into the proper places and to make one of three decisions for people.

[01:07:40] We are not in the business of telling people not to get transplants. So that is often the fear of people who show up that they're coming to our clinic to hear that they've been ruled out for the possibility of transplantation. Most of them have come to us from other institutions that have said, essentially, you're this age and we don't transplant people who are over that age, which is

[01:08:00] is really a discriminatory approach to patients who really should be transplanted based on fitness and the ability to complete the trial. And so we've tried to redress that difference. So what we say is this is a healthy person who happens to be older and they should be treated like every other patient who enters into transplantation.

[01:08:20] go forth with the plan. At the other end of the spectrum, we say this is a very high-risk patient. Here are the risks of the toxicities that they'll experience. Here are the risks that they may even have a disease that will limit their life with a successful transplant or not. And you should be clear with the patient about those risks before you go forth.

[01:08:40] The middle category we call defer and optimize. So there's often something that can be corrected, which is the value of a geriatric assessment because they are addressable, correctable problems. So you can defer the transplant for some time until people are optimized. And our outcomes have shown that we continue to have

[01:09:00] outcomes, especially for this middle group of patients. And a couple of publications have documented this and we recommend it for others and happy to share. So this is what happens in general. So over half the time, proceed is the answer. But with about 25% of the time we do a defer and optimize.

[01:09:20] and the outcomes have been quite good after that. This one I'll keep in the slide deck, but really explains in more detail exactly the workflows that we've put in place that really maximize disease control, improve the resilience of the patients after they recover, and then

[01:09:40] then tailor the platform so that we don't intervene on everything but on those things that matter most for patients and that are correctable. We can't make them younger, but we can make them fitter in many cases to tolerate the treatments. Last two slides. I'm going to do mine in under 10 minutes, I think, so you guys can give me

[01:10:00] round of applause for that piece. So we have funding to create infrastructure to help care for older adults across the country that combines our Rising Tide Foundation with what's called the Geriatric Oncology Treatment Optimization Program. We have,

[01:10:20] collaborators across the country, as you can see in the lower left. Infrastructure on the right I will highlight. This is an NIH infrastructure grant, an R33 grant, that supports an analytics core, a measurement core, a supportive care core, communications.

[01:10:40] and analytics along with a bunch of other things like this scoreboard that I mentioned. These are patient partners who are over 65 years old who have survived cancer, who are close collaborators in all the work we do so that patient input happens from the very beginning of all of our studies. We've had people come to us and say,

[01:11:00] to our cores, which is available online, to join us and get advice. We've had 50% success rate that those who have come to us and have utilized our cores in getting grants, mostly NIH grants, from the input that we give, and we just had a number of R01s funded across our network.

[01:11:20] This is the rising tide studies I wanted to mention, the go-to studies highlighting our hematological carte therapy study. Five different randomized trials with the same geriatric assessments, which are going to give us answers to questions relevant to older adults for lung cancer, breast cancer, prostate cancer.

[01:11:40] cancer, and community-based cancers along with our cartease therapies. These are all my friends who help us do all this work, many of whom I have close contacts with, especially like Beverly, who's sort of in the middle off to the left with me there. She's a 90-year-old person.

[01:12:00] old African-American woman who's been a patient partner for many, many years and has been instrumental in forming Scoreboard and making sure we have patient representation in everything we do. These are the answers to the questions. You guys will have to figure that out if you are doing your CMEs, and I'm finished. Thank you.

[01:12:20] Thank you very much, Dr. Dale. So we made up a lot of time here, so we'll give everybody a quick bio break, get a beverage, go to the bathroom if you need to, and then we'll resume for our last portion of the programming, which will be a panel where we invite our participants back up on.

[01:12:40] on stage and we really welcome any questions from the audience whether in person or online. So if you're online please send them in now and we look forward to hearing them. Thank you. Alright ladies and gentlemen let's get started with our panel discussion. We have many of our esteemed faculty and I invite you up to the stage.

[01:13:00] sitting there? And this is your chance. Okay, this is what it's all about. We kept it small so that you can ask all these famous people some questions about what they've talked about. I've got some questions ready, but I really like to hear your questions. Dr. O'Donnell's there on the other end as well. So we'll kick it off. We also have some online

[01:13:20] questions that will go up, but let's start with the audience. Don't be shy. These guys are not so scary.

[01:13:40] You can. You want to have one here too. Alright, we got it. We got it everybody. How about it? Alright, this is an important task. Could we take this slide? Alright, so let's see. Anyone from the audience? Raise your hands. Don't be shy. We got mics for you. We can come out and find you.

[01:14:00] Alright, just to break the ice a little bit and start it with a question, we'll start with Dr. Jane. Dr. Jane, beautiful two talks on CLL and CAR T cell therapy. I'd like to ask you something about CAR T cell. You gave a really nice discussion about OB cell and the new therapies.

[01:14:20] One thing I want to know about more is the use of MRD and how you use that to guide sort of a consolidation therapy, maintenance therapy, CAR T cell, as well as the use of alginate stem cell, or the indication for transplant in people who are MRD. And also use adaptive clonosic as well as flow.

[01:14:40] asking the context of ALL. ALL, sorry, yes. So, you know, so ALL is ample data that if you're MRD-positive, whether it's by flow cytometry or by clonosic or NGSMRD, there's a high chance of relapse if you don't act on it or do something about it. So in the context of cortisol therapy,

[01:15:00] I guess the question is, if a patient is MRD positive, can you use carticel therapy as a therapeutic approach? So prospectively that is being studied now in several clinical trials. They have not been, they're still enrolling. But at our center we have used in retrospect, in a real world setting,

[01:15:20] cardiac cell therapy in patients with very low tumor burden, less than 5% blast. Some were flow MRD-positive, some were clonosic MRD-positive, some were in fact clonosic-negative. And we have seen cell expansion on those patients. So I think, certainly I think cartees would work in low tumor burden setting. Now how low you need to go and whether there will be a lot of pain.

[01:15:40] will be a threshold where maybe cartease won't expand as much. I think that remains to be seen. I guess MRD post-cartee, if your day 28 post-ALL cartee was anyone like Zoma 3 brexacil or obicil, and if you're MRD-positive, whether by clonosac or flow, I think that's a very high risk of relapse.

[01:16:00] I think those are the patients. You can wait, but I think that these patients are not going to do very well, very likely going to relapse, and you really need to think of that as a potential disease to relapse, and depending on what therapy patient has received previously, you may want to think about adding the next salvage therapy. All right, so just a quick highlight, just a quick high-yield question. If a person is a salve,

[01:16:20] With a person with ALL who is high risk at baseline, is clonosic negative 0.0000? Do you still stand that patient to transplantation? So yeah, so that's an area of new research to see. So that's a, in our setting, I think if I personally, if someone is a serif 2, which is the high risk marker.

[01:16:40] rearrange young patient, has a good donor, I personally would still after CAR T do an allotransplant. Though I think if the, but on the other hand if you, like if the MRD, sorry I missed that part of the question.

[01:17:00] to transmit the amartipos. Yeah, yeah, so I think that, I think you can salvage that, what was the patient scenario again? Just a high risk patient. Yeah, high risk patient. So I think the question is if the other high risk patient, for example, complex keratitis, P3-mutated, which are maybe high risk in some settings, if they become clonosic negative.

[01:17:20] after using hyperceivative based therapy pediatric regimen where you have now incorporated a monotone map, maybe anatos of map, and if they become clonosic negative, I think it's quite possible for those patients you may not need transplant. But I think that's something we need to study prospectively because all the data that these are high risk markers.

[01:17:40] were derived from the era when we were using chemotherapy alone, like hyperceivad and augmented BFM regimen, pediatric regimen. Now that we are adding Inu and Blena, and Blena as you know has become now standard to be added to every regimen, adult and pediatric included, I think those high risk markers need to be redefined what remains still high risk marker.

[01:18:00] So I think that it will take some time because B cell AL is a rare disease, especially adult BLL. So I think it will take some time to generate that data. Excellent. Any audience takers so far? Yes, sir. So when those patients that are getting treated for limited or with the kind of progression of treatment or inpatient treatment, they can't be treated.

[01:18:20] they come up with treatment. How do you monitor them after that? And when do you decide that they need to do that? So this is CLL, right, Rastin, right? Yeah, so one thing is that MRD per se is not a criteria to treat CLL patients, right? So it's very different from ALL setting.

[01:18:40] You know, so the recommendation right now, prove regimen for example, when opening to Zomad or vendor tax on the lab setting, everyone is for one or two year duration. And in fact, the upcoming Akala Ven regimen will also be a one year duration regimen. So if they are MRD positive at the, at the, at when you're stopping therapy, one thing is clear that if you're,

[01:19:00] MRD-positive, mostly data is with flow, but clonus included, those patients will have a shorter PFS. Makes sense. If you have active disease, still some remaining disease, they're specifically short for PFS. Now the question is how can you intervene on MRD-positive patients? What you should do? Should you extend the duration of treatment? Should I continue a cholera treatment?

[01:19:20] than two years. Should I add opening to is a member at that time? Some data from our group and others have suggested that longer duration of therapy improves the PFS. We have done two years of the protein plaques and that improved the PFS at five years. But that is still not kind of standard of care. So I.

[01:19:40] I do use MRD at the end of treatment to get that knowledge if the patient is MRD-negative bed flow cytometry, I'll be very comfortable that maybe that patient will have a five, six, seven year remission duration and that's on the flip side if they're MRD-positive, it's possible in the next two or three years that patient will relapse. Now, whether I'm going to act on the MRD at this time.

[01:20:00] time, depending on the regimen, I may continue it. I have the neudoplex longer for those patients, especially in the relapse setting, because then you are worried that the patient will relapse and they will not have very good options. But I think the MRD connotation in terms of CLL and ALL, which was talking before, obviously very different because CLL, if you're MRD positive, CLL, you don't have any treatment.

[01:20:20] that you don't treat in general, right? And that's not a recommendation at all. So I will treat it maybe in a part of a clinical trial, but in routine practice, I would not recommend acting on it. Okay, other questions? So then there comes a different thing. Then you have active disease, then you treat, but just MRE-positive, normal counts, normal lymph,

[01:20:40] practically no symptoms, these patients can gone for some years without needing treatment criteria. Ma'am. So with the new AV and AVO regimens coming, are we seeing patients needing inpatient treatments at the beginning of the year?

[01:21:00] therapy for TLS or are we kind of past that phase of things? Yeah, so I think one of the things with the AV and AVO is that the first two months in the AV, for example, is a collaborative alone. So that, the B2K inhibitors are very good in debulking strategies and we and others have shown that 80 to 90% of high-end inhibitors

[01:21:20] high risk tumor lysis syndrome or medium risk tumor lysis syndrome become low risk at the end of two or three months of BKK immunotherapy. So you start a patient on day one on a calabrotona, two months later you add an atoclax, but by that time the tumor bulk will be much decreased. So I think the number of patients required

[01:21:40] hospitalization because they're still high risk at and when you're starting an interplax I think we'll be less than 5% probably like 1 or 2% range so majority of the this regimens will be outpatient regimen in my opinion for majority of the patients thank you doctor O'Donnell yeah so I have a question for dr. Yi so you shared with us some

[01:22:00] good data from Dream 7 and Dream 8, specifically looking at bilentomatomatodontin in combination with portesamid and dexamethasone in comparison to daratuma. But really, I think the bigger question when it comes to BCMA-directed therapy is how do you think of this BCMA drug versus some of the others, the bispecifics and the

[01:22:20] in a CAR T cell when you think about your recommendations for patients. Right, so, well thanks, thanks Betsy for the question. So this, you know, when you have all these things to choose from, I mean back, you know, years ago, if you didn't have many choices, the decision was a lot easier. But now that we have all these different drugs to choose from, then the decision is over.

[01:22:40] you're making gets a little bit more complicated. So essentially, I mean, I guess it's a broader question and this question comes up, do you pick an antibody drug conjugate, blood from a methadone, do you pick car T-cell therapy or do you pick anti-abusement by specific antibodies? And a lot of it depends on what you have.

[01:23:00] have available to you, what do you have available to you? So I think if you go to a major medical center, now here we have access to all those therapies available, so then it is kind of a decision, whereas I think in the community, say if you live like two hours away, like you don't live right next to Amity Anderson or something, but if you live in, you know,

[01:23:20] in a more resource-limited area, you don't necessarily have all those therapies available. So then the choice may be more constrained by what's available to you. So I think all things being equal, I mean just to answer the question rather than just dodging around and say, well it depends and so forth. Okay to answer the question, so if I see a patient who's had four prior lines of therapy, I think a lot of those things

[01:23:40] At that time, all those therapies, in a CAR T cell therapy, or a bi-specific antibody will be available. And I think all things being equal, a patient at that time, after they've been through four-pride lines of therapy, usually is kind of ready to try something completely different. I think all things being, I think CAR T cell therapy, what we see with the cell therapy.

[01:24:00] the cell data in terms of the PFS of 3 to 4.9 months, I think that is a high benchmark to clear. And I think there'll never be a direct head-to-head comparison so typically if a patient has been through multiple lines of therapy, I typically would recommend a CAR T cell therapy compared to a bispecific antibody. Now granted,

[01:24:20] In the future, I think by specific antibodies, you could probably augment the response further. They're looking at combinations of anti-BCM and anti-GPRC5D. Then there is also trispecific. But I think that CAR T cell therapies are probably, I would typically recommend a CAR T cell therapy. This also gets into the sequencing as well, because we do know that,

[01:24:40] If you've had a prior bispecific antibody that could theoretically compromise the efficacy of a subsequent carb T-cell therapy. So granted this is really tiny, a small number of data, but people looked at patients who received an antibesamine bispecific antibody, then they had siltacil. And then those patients, there's only seven patients.

[01:25:00] I think the PFS was like five months. Granted, there's probably some small numbers of patients and confounders, but there's that theoretical possibility. Now, the alternative would maybe you could do a taucatamab instead and then you could do like a TMA for a B-smead-Car T cell therapy. Now, in terms of...

[01:25:20] At the same time, I also, I mean, these questions come up all the time when patients come to see me in clinic. At the same time, I also recognize that CAR T cell therapy, I mean, it's a lot of work, right? In terms of, there's a lot of logistical, there's a lot of logistics involved in terms of, A, the patient has to get to the medical center to get, and then they have to.

[01:25:40] They get the cells collected and then you get to think of up bridging and then they have to stay around the area for around 30, you know, for about 30 days. They have to have a caregiver with them. So they have all these T's to cross and I's to dot and not every patient has all the, or not every patient wants to go through all that. And I think for some patients or many patients, I think the bispecific antibodies can work.

[01:26:00] exceptionally well, I think for patients who have a biochemical relapse. I think the bispecific adibis can be a really great option for those patients. Now, then we get to, I think, Belantimatidodin. I think that DreamSabot and Dream8, granted, it has a movie behind it, right? Okay, that was a joke.

[01:26:20] I think in terms of all things being equal, keep using that, how'd they come up with a different expression? I think the bispecific antibodies, when they work, they work amazing when patients are really happy with them.

[01:26:40] And I think the infection risk that is generally a lot of concern, I think it's less of an issue in 2025. I think when they first came out, yes, it was really high infection, but personally, I've just not seen that degree of infection. And the whereas the bollantoat methadone, I think the major limitation is the ocular toxicity. So I think personally, you know, I

[01:27:00] I think it's as easy to buy specific antibodies and easier cell than the than Bellatine methadone. But I think if you're giving it out every eight weeks, maybe you have to get an eye care professional. I think that these start with all things in flux. That was kind of a long woody dance. Thank you, Dr. E. Any questions from the audience guys? Anything else? Bravery? Yes, ma'am.

[01:27:20] I have a question also for Dr. E. He mentioned when you talk about the plistimatidatiminatorine tosylizumprophylaxis, can you speak about that a bit more? Right, so tosylizumprophylaxis, so you saw that some of the initial data for 25 patients, the risk of CRS went down like 75% to maybe 25%. And then there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things. Okay, so there were some other things.

[01:27:40] some data that was presented at ASH University of Miami. It's only 14% total CRS, and now that's in the NCCN guidelines. Have we been doing that as a product? Those are just fresh off the press. So we haven't been doing that yet, and we have our own protocol where we're not using total salism abs.

[01:28:00] I think the major limitation, if it can be covered by insurance, why not? I think it's probably a no-brainer to try it. If reimbursement is not an issue, I think I would totally explore that. I think the dosing would be the same as the standard for the occurrence of CRS.

[01:28:20] I brought off the top of the head, you know. Great. Love the audience participation. Others? Sir. I have a couple of questions about M-E-N. You practice at altitude and I don't know what comments you might have in terms of a somatic or potential for patients with low altitude. Some of our patients come from...........................................

[01:28:40] Yeah, thank you for that question. So the first question is an important one. The altitude does come up a lot. It comes up in clinic for patients who travel

[01:29:00] quite frequently and especially here we are in Vail. I just pictured the board dissociation curve in my mind when you said that. So it is a real issue and I'll tell you, it affects us in two ways. One is in the secondary or reactive workup, which I mentioned briefly. So there are two, three DPG abnormalities.

[01:29:20] And so it is a good one. It's not just a board question, but there are subgroups of patients, Tuvos region of Europe and others, Andean region, Tibet. So people who live at higher altitudes, you think they have PV, but it's actually a reactive thrombocytosis. And then there are also people who have von Hippel, Lindau, and other sort of

[01:29:40] sort of gene family mutations that can have an erythrocytosis. So I think this is an important point. So differentiating secondary from primary. In patients who have PV, you're right. We still say below 45%, but actually we make caveats all the time, don't we? So sometimes for our female patients, we do below 42% hematocrit, altitude, we make an exception.

[01:30:00] There are people who split their time. Obviously you guys know here, half the time here, half the time at sea level. So you're right. I have to say, you're not going to see it in a textbook, but we do make those changes. What was the second question you said? It was about variant alien triclids.

[01:30:20] like an intern at Johns Hopkins. We envied CML, now even Flit 3. Everybody is following a leo bird and we were the last ones. But I did show one slide on this and I'm glad you brought it up because I want to make sure that's one take-home point for today. For the very first time, very little fraction matters. There are two classes of drugs and interfereal drugs.

[01:30:40] interferon, so the Rope-Pegg interferon. But even before that, in Pegelated interferon, those studies showed a clear decrease in JAK2, allele burden, and even CalR as well. Not always correlating with outcomes, but it's often. And then in the MAGIC study by Claire Harrison, UK, that's the one that I want to focus on. That's Ruxallit, NIB.

[01:31:00] versus best available therapy. Hydroxyurea was the first one and for the very first time, decrease in allele fraction correlated with EFS and overall survival improvement and possibly even reduction in thrombotic events, all the things we care about. And this is something that caught everyone off guard. It's one of those things we've been saying for 20 years.

[01:31:20] It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time. It's been a long time.

[01:31:40] Is it the allele burden? Is it, you know, so actually people are reporting it differently. And then what are you going to do about it if it goes up? We're not making therapeutic decisions based on it. So I think both of your questions are super important practically and they've come up for me in clinic in the last six months. We have a question back here.

[01:32:00] So I work at even higher altitudes than what you do. I work in Dillon and then my patients are in Leadville which is 10,000. So we're, most of our patients, I mean I do a JAK2CalR NPLBCR-able testing all the time because we have to. It's just one of those things. Well that's interesting. But then on top

[01:32:20] of that too, the other side of it is with polycythemia in this population at altitude, you do get blood clots, you do get chest pain, you do get vision changes and headaches. So I am, I have to do phlebotomies on these guys and I set it to 50% because there's no data on that. Tibet is the only paper I could find that actually looked at that. That's what I was thinking of, right?

[01:32:40] that's probably equivalent to living in Breckenridge and Vail and all these places. So I will say Denver's a little lower. Salida is like 7,500. So you get to know everybody from what their levels are. I was off that. This is a great, and if I should add, I practice at sea level in Houston.

[01:33:00] Joe Prakal, Joe Prakal, some of you may know him. He's one of the really great investigators in our field, an MPN. He's in Salt Lake City now. He's done some of the studies you said. So he's taken the Johns Hopkins cohort in Baltimore relatively at sea level and compared to Salt Lake City. So it's exactly what

[01:33:20] both of you said, precisely what you said, both practically, but also they're looking at HIF1 alpha, hypoxia, so there's a whole thing. And then I should also mention, Prochol had an ash plenary session this past year on exactly what we're talking about. He studied an Andean South American population who has exactly what you said, differential, and they found some

[01:33:40] some EOR gene variation. I just can't tell you how excited I am, both of you. We're going to take over this total. They had no idea what was inside of her when they had us here. I mean, what we're hearing is there's probably a lot more polycythemia out here because of the altitude. And how do you differentiate that? I was going to say I do have a second question with you too. So one of the things, because I am an artist, I'm a scientist.

[01:34:00] end up screening all these people, I find way more mutations than probably I should, mostly because I screen everybody that comes in the clinic. I never did that when I was working in California. That was just not a thing, right? A little more, I guess, reserved in ordering that stuff. What I have noticed also up here is I have a lot of CalR-

[01:34:20] myelofibrosis in my clinic and how best do you treat those because obviously the JAK-2 inhibitors don't work as well. We know that from some of the data and I mean I'm struggling because I'm having patients progress. What do I do? Great. So CalART's one of my new topic areas. I really love this area. So three things to say quickly.

[01:34:40] One is by and large the JAK inhibitors are working regardless of triple negative, JAK2, calorimple since they at least signal through the same ultimate pathway JAK-STAD. But as you mentioned there are cases where it's not working as well. So I think that's important. Two, sometimes these callores will have inflated counts. So thrombocytosis, young

[01:35:00] people. I think that's great that you're picking those up. And then three, we have these immunotherapies. So right now, they're in phase one therapy. I'm leading the J&J bispecific, for example. We have the Insight monoclonal antibody. Those two are fantastic treatments to give to someone who's had one prior therapy. It has to be a JAK inhibitor. And I'm moving those patients.

[01:35:20] quickly to those clinical trials because they're designed exactly for these challenging patients. Before these two, the monoclonal antibody and bi-seism, we had a vaccine trial which was either by itself or with Ipilumimab, CTL-A4, but those results were not very exciting. That's why you don't hear about it. So I would say clinical trial, we have these trials open at multiple sites.

[01:35:40] And I have to tell you, you hit it spot on. Let's not treat, nobody else is treating their mutation patients the same. AML, they have mutation-specific. So now we finally have that era. And then same thing for JAK2. So thanks for bringing that up. And by the way, thanks for checking because if you didn't find those patients, nobody else would have and they would have presented with a heart attack or stroke so you're saving people.

[01:36:00] slides. I have a question I have to ask so on this so as someone who's raised the Levilville 100 that's a very qualified for it and so it's up 10 hour anyway but uh so just saying so I'm just curious so who's your demographic because that's such a niche population up there in Levilville is at 11.5 right I'm

[01:36:20] is it 10-5 or 11-5? 10, yeah, so it's high to start with. And so are you finding it in a different demographic when I think of some of these older individuals, but that's a somewhat young community. So I'm just curious.

[01:36:40] treatment because they've been stable, but some are, I have like MF1 and MF2s, and that's why it's like, I know I've talked to some other reps, they know how they're like, why do you have myelopibrosis patients? I was like, because I'm picking them up. Right. Because I'm screening all of them. Everybody comes in and I will say like our primary carers are very good. They're like, oh, polycythemia, go see me. So they're very good about that because they don't want to manage.

[01:37:00] is great and we're the people who do the phlebotomies but then the other side of it too is I do send them into iron deficiency that's a that's a fun one because I do so much phlebotomies up here but yeah so it's to speak to your point people up here are healthy they're younger because you can't completely different demographic than what I'm seeing people who do live in Leadville fair play

[01:37:20] pressure, pressure, pressure, pressure, pressure, pressure, pressure, pressure, pressure, pressure,

[01:37:40] because the ones who do die up here are, you know, they're older. You weed them out. So. Weed out the. You weed out the. Yeah. You got to. Yeah. These are also the transplanters. These are also the transplanters. I was going to say, these are the transplanters that are 80. Like, these are those people because the, and that's, it's hard to tell. Our patients is like, yeah, they're like.

[01:38:00] They handle this stuff. They're really good at this stuff. And so as you were talking about, we shouldn't be doing just an age. That's this population. It's a functional thing, yeah. There was a question up here in the front. I have a question. I mean, I was just discussing polycythemia. Polycythemia in patients can be diagnosed with JAK2 mutation, not uncommon over here.

[01:38:20] But the question is how much will you attribute a high-altitude polycythemia in presence of JAK2 driver mutation? And would that impact your hematocrit level? Because we have patients, I can tell you a lot of patients who are

[01:38:40] are living, I think, six months, less than six months, at high attitude and then they go to sea level, very common taxes in Florida. We don't see a huge difference in their hematocrit if they are JAK2-positive. Right. Yeah. I mean, there's at most like 3%, 4% difference.

[01:39:00] It's not a huge difference.

[01:39:20] If you have JAK2 V617F, you do have an MPN. It may be masked PV as you and I were talking about in the break. So the answer is you can have elements of both. You and I talked about, I've had a couple patients who have both obstructive sleep apnea and JAK2 PV. So even though I'm phlebotomizing them to the goal, they're still short of breath symptomatic.

[01:39:40] you're not wearing your sleep apnea mask at night. So you're having to treat simultaneous reasons through two different pathways of erythrocytosis. So the dogma that you can only have one or the other either reactive or primary is wrong. You can have both. But Naveen, don't healthy people also have JAK2 potentially mutations? So I guess the point is if you take

[01:40:00] hundred people living at a high altitude and they will have some increase in matricure and you do JAK-2 screening on them. How do you know that this is a pathognomic JAK-2? That's what you guys are asking. I don't know if you can. So Dr. Dauber is right. So JAK-2 is the fifth most common chip mutation. That's what you're talking about. Now I wasn't even thinking about that. Okay I'm only thinking about an NPN. So now you're introducing

[01:40:20] producing a very important, that's what he's talking about.

[01:40:40] death.

[01:41:00] But I'll give you I'll see the point that you can have jack to be 6 1 7 f but it is pathologic in some way It's either a chip if there's no morphologic or it's pre-npn or heading into it So basically do the work of check EPO levels and then watch the person carefully. This is another good reason to keep EPO level in Yes

[01:41:20] Please do a bone marrow because then you can look for a degree of fibrosis. Yeah, degree of fibrosis, you can send cytogenics molecular a little bit easier, rule out concomitant blood disorders or blood cancers. Absolutely do the bone marrow. It will help you later on. I want to get some of the other panelists involved here. Dr. Dale did a very nice and structured talk earlier about ulcer.

[01:41:40] older patients in AML and in leukemia and in hemolignancies in general. So William, for your own mind, I'm going to piggyback on these two guys here, Dr. Dauver and Dr. Oluse. Dr. Dauver, just really quick highlight points of practical stuff for how we treat patients who are older with AML, which is the majority of the people that we see. How do you treat them with, for some reason,

[01:42:00] frontline therapy, flit-3 inhibitor-based therapy, and now with these men in inhibitor-based therapy. And then when you're done quickly, Dr. Oluse, tell us a little bit about the prehab program when he's done with that. Go ahead.

[01:42:20] 20 minutes. I'm going to get everyone involved in this now. Okay, so I think I would start with saying what is older, right, AML? I would say today and as you know, Dr. Kadiyan, many large academic centers, people above 60, today coming to us every week we see many patients. We are thinking about the potential of lower intensity.

[01:42:40] therapy. So I don't know if I call them older or not. You know it's an ageism thing. I just think that's low intensity therapy may be an option for those patients especially if I find a targetable mutation, IDH, Flit 3, maybe now the KMT to NPM1 because we have these HMA VEN plus potentially triplets emerging showing very good efficacy where I don't feel

[01:43:00] push to give intensive chemo like I did 10 years ago because we're getting equal or better response rates. So I would say above 60 we're not using intensive chemo in general except for somebody with a core binding factor. We used to have a very high cure rate even the 60 plus, NPM1 mutated, and maybe certain flit-through very proliferative features or other proliferative features.

[01:43:20] where you need something. Everybody else, I'm thinking of a low intensity, whether it's HMA vent-based, cladridine-load of Cetanide as you've nicely published, and potentially maybe adding a targeted therapy. I think Flit3 is where the data is most mature in this setting of adding a Flit3 inhibitor. Now we have a very good dose optimization regimen, how we can do it. Still, you know, I wouldn't say it's a full

[01:43:40] standard of care, but the data continues to grow and I think there's more and more momentum towards doing that. HMAVN with the Flit3 inhibitor. Menin I think we're really early, but that is where the field wants to go quickly, especially since NPM1 is a founder mutation, the menin inhibitors are showing good activity. There may be less myosuppression with menin. I say maybe. I'm not sure we're starting to see some thrombose-

[01:44:00] and I do think that's the direction the field is going to go. Then transplant. The big question is do you need to give intensive chemo if you're going to go to transplant? No. Actually our group, including you, Dr. Short, and others showed that when you take people above 60 and you look at the therapy, 3 plus 7 or CLIA.

[01:44:20] type intensive, HMAVN or clavrid-bene-noticenter CVN, and those go to transplant. In fact, the outcome was best in those who went to transplant after lower intensity therapies. So it's not that intensive chemo has some special, powerful response that the transplant only benefits after it. So then if I have a 60 year old and I wanna get him transplant and they have a Flit3, I prefer to just have Flit3.

[01:44:40] go with the HMA mentoring and go to France plan and there are randomized studies starting. So I'll kind of turn it here to Amin to pick up the time. So we'll move to Transma and then Dr. Dale. What I want you to think about is, you know, we as leukemia doctors, lymphoma doctors, myeloma doctors, we see these older patients. We often find we don't have the ability, the tools, the quick way of just saying, hey, how do we?

[01:45:00] measure the fitness. You show beautiful tools. But to apply those tools in a clinic environment, so think about that. But I mean, tell us about prehab. Sure, I mean, it's very similar to what Dr. Dale reported, at least what we do at MD Anderson, where these patients undergo a comprehensive assessment.

[01:45:20] All the prognostic factors that Dr. Dell presented in his talk, including cognitive testing, nutritional assessments, biomarkers, functional status, rehab and PT and OT.

[01:45:40] You know, we're screening them for for fitness, but more importantly as Dr. Dale pointed out, we're screening them for modifiable factors, so we have our transplant pharmacists review their medications and look for medications that commonly our patients are on that may pose problems in the post-transplant

[01:46:00] sedative meds, overlapping sedation that's maybe poorly, more or less tolerated when they're going through the transplant process. Our rehab doctors and physical and occupational therapists have them engage in

[01:46:20] prehab exercises, which they continue through the transplant process and post-transplant process and they're followed and tracked from their outpatient to the inpatient. We have our financial people look at some of the financial burdens that may be unique to this population.

[01:46:40] Again, really looking for those interventions more than just prognostic, but looking to see how you can improve outcomes in this population. But I'm sure Dr. Dale. Dr. Dale, is there an app for that? No. It's interesting that you sort of raised it that way. So we've moved into implementation.

[01:47:00] science more than anything else. Like we spent, I'll immodestly say, like we spent a lot of time figuring out what matters. And we think we know now what matters to get some patient-centered prognostic information to assist our hematology and oncology colleagues who are the experts on all the other stuff. But what we're having

[01:47:20] trouble with now is we are only treating the people who get to us and I'm in city of hope and they don't all get to us I can promise you have but the people who get there get good results so how do we actually bring what we do to them and so we're doing telehealth-based reach out to Antelope Valley so if you know where city of hope is that's 60 miles from

[01:47:40] us out in the middle of nowhere essentially and we get 95% patient satisfaction with essentially the same assessments I just showed by doing a telehealth intervention. So one answer is we need to understand that not just do it practically, but actually study implementation science. Can this be done? Does it actually work? Does it matter?

[01:48:00] I'm fascinated by this idea that we have people who are essentially functionally experiencing what old people experience because we now put them on mountains at the 10,000 feet, where as a mountaineer, I experience myself. I know what that feels like, right? But get away from age-based anything. Can we please get to some patients?

[01:48:20] centered fitness assessment that's integrated into the studies, which is the second part of what I'll say and then I'll shut up. The trials, we are not doing these assessments and we're not enrolling the patients who get the disease into the trials because it's too hard, we haven't figured it out, it doesn't fit

[01:48:40] didn't work flow, nobody wants to pay for it. That's not a criticism, it's just a reality of if we're going to apply them later and in post treatment, we're like oh my God, all this stuff is happening, no one knew it was going to happen. Think we could avoid some of that if we had these simpler assessments up front. So my advertisement is.

[01:49:00] We'd love to work with you guys. I think it would help both of us to integrate all of this cool work. But in all seriousness, is there an app or some sort of electrical connection we can go through? Yeah, I can't say there's an app, but I've been asked that a bunch of times. I will direct to the MyCarb website. We're putting up every tool as we get them onto the

[01:49:20] the website and trying to make them available. But I do need a little help in that getting them into the trials is a little hard. There's no support to get them into the trials and we need help with that. I have boiled everything I do down to the smallest package, minimal.

[01:49:40] effective dose that I know how to put it into and I think that's fair on our part, but it's not magic. So people will tell me what can I do in two minutes in clinic to figure out their cognitive impairment and functional status and their comorbidity. You can't, I can't, it's not magic, it's not pixie dust, I can't sprinkle it out there and figure it out.

[01:50:00] outright. But I think we can and we need a little bit of partnership on that. So we're close. Please contact me. We need partners. We're hearing you. Okay, all the answer questions. I was going to add just to that I completely agree that I think age is a construct that somehow an AML has been stuck because of the five decades of seven plus three, right?

[01:50:20] Yeah, and I think it's up to us and we are moving away quickly from it because if you look at the outcomes are heavily driven by the molecular entity. So if you take a TP53, the person can be a 30 year old marathon runner and it can be a 65 year old person in the wheelchair. Unfortunately, the outcome is the same, 6 to 8 months. And if you take a core binding factor, again a 40 year old and a 7 year old.

[01:50:40] can actually have very similar outcomes. So, and I think we're getting to that point where there are studies now looking at HMA-van versus intensive chemo, which hopefully we'll read out very soon. And I think if that study is equal, it doesn't have to be P3 plus seven. At least I think me and many people I know overnight are gonna be done with it. And so then we're gonna be in a myelomatary.

[01:51:00] treat where you have a rev bortezumib dex. You have a backbone, it doesn't matter what your age is, you just have this backbone and can you build on it? And I think that is where we need to be in AML because I agree you know we have to do this because the regulators want it today. They want to cut off in the LA of 75, then they say it's 60, but I think if we make it like they've done in CLL.

[01:51:20] like they've done an ALL it doesn't matter what your age is you have Philadelphia positive you get blown upon adnip 20 80 60 doesn't matter I think this is where AML is going to go now molecularly driven thank you doctor actor disease status before transplant

[01:51:40] So I wanted to see how you guys work in the same center when it comes to deciding when the right time for transplant is. Dr. Lussi. What's that supposed to be? Standard? Standard? Standard. Standard. The right time for me is always yesterday. Yeah. I think that's a question for Lussi, because we know what we're talking about.

[01:52:00] Alright, good. Well, how do we do it? Well, certainly upfront, seeing these patients very early and getting the donor's stress process, that's important. But how do we know when it's the right time is a balance between our leukemia and colicis and its conversations?

[01:52:20] I'm sorry, my point is MRD has, does it affect your decision that that's- No, the short answer is no. I mean if somebody is MRD positive or MRD negative and they're a transplant candidate, we're probably going to take both of those in there as you're sure where to support that approach.

[01:52:40] Yeah, I want to push to get yeah, so this is it's good. It's as I mean knows and you know is getting more nuanced So there are certain molecular subsets where even the decision should we transplant or not? Every week we discuss a lot in our group. Dr. Kadiya himself others and those are NPM 1.3 because now that we have access very recently to this

[01:53:00] ulter-sensitive 10 raised to minus 6, I call it like the AKA clonosic of AML, which is now showing in publications very strong predictive 90% survival. You know, if I have a 63, 64 year old borderline fit and I get an NPM1 molecular MRD negative in two cycles of intensive chemo and the donors are not.

[01:53:20] on 10, 10, and 10. Do I want to push? Do we want to push? We may say, no, in this setting, this person may have more risk than benefit. Same is happening for FLIP-3. And then for maintenance post-transplant, we are still starting to think about the pre-transplant molecular clearance, especially for FLIP-3. But outside of those two subsets, and they're maybe for KMT2A, a PCR coming.

[01:53:40] very soon. We've been working with In vivo scribe. I agree with what Amina is saying. We plan to give two to three cycles. That's the time it takes to achieve all the logistics and all that. By then they're in remission. If the MRD is a low level positive and the transplant is ready, we would probably not change our course. We may say I'll give some maintenance, other things post-transplant. But yeah, we're not.

[01:54:00] Using it to because I've heard from many other centers Which is why I think earlier their question is that they're saying if you're not MRD negative We won't transplant and then we see a lot of those patients relapse and then they come to us in a relapsed High-risk situation where the window may be lost many times. Yeah, dr. O'Donnell These are all great questions

[01:54:20] But I wanted to bring Dr. Angelos into the conversation for an inclusive. One of the things that most excited me today was talking about gene therapies. I started my fellowship in 2010. And there was not a lot that was available for patients with sickle cell. And so what you talked about today was particularly exciting to me because I think it's really revolutionary. And so

[01:54:40] So one of the questions that Andrew and I were discussing is why is the focus on hemoglobin F and producing more of that and not editing to fix or correct the underlying hemoglobinopathy? So maybe you could just tell us a little bit about that. Yeah, for sure. So this has actually been looked at initially trying to just repair the very well-known characteristic mutation that causes

[01:55:00] hemoglobin, adult hemoglobin to be misformed, and then sickle disease. They didn't work too well when they tried to do that. And it really is dependent on the cells having very clear homologous recombination, as opposed to non-homologous end-joining to occur. And that was not just robustly occurring every time.

[01:55:20] time utilizing a CRISPR-Cas9 technique. So that really wasn't a good option. And with the newer technology now, would that change? Well, so with the newer technologies, with the base editing approaches, the sickle mutation is not amenable with that particular technology because it's a single nucleotide change and it either has

[01:55:40] has to be an A to G or a C to T repair, which is just not the case for the sickle mutation. Now to the other end here, using an upstream enhancer region which controls the downstream regulation of hemodilibis F, which we know when it's increased, it's like hydroxyurethane.

[01:56:00] does, when it's increased it causes these cells to un-sickle and prevent the sickling from happening. If there's a mutation within that enhancer region, it now becomes a much more versatile therapy. This area in the enhancer region is actually a non-coding region as well, so it's much more easier to edit that area and it's also an easier

[01:56:20] a place to get a very high efficiency edit. And so that's really why these companies have targeted in on this enhancer region because it's a lot easier to edit that area. You're functionally getting what you need, which is hemoglobin F at the end of the day. And it now turns into a more universal therapy. So it's not only just for sickle cell, but it's also for phenothalassemia, right? Where there's also

[01:56:40] issues with the adult flocculous genes, either having loss of particular exons, multiple copies that are lost, things like that. So it becomes kind of a trifold answer. It's easier to edit. It's much more reliably edited. And then it also is a much more universal approach. So that's why that one particular adult mutation hasn't been taught on just yet.

[01:57:00] found your talk fabulous. I mean it was my favorite I think because it was like it's science fiction but now it's reality. You know it's like these people are getting cured of sickle cell disease. So my question to you is along the same side as Dr. O'Donnell is if we can do this with sickle cell disease why are we not looking closer at cancer? Why not take a person who has a hematopoietic sem cell that has a

[01:57:20] a P53 mutation, say, bye-bye, or a MECON rearrangement and just CRISPR that thing. Yeah, or JAK2, right? Or JAK2. Yeah. Yeah. What's the obstacle? What are the challenges? Yeah. You know, I think the biggest challenges are making sure that you're having the right technology that's going to be able to hit each one of these particular mutations.

[01:57:40] to be able to kind of be at the right place at the right time for having the right machinery to very reliably correct these pathogenic mutations over and over and over, right? And so we're starting to do a little bit more of this with some of the, and I'm certainly not an expert in this area, but some of these inborn metabolic diseases like PKU and

[01:58:00] like other types of issues. There are these single-point mutations that are in fact targetable for gene therapy. And so disease groups outside of hematology are now starting to get more on board with these gene editing approaches. Same thing with like CAR-T cells, right? CAR-T used to just live in the hemic space for many years when it was first started.

[01:58:20] coming about. Now we're seeing a lot of groups that are using it for leukosnephritis, you know, neurological disorders that are autoimmune-based, and so more and more physicians outside of, you know, our specialty are starting to use this technology. And I think, you know, groups are becoming a little bit more comfortable in administering preparative chemotherapy regimens.

[01:58:40] as well. At least at our center, we have multiple trials that are open in the autoimmune space, the neurology space, the renal space, and we partner with our colleagues in these divisions to safely administer preparative chemotherapy and then also the cellular therapy that can target these clones that are causing those non-cancerous diseases.

[01:59:00] So I think really the field is moving quite rapidly in these diseases that are outside of the oncology space and it's really exciting. I mean, just think about bone marrow transplant, right? I mean, bone marrow transplant just came around. That was science fiction too, right? So I think we're still kind of coming to a certain point. One point I was going to say, a lot of what you're saying though are deficiencies, right? Where you have a

[01:59:20] loss and you are able to produce it. Is there an example of successfully suppressing and overproduction because that's the problem in cancer which at least I have very little knowledge is from what I've heard from others is much much harder to suppress multiple clones and do you think the same technology will be done or do you think what do we need to do because I think it's very different

[01:59:40] know. Yeah it certainly is and I don't know if I have a good answer for that question for sure. It kind of is. I mean you know if you think about just the biology of cancer there's a lot of like feedback loops and things that really just converge on a common pathway and so it can be very difficult to kind of

[02:00:00] target a lot of these different things that are all upstream that really kind of converge on one gene or one protein. So it's definitely an interesting thought, especially with the TP53 mutated disease. TP53 mutations come in a lot of different flavors, point mutations, bialylic loss. So it's very difficult to really

[02:00:20] generate a universal strategy for each one of those specific mutations. Certainly I think we could start to chip away at particular subsets and maybe make an impact. Great, thanks. Any last questions, comments from the audience? Yes, ma'am. So one of the things, as a community oncologist, you get these cytopenias that come in, and how do you work these up?

[02:00:40] And where do you go from here? You know, kind of the rule of thumb from my training was, you have two cell lines down, you do a bone marrow. But I know that as we're getting into the more specifics of like myeloid NGS panels and things like that, how does that direct you guys, I know what I'm doing in clinic, but I wanna hear what you guys are doing, on when these patients perhaps, and maybe they're not coming to you,

[02:01:00] Maybe it's the community physicians and then you guys at that point. Are you seeing more community oncologists doing testing for myeloid NGS panels, utilizing that to determine should we be doing a bone marrow on this one cell lying down individual to help decision making?

[02:01:20] It could be one cell line down, but there are other clues. They've already had the iron studies, they've had the scopes, they've had other testing, rheumatologic that suggests that this is not a non-malignation issue. So in those cases, even if it's a single cell line, I'll go take a look. If it's a single, if it's thrombocytopenia, maybe I might empirically treat them with steroids or IVAG to see if it's ITP.

[02:01:40] down and do the bone marrow. I mean, to be fair with us, the people that we can refer to us because we're so specialized, we sort of do bone marrow. There are a lot of these people right up from when they come in. But I mean, I think it's a good rule of thumb to, if you do have a single cytopenia, a monocytopenia, if it's anemia, obviously rule out all the anemia causes. If it's thrombocytopenia, maybe empirical treat of ITP.

[02:02:00] Neutropine is interesting. We see a lot of those. They often tend to be a lot of LGLs. So a low grade LGL. They have no infections. They have ANC of 0.6, 0.7. You can do a peripheral blood flow for T-cell, CD8-positive T-cells. And you can do TCR alpha and beta rearrangements in the peripheral blood, get monoclonal.

[02:02:20] it is. And so I think that certainly two-sided penias, we're more likely to do it, but even monoside penias, if everything else has been ruled out, we go to the bone map pretty quick. All right. You want to start? Yeah. And the other side is we are definitely seeing a lot of patients refer to us with TP53 chip, TP53 C-cuz, you know, coming in, I've had like three or four coming

[02:02:40] through the transplant department. They referred for transplant saying I have TP3, 18% sent to transplant. Normal counts are like hemoglobin of 10.5 or something. And it's tricky because everybody's nervous about TP3, but we have generally not transplanted them. We've followed those patients because even with a single TP53 chip, the hit rate, the conversion rate is very high.

[02:03:00] low, it's actually 5% or so. In fact, some of the other chips have a higher penetrance rate, IDH and others. So we're seeing a lot of this noise, but I think it's okay because through this we will eventually come up with formulas to say, okay, if you have such and such mutation, and it's not going to be a single time point, there's a physician, Parish Vyas, in UK who's developing models for

[02:03:20] for genetic changes in these mutations. We're probably gonna be able to predict if the TPF3 changes by this much over six months, one year, 18 months, then this person has an 80% risk of TPF3 MDS-AML. You may need to do a pre-emptive transplant. Like they do pre-emptive colectamies and breast surgeries for certain patients. So we're not there yet, but we're.

[02:03:40] starting to see a lot of these referrals and I think we'll eventually get there. Similar to treating spool-dramyeloma. Yeah, quick question.

[02:04:00] get resistance or up front, what would you, what's the? Does that happen? Abstain from this question. So can you, so you're talking about if you haven't given Panatnip yet, right? Right, now, similar as frontline, I proved,

[02:04:20] right? So like if they come for up front that if they lose their response, then I think if they're naive to every other TKI, if they haven't had a traditional TKI, I think they'll still be sensitive. Dr. Cortes showed you that among the patients who have a siminib, there is, you know, there's these high IC

[02:04:40] disease.

[02:05:00] is by next language therapy. I mean I think that would be a good person to just do the able kindness mutation profile. Then if you have an E299 or V5 then choose. But if not I think yeah rule of thumb if you want a more powerful TKI. Most of the times those mutations are not really all the time in that table that you're looking for.

[02:05:20] then I think when that you know I mean Dr. Carton said this a lot and he's obviously studied TML tremendously if you look at the potency of these drugs pre-clinically and even clinically monotonous is the most potent still today so I think if you're in a pinch and you're failing a TKI and there's no mutation and you want to go to the more powerful drug and the patient is

[02:05:40] young and healthy. I think for that name is still the best. The chances are if they're only resistant to Acinet, which is a completely different allosteric site, they likely be sensitive most of the traditional TKIs. One more last question. That's it. High risk. I mean you are not sure about CHIP in those patients.

[02:06:00] like microcytosis or very mild cytopenias. When do you decide to check for telomere instability? Do you check it on all patients or there is some type of mutation you should be looking for? Yeah, we're not doing it that much. I think I don't really do it frequently. We have a hereditary leukemia clinic, Dr. Dardow.

[02:06:20] we will refer. I think it's in people who are either really young with MDS, 40, 45 or below, or have a family history. But if I have somebody like 70 with macrocytosis and a mild chip C-cuss, I'm not thinking about telomeres and that, but I don't know other... Yeah, so I think typically if they're under 50 and have MDS...

[02:06:40] I usually do all that testing, genomic testing, and telomere length testing. The genes you want to look for for telomere, the TURC, TURC, and all the telomeres sort of associated genes. Some of them are included in the 81 gene panel as well as some of the commercial panels that are available. Other is you have to actually go to a genetics counselor that does all the non-common sort of TURT mutation sequences.

[02:07:00] is. It's usually turquoise. DKC is just keratosis congenitae. The other one is fangcones. Usually 40s have MDS for no reason. They have maybe some family history. They have some morphologic dyslexia, either short stature, extra fingers or toes. Those fascios usually have double-stranded DNA break repair defects. It's the fang-

[02:07:20] You can do like a, what do you call it, diaboxibutane acetates, they're very quick and dirty. If they have easy chromosomal breakage, they typically have some sort of DNA to repair defect, and then you go and do the genetic studies. But for usually just those young people that we typically look at. But I want to kind of wrap up here unless there are some burning questions. I really want to thank you all for staying. I think you've been a great audience.

[02:07:40] Thanks for trudging all the way up here to Vail, Colorado. I want to thank Madison back there and her Total Health team. And then I want to thank my co-host, Dr. O'Donnell. I'm going to hand it over to her.

[02:08:00] panelists as well and I get the best part of the day I get to announce the lottery winner or so Julie Elliott congratulations you have won a raffle as our winner please stop by the registration table to pick up your parting gifts all right thank you all have a wonderful and sick day and

[02:08:20] travels.