AML: Treatment Advances 2026

New & Emerging Treatments in AML  2.23.26 Transcript

Participants:     Dr. Eunice Wang, Roswell Park Cancer Center

Lindsey Whyte, Leukemia Research Foundation

Hello, thank you so much for joining us today for the second installment of this year's New & Emerging Treatments series. The topic of this session is AML and we're joined today by Dr. Eunice Wang from Roswell Park Cancer Center in Buffalo, New York, who will share some slides about the latest treatments and research for AML, and she will also respond to some questions that have been submitted previously, as well as some questions that are submitted during today's program. My name is Lindsey Whyte and I am the Director of Programs & Partnerships here at the Leukemia Research Foundation. Thank you so much for joining us.

 

I'm going to briefly acknowledge the support that we've received from various companies. Among them, Autolus, Novartis, Merck, Menarini Stemline, AbbVie, Astellas, and Johnson & Johnson. We appreciate the support to make sure that we are able to provide these programs for patients and caregivers.

 

The Leukemia Research Foundation's mission is to cure leukemia through innovative research funding and to support patients and families. The foundation has raised over $95 million in support of our mission since our founding in 1946, and we've funded research to over 750 investigators worldwide during that time. Our support programs for leukemia patients and the information that we have on our website are available to anyone and we encourage you all to take a look at that information. We also have education programs like today's, and we have a directory of other organizations also on our website that may be helpful for patients and caregivers.

 

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So we're grateful today to have Dr. Eunice Wang. As I said, Dr. Wang is the Chief of Leukemia Benign Hematology Service and Professor of Oncology, Department of Medicine at Roswell Park Comprehensive Cancer Center. She is also a tenured professor in the Department of Medicine, Jacobs School of Medicine and Biomedical Sciences University of Buffalo, which is the State University of New York. Dr. Wang earned her medical degree from Keck School of Medicine, University of Southern California, followed by a medical residency at Yale New Haven Hospital and hematology oncology fellowship training at Memorial Sloan Kettering Cancer Center in New York. As an academic physician scientist, Dr. Wang has spent over two decades pursuing clinical and translational research in acute leukemia and myeloid malignancies. She has led and participated in multiple clinical trials of numerous novel therapies for AML.

 

Dr. Wang, thank you so much for joining us today. Please, let's get things started with an overview of the latest treatments and research and trials for AML.

 

- Thank you so much Lindsey. I really appreciate the opportunity to speak today. I'm going to just try to share my slides now. I hope everybody can see those. And this was just a photo that I took last year in Hawaii and after a very long midnight sort of trek up this mountain, I was rewarded with this glorious sunrise. And I think that's an apt analogy for the development of new therapies for AML, which has been quite a struggle over the last several years and I think that we're really starting to break through now. So kind of wanted to show that.

 

So acute myeloid leukemia, as you know, is a disease in the US largely of older adults. The median age has been rising, it's now about 70 years at presentation and it's a biologically diverse cancer but is also clinically aggressive. And this cancer can have a survival that's measured in days, weeks to even a few months. As you can see here from this graph, I just wanted to remind you that this is an incredibly biological heterogeneous disease. So this is just not one type of disease, but it's a disease made of multiple cancerous clones. And you can see about half of the patients that present with acute myeloid leukemia have normal cytogenetics, but they can have more than one mutation and no mutation in acute myeloid leukemia is found in more than a third of patients. And so it is really essential at the time of diagnosis or suspicion of diagnosis of acute myeloid leukemia that we perform what we call a comprehensive diagnostic workup. In 2026, what does that entail? And that entails not only morphology to determine that these are immature myeloblasts which are driving the disease, but as well flow cytometry to look for surface proteins to make sure this is a lymphoid versus a myeloid cancer. In addition, we typically need to perform conventional cytogenetics or fluorescent in situ hybridization to look at chromosomal changes as well as most importantly potentially mutation results. Typically at our center, we do this through a comprehensive next-gen sequencing mutation panel. And per the NCCN here on the left hand side, you can see the numerous mutations which are recommended to be tested for in every new patient with AML because of the prognostic and therapeutic implications. And on the right hand side are additional gene mutations, which are not essential, but are recommended to be performed anyway to help guide or inform us of the disease.

 

How do we select acute myeloid chemotherapy? Well, we really look at, I typically look at two things. One is an evaluation of the individual patient. We're all individuals, we all have individual goals, we have individual activities and likes and dislikes. And so it's really important to just not assess a patient based on age, but also look at their functional and activity level as well as their stated personalized and individualized goals for a new cancer diagnosis. We then partner that with the knowledge that we've gained from that comprehensive diagnostic workup to select a chemotherapy backbone. Now in younger fit patients, this typically is an intensive chemotherapy regimen, but cytarabine and an anthracycline drug that requires a four to six week inpatient hospitalization because of the mortality and morbidity, specifically related to profound cytopenias and infectious risks. We also have for our older patients initially designed for patients 75 years and above lower intensity therapy with hypomethylating agents with the addition of a BCL2 inhibitor. And we'll talk a little bit about that backbone later. We also have the ability, again, based on that diagnostic workup to add targeted therapies. And one of the most important advances with the diagnostic workup and the genomic sequencing of myeloid leukemia is the development of targeted agents that are mutation or genetic lesion specific to enhance the outcomes of conventional chemotherapy. And then in younger fit patients, or not even younger, but even older fit patients, there is a possibility once patients achieve remission to receive allogeneic stem cell transplantation or maintenance therapy. We traditionally have thought of the prognosis of acute myeloid leukemia as being related to their ability to tolerate or intolerate or respond to intensive chemotherapy. And you can see here again, the complicated prognostic criteria that divides acute myeloid leukemia patients per the European Leukemia Net into favorable, intermediate or adverse risk disease based on their ability to respond or not respond to intensive chemotherapy with cytarabine and anthra-based therapy. You can see on the right hand side, depending on all of these very subtle genetic and mutational events, you can divide patients into a good prognosis group where they would be expected with conventional chemotherapy to have a five year overall survival in the 80% range. All the way down to patients that have poor prognosis disease. You see here complex karyotype KMT2A or MECOM rearrangements where you can see the five year overall survival is only in the 20 or even 10% range with conventional therapy.

 

So right now, as I just to review, when we think about therapy, we think about the mutation agnostic chemotherapy. These are the chemotherapy backbones that we piggy upon to really get rid of the majority of the bulk rapidly proliferating disease in our patients. And these can be divided into intensive chemotherapy regimens, incorporating cytarabine and anthracycline drug or non-intensive regimens as I talked about with the hypomethylating agent like Azacitidine or decitabine or low dose cytarabine combined with venetoclax. We see here on the right hand side the mutations or genetic events and their frequency. For example, you can see that in patients with P53 mutant disease, which makes up 5 or 10% of acute myeloid leukemia, that there really are very few, there are no real targeted specific therapies except for clinical trials for those agents, for those patients. In contrast, you see patients that have IDH1/ IDH2 mutations have three different inhibitors, ivosidenib, olutasidenib and enasidenib that they could be eligible for. FLT3 mutant patients which make up up to 27 or 30% of patients may be treated with inhibitors of FLT3 and patients with NPM1 mutant or KMT2 rearranged leukemias that could make up 30 to 40% in total of newly diagnosed patients have now the access to two drugs, revumenib and ziftomenib specifically for treatment of relapsed disease with these abnormalities.

 

So moving onward, what are the New & Emerging therapies for AML now that we've reviewed a little bit of what the standard therapy is. How are we improving upon these therapies and branching out into new directions? So I'd like to talk a little bit briefly a lot to cover here on the advent of triplet regimens for upfront therapy, which is combining targeted therapies with conventional chemotherapy and new and novel ways to improve the outcomes of newly diagnosed patients with acute myeloid leukemia. I'll talk about novel menin inhibitor combinations, novel antibody drug conjugates, immunotherapeutic approaches. And this was particularly of interest, I've already reviewed some of the questions that people have submitted and one question that came through was, what type of immunotherapeutic approaches are we developing for patients with AML? So I'll talk about a couple of them here.

 

So triplet therapy we think of as, a little bit scary here. You can see here this picture from Harry Potter of Fluffy, the three-headed dog. Somehow when you give chemo and single agents or double agents, it's not quite as scary as when you add a third drug. And so I think initially when we were confronted with triplet therapy, we were really scared by the toxicities and, I think as in the Harry Potter example, it turned out that, you know, this is not actually as scary as it initially seems. And so what is the current therapy for patients with newly diagnosed AML based on fitness? We talked about that here. So here's the patient and if you have a fit patient, very functional status, who wants aggressive therapy? We give intensive chemotherapy with that, my example with just seven plus three, and if you're unfit, you get less intensive therapy with what we call like a venetoclax azacitidine based therapy. And so we're talking about in triplet therapy was adding a third targeted agent to frontline therapy, adding a third agent to the fit intensive regimen and adding a, more importantly, potentially adding a targeted therapy to less intensive therapy. And if we do that, we might be able to decrease the intensity of the backbone, which might be beneficial for patients of all ages to have fewer side effects and risk of mortality or morbidity.

 

So the first triplet I'll talk about is this triplet, which combines a FLT3 inhibitor gilteritinib with the conventional Venetoclax Azacitidine backbone. Now Gilteritinib is a FLT3 inhibitor, which is approved for treatment of patients with FLT3 mutant disease in the relapse/ refractory setting. And that setting actually Gilteritinib was found to be superior to intensive chemotherapy. This targeted pill was better than intensive chemotherapy for treatment of relapse and refractory disease because it is so specific in targeting the mutant cells. So if that's true, why don't we take this drug, add it to patients in the newly diagnosed setting and see whether we can decrease the chemotherapy they're getting and maybe give them a less intensive approach? So you can see here newly diagnosed patients 18 and above who were considered ineligible for intensive chemotherapy got the combination of that backbone Azacitadine and Venetoclax in combination with the pill Gilteritinib for up the first 28 days of therapy. You can see here that there were no dose limiting toxicities. You saw that there were no deaths due to the addition of this drug, and they did the, they did try this at a couple of different doses with the Venetoclax drug and they found a few patients with increased liver function tests and a few with febrile neutropenia due to low counts, but really was very, very well tolerated. And in subsequent cycles, they were actually able to drop some of the durations of some of these three pills. This is an entirely oral regimen which makes it very attractive if we can give a potent therapeutic regimen for AML completely as pills in the outpatient setting. Shown here is the overall response and so conventionally we think that Venetoclax Azacitidine was probably going to lead to about half or 60% of patients having a remission. And you can see here that when we looked at patients getting this triplet, we're getting CRC or complete remission with incomplete count recovery rates of 90% as opposed to 67%. So that clearly seems to be improving upon the standard Venetoclax azacitidine. And you can see here we would expect an overall survival for these patients with FLT3 mutant disease of the range of 13 to 15 months. And you can see here that that triplet seems to be extending that survival all the way out to potentially 23 months. So this regimen is now going forward to see whether this could be used again as standard of care. We'll have to wait for that data to mature. But this certainly looks very promising in that regard.

 

What are other triplets? Well, we talked a little bit about these menin inhibitors. Now these menin inhibitors are drugs that block the interaction between this menin protein and this transcriptome complex made of KMT2A. Now this KMT2A MLL complex you can see here in these diagrams interacts with the DNA to trigger upregulation of transcription factors that drive leukemia generation and persistence in these patients. We've tried to inhibit this particular complex to decrease these transcription factors and convert leukemia into normal cells, but until now we haven't had a great way of targeting it directly. So rather than targeting this DNA, this transcription complex directly, what we do is we target the interaction between the complex and this menin protein. And by doing that, we actually have found we can then just as effectively turn off this complex and lead these immature myeloid cells to differentiate and die leading to overall responses in the 21 to 23% range in the relapse refractory setting. Now you can see here that these drugs, however, revumenib and ziftomenib, although they've been approved only lead to a median overall survival benefit around the range of about six months. So 23% response rate, six month overall survival. Can we move these drugs also into the upfront settings? You can see here the BEAT AML trial that looked at older unfit patients that had these particular lesions, NPM1 and KMT2A and combined it with this revumenib menin inhibitor. And you can see here, again, similar to what we saw with Gilteritinib, we see CRC rates or response rates in the high eighties to 90% range. No patients had disease that did not respond after one or two cycles. And a hundred percent of these patients actually cleared even minimal levels of disease with we hope prolongation again of their median overall survival, having this excellent response to upfront therapy.

 

We also looked at another menin inhibitor here, this data with another menin inhibitor of ziftomeninib combined with Venetoclax Azacitidine for patients who have specifically newly diagnosed AML with an NPM1 mutation. And again, you're seeing overall response rates, so ORR of 89% and instead of a median overall survival in the range of 15 or 14.7 months, we're starting to see median survivals that up to up to 26 weeks have not yet been reached in these patients. So shown here is a summary. You can see overall that all of these agents in triplets seem to be leading to overall response rates of 80 to 90%. And we hope that that will be translating into again, prolonged survival. And so what about combining some of these inhibitors with standard intensive chemotherapy?

 

Well, here's data showing that the menin inhibitors ziftomenib can be made to be effective in a triplet with intensive chemotherapy backbone. So you see newly diagnosed patients with NPM1 and KMT rearranged disease, getting intensive chemotherapy again had overall response rates 80 to 90% when ziftomenib was added to these patients. And the median overall survival of these patients has not yet been reached. Are there new menin inhibitors that are out there? Yes, we are always building to improve. So as we know, our current menin inhibitors have lower response rates and overall survival benefit. So this is bleximenib, which is a novel agent. It turns out that the reason that some of our other menin inhibitors are not long lasting or durable is that they, that the cancer cells rapidly develop resistance through rotations in the menin protein. And you can see here that this bleximenib and preclinical testing has the ability to overcome some of these menin resistant mutations that develop on the other menin inhibitors. And you can see here that as a single agent, this drug appears to have potentially improved response rates potentially in the 30 to 40% range.

 

What about combinations of Bleximenib? You can see here that this has also been combined with that lower intensity backbone, Venetoclax azacitidine for both relapsed and refractory and newly diagnosed patients. And you can see focusing on the right hand side overall response rates when Bleximenib is added of, again, 90% range with the combination of this triplet in newly diagnosed patients. So we are, this is just an example. All of these sponsors of these menin inhibitors are performing or rapidly embarking upon phase three trials, which will compare the addition of a menin inhibitor to standard chemotherapy as compared with standard chemotherapy to see whether this improves upon and can evolve into our new standard of care for patients with some of these targetable mutations.

 

What about patients that don't have targetable mutations? What if you don't have an NPM1 or KMT2A or FLT3 inhibitor or a sensitive mutation or you don't have an IDH1 or IDH2 mutation? What do patients do then? What are the prospects for these patients? And one category of patients that have a particularly poor prognosis as we highlighted initially was those that have P53 mutations and these patients tend not to respond to either intensive or less intensive chemotherapy. And so I'd like to present data on this study which involves a newer drug. This is an antibody drug conjugate. What is the antibody drug conjugate? It is an antibody against a surface molecule surface protein here the 80 to 90% or more of the AML cells will express the CD123 protein. And so using that information, investigators developed an antibody against CD123 and attached the other end of the antibody to a DNA damaging cytotoxic agent. We had this concept explored previously with a different antibody drug conjugate gemtuzumab against CD33, but this CD123 was thought potentially to be a, again, an AML specific marker with a high degree of involvement of AML cells attached to this novel DNA damaging agent. So as a single agent, this antibody drug conjugate PVEK did induce responses in about 20 to 30% of relapsed patients. But again, the thought process was that they could potentially move this into a triplet therapy. And because so many AML cases express CD123, regardless of their genetic makeup, that this could potentially be a targetable lesion for patients that have other difficult to treat profiles including P53 mutants. So you can see here the design of this study where this PVEK antibody drug conjugate, again was combined with venetoclax azacitidine and patients with newly diagnosed acute myeloid leukemia. You can see here their overall response rates. Now, if you look on the right hand bar graphs, you can see overall response rates 88 to 94% similar to what we saw with the addition of those other targeted therapies to Venetoclax Azacitidine. On the left hand side, you can see that on more than half of patients that had that P53 mutant disease, which typically does not respond well to Venetoclax, azacitidine had responses to this triplet. The duration of the remission in these P53 mutant patients in particular seem to be a little bit longer than what we would be achieving with the venetoclax azacitidine alone. And so this is also moving into additional testing potentially in younger fit patients rather than older unfit patients.

 

Now, as we get into, just as a, just a shout out, you'll start to see a lot of things in the literature about minimal residual disease. And this is the ability to detect levels of disease that we cannot see by conventional cytogenetics or morphology wise. MRD is important and is going to become increasingly important over time is because as you can see, some of these triplet therapies are resulting in responses in 80 to 90% of patients. And how do we know out of this 80 or 90% of patients which patients might actually be benefiting long term and survival long term and which of them are going to relapse? And so when you get to the 80 to 90% remission rate, which is our level of detection by morphology, it's essential in order to move these drugs forward, is to determine who will relapse and who will not. And that is why MRD testing as are therapies for AMLs advance is going to be become an increasingly important, I think, clinical correlate to predict and to move forward with the development of these drugs and to benefit patients who really need it versus those that don't. And I'd like to end with just a shout out to immunotherapy. Immunotherapy has changed the paradigm of treatment for solid tumors as well as lymphoid malignancies, but we've yet to see a significant enhancement of outcomes or actually even development of effective immunotherapy for patients with myeloid malignancies, specifically acute myeloid leukemia. So I'd like to talk about two different types of T-cell directed therapy and give an example of each one is called a T-cell engager antibody where we develop both an antibody that binds T cells and the AML cells, brings them together and activates an immune response. The second is to take immune cells, whether this be T cells or NK cells from a healthy individual or the patient, take these cells out of the body, genetically modify them so they recognize antigens on the AML cells and re-infuse them to have those live action cells be finding and destroying the leukemia cells. And so this is an example of a T-cell engager CLN-O49. This is directed against FLT3. FLT3 is an important gene in myeloid development. It's not only mutated in a certain percentage of patients with AML, but in almost all patients with AML, this FLT3 normal gene, normal protein is expressed on the AML blast. And so taking advantage of this, these investigators have developed an antibody that binds the FLT3 protein on the AML cells, brings them in contact with T cells and activates an immune response. This drug was very effective in early development where they increased the dose of this drug, they found a hundred percent of patients were developing immune activation or cytokine release. So they actually modified the treatment regimen to do two step up dosings to make sure the immune system doesn't become overactivated in these patients. And they've gotten a dose where they only get cytokine release low level in about a third of patients. And this is very well tolerated with low levels of neurotoxicity. And you can see that this agent actually leads to responses. You can see about 20, 30% of patients in the very, very relapsed, heavily pretreated setting were having clinical responses to this T-cell engager therapy. And we see that there are also responses in patients 40 to 50% potentially patients with P53 mutant AML. And these responses lasted three or four months. So this apparently appears to be something that's very effective potentially for patients that have P53 disease. We'd like to end with one more example of a novel agent, and this is SENTI-202, and this is a novel cellular therapy for AML. And this is not using cells from the patients and pulling them out and regenerating immune cells and putting them back in, but this is actually what we call allogeneic off the shelf NK cells where they take immune cells NK cells from normal healthy donors, pull them out, genetically modify them so that they're able to recognize CD33 and that wild type FLT3 on AML cells and infuse them as an off the shelf cell product for patients that have acute myeloid leukemia. And you can see here that they use a novel technology called this Logic Gate, which identifies and kills specifically leukemic cells and leukemic stem cells, but does not attack normal healthy hematopoietic stem cells and hopefully will prevent patients from having significant hematologic side effects. Just like in normal other CAR Ts or other cell therapies. Patients require what we call lympho depletion where they have all of their other immune cells depleted with chemotherapy followed by infusion of these CAR NK cells, which have been modified to recognize CD33 and FLT3. You can see that there are some side effects from infusion of this antibody, from the infusion reactions, but no significant side effects. And they saw that at the highest dose level that they started to see patients almost 60 to 70% of patients achieving some level of response with infusion of these cells. So with that, I'd like to, I've covered a lot of information in a very short amount of time, but we have made over the last several years enormous strides, but we still have a ways to go on this mountain. And as you can see here, we really rely upon in order to further advance and improve outcomes to leukemia patients, a lot of different people helping us all up this mountain. So thanks, one, a shout out to the Leukemia Research Foundation, which supports research and education efforts like this lecture that I've just given. And I also wanna give a shout out to the patients and their caretakers, those individuals who've sacrificed life and time and effort to participate in some of the clinical trials that have led to the advances that we have now, the clinicians that support them and all of the other groups including foundations, pharmaceutical support and et cetera, which has allowed us to continue to make strides up that mountain so we can all see the light breaking on AML therapy moving forward. So with that, I'd like to stop here and, and happy to take some questions.

 

- Thank you so much. That was very sweet of you to include that. And you know, we're equally grateful to you and your colleagues for all that you do for patients by persevering in this research and, and sharing what you're learning with us so that patients can be better informed and, and go to their next doctor's appointment with more information. And, and most importantly, just the confidence to, to ask for, you know, like alternatives, right? So I think one of the things that I always like to emphasize with patients is that they are empowered to ask for alternatives and to have a productive conversation with their doctors. And so I don't, I don't know if you wanna just share briefly your thoughts on that and maybe share how, you know, what, what an average encounter with patients is like in your experience and what's a good thing for patients to do to prepare for their visits with you?

 

- I think that it's always I think that my preferred method is sort of shared decision making. So I provide information on the different options. I think it's incredibly difficult when one hears the word cancer, acute myeloid leukemia, people immediately jump to their phones, they, they Google it, they look at the outcomes, they become discouraged, and then those, the really motivated patients, they try to go search out and, and figure out what there is about the disease. And I think I highlighted this a little bit. This is incredibly complicated disease. So there's lots of different drugs, lots of different mutations, lots of different genetics and DNA and RNA and science behind this. And then there's a multitude of options. Chemotherapy, intensive, non-intensive allogeneic stem cell transplantation. We've had 14 drugs approved for some aspect of AML therapy since 2017. So none of that can be encompassed within a 25 minute lecture. But I think it's a matter of just meeting with your doctor and sitting down with him or her or that care team or the, the patient navigator and just trying to walk through the process and then to make decisions together. I think in this day and age for you to come in and be told, do this, this, and this I think is not really the best method. I think we're more informed about this. I think you need to sit down what might be the best decision for my mother or for my husband or my child may not be the best decision for Lindsey's husband or mother or child. And so I think a lot of that needs to be taken into consideration and there needs to be agreement moving forward in how we're going to treat this disease. I think second opinions I think are very important. AML is, I think many times access to clinical trials and stem cell transplantation is limited to larger medical centers. So I do encourage people to take the time and effort. I think a lot of us have programs to try to expedite or facilitate referrals. We have local housing for patients, transportation support so they can come and get an opinion and feel that they have been getting the best care. So just wanted to encourage that.

 

- Thank you. Thank you. And I also love that you included the other care team members besides just the clinicians because they can also be very helpful. Okay, great. So we do have quite a few questions in the registration process, I saw a few questions come in from people who were focused on MECOM, which is kind of a new one for me. And I saw you had it on an early slide with TP53. Just wondering if you could talk briefly about where things stand with that one.

 

- So MECOM leukemias are considered to be one of the poorest prognosis acute myeloid leukemias. There's been stuff, there's been a lot of press about Tatiana Schlossberg, who is one of the Kennedy grandchildren and how she recently passed from a acute leukemia that had a MECOM abnormality. This translocation or this genetic abnormality is found sometimes in patients in a treatment related setting after prior chemotherapy, sometimes spontaneously. It's one of those mutations that does not respond to intensive or non-intensive chemotherapy. And when we see patients that have that mecom abnormality, we attempt either intensive or low intensive therapy failure to try to achieve a response. And as Tatiana Schlossberg did to try to send them to a potentially curative allogeneic stem cell transplantation which offers the best hope of survival. We do enroll them also in actively in clinical trials. This translocation is one that's difficult to treat and this is one that if it is diagnosed and you or somebody, you know, I strongly encourage referral at an early point to a major medical center to see what types of clinical trials are available. It is, as you saw, the outcomes of that particular subset remain challenging. And unfortunately, I can't think of very many conventional therapies that would work. I think that immunotherapeutics, just like for P53 mutant disease potentially offers the most potential to have effects because those therapies rely on targeting or activating the immune system and are not targeting the cancer cell, which we think is resistant to chemotherapy because of the underlying MECOM abnormality.

 

- Hmm, okay. There was a question actually about the difference between translocation and, let's see, I'm looking for it in this.

 

- What is the difference

 

- Mutation and the translocation in a,

 

- So both are considered abnormalities that occur in cancer cells. Translocations means that by part of the DNA, the chromosome part of the, a piece of a chromosome of DNA is actually swapped. So a little piece of, for example, in chronic myeloid leukemia is a piece of chromosome nine gets swapped at the piece of chromosome 22 and that the, those pieces get swapped and they get fused. And the fusion of those two pieces of chromosomes that don't belong together leads to an abnormal protein, abnormal RNA and protein that then causes the cancer. A mutation is a part of the RNA that is damaged. So there is an amino acid that's swapped out when that amino acid is swapped out, that gene gets made. But there's an abnormality in that gene and that leads to a different product. So a mutation typically occurs in the RNA level and the DNA, the chromosomes, but damage to chromosomes such as DNA causes the translocation. So for example, when you think about patients who have leukemias that respond to menin inhibitors, you can have a mutation or an abnormality in the NPM1 mutant gene or you can have a rearrangement or a swapping out or a fusion of the KMT2A gene that's at the DNA level. So I think it's DNA versus RNA.

 

- There's another question here. How does de novo AML typically vary from secondary AML? And I think maybe to take it a step further, do you treat patients differently?

 

- Yeah, so that's a question. So de novo AML means no AML that's arises spontaneously from a hematopoietic stem cell that's gone be gone berserk. Secondary AMLs are those AMLs that have occurred as a result of prior damage. So if a lot of older patients are notified now to have a myelo failure syndrome like myelodysplastic syndrome MDS or they may have polycythemia or essential thrombocythemia or a myeloproliferative neoplasm or they may be a young woman who has breast cancer who's been treated with prior lines of chemotherapy or an older woman with ovarian cancer who's gotten PARP inhibitors or a multiple myeloma patient who's been treated with Revlimid. Patients who have received specific agents like those may have damage to their underlying bone marrow that then evolves into a second leukemia. So secondary AMLs or leukemias that form not from spontaneous alterations in the stem cell but actually from damage to the bone marrow stem cells from some type of prior therapy or some sort of underlying disease. Up to 25 to 31% of acute leukemias in the current era are secondary leukemias. And this number is expected to rise as people live longer and longer for example, with prior cancers. That is actually a poor prognosis. Patients with secondary AML tend not to respond to chemotherapy nearly as well as patients with de novo. They tend to have different mutations in their damaged stem cells and patients with secondary acute leukemias typically will need to undergo an allogeneic stem cell transplantation to eradicate and replace those damaged stem cells in order to have curative intent in many cases for their acute leukemia. So it is considered a poor prognostic sign to have an acute leukemia that's thought to be secondary.

 

- Great. Okay. There were also a couple of questions regarding CNS involvement. I could read one specific one or if you would like to talk just generally about that. It's up to you.

 

- Well what is the specific question?

 

- Okay, so in this case, my brother diagnosed with AML six years ago has had two transplants six months ago was found to have CNS involvement. He had intrathecal chemo, not well tolerated because of bone marrow depression and subsequently radiation therapy, no clinical trials.

 

- Okay. So about 4% of patients with acute myeloid leukemia maybe even more have will develop acute leukemia that does not stay within the bone marrow the blood, but it moves to other places. When it moves to disease spaces outside the bone marrow or the bloodstream, then we consider it to be called extramedullary leukemia. And one of the places, as I mentioned it can go, it can go into the spinal fluid surrounding, the cerebral spinal fluid surrounding the brain and the spinal cord. When it goes into that site, it's considered a sanctuary site because the way that humans are built is that there's a blood brain barrier. So a lot of times the chemotherapy that we're infusing into the bloodstream to kill off leukemia cells and the blood and the bone marrow will not infiltrate into the CSF space. And that is why when we diagnose that it requires us to have CSF directed therapy with chemotherapy directed specifically into the spinal cord via spinal tap or lumbar puncture that's called intrathecal chemotherapy or we have to do radiation in those areas. This is a site of disease that's extremely hard to eradicate. It's also a site of disease that we're seeing commonly following, as in this case, an allogeneic stem cell transplantation. Because when you do a transplantation, you're replacing the blood in the bone marrow and the immune system. But the transplant does nothing to treat leukemia in the CSF. And that's why we increasingly are seeing that as a site of relapse. There are very few clinical trials that have looked at how to treat CSF disease outside of chemotherapy or radiation and another disease acute lymphocytic leukemia, which is a separate disease than AML but has some overlap based on disease biology. There are some studies that suggest that CAR T therapy has the ability, those immune cells to cross the blood brain barrier, and that patients with CNS acute lymphocytic leukemia have responded by clearing of the CSF when they've received CAR T therapy. As we can see, CAR T therapy for AML is really in its early stages. And so I wouldn't be able to comment on that. So unfortunately that tends to be something that is difficult to treat. It's also concerning because patients who have relapse and refractory disease that have disease in the central nervous system are often excluded for better or for worse from other clinical trials because of the complication that these newer drugs under development may also not cross the blood brain barrier. So tough question, tough situation.

 

- Okay, here's another one. This individual is asking about a different type of therapy that is known to be used in multiple myeloma. And so when I went back to him and asked for some clarification, essentially he was just kind of looking to understand are there new drug combinations that have shown any remarkable results? And I know that you shared some during your presentation and you know also the, this particular patient has asked several times how long should maintenance last? Because I know that a lot of people are like, well I've already been through this, I went through my transplant, I'm kind of sick of taking all this medication. How long is this going to have to go on? So I guess if you could comment on one or both of those topics, that would be great. Thank you.

 

- So I'll talk a little bit about maintenance. So once people undergo a transplantation that doesn't always cure the disease. There's after a bone marrow transplant for acute myeloid leukemia, there is two risks after the transplant. One is you can develop what we call graft versus host disease, which is when your donor cells attack the skin and the gut and other organs in the patient receiving the transplant because the new immune system doesn't recognize the patient's organs as belonging to the same person. The second complication is acute myeloid leukemia relapse, that the recurrence disease that before the new transplant can establish itself and the new immune system can make, can make a case to defend itself from the development of cancers, the leukemia cells recur. Now in order to prevent that from happening, we've been trying to implement maintenance therapy. So some of these targeted therapies that we've discussed that are being, that are specific against specific mutation types, they can be resumed after a bone marrow transplant. And typically for patients that have evidence of any residual disease, we would start them back up on a FLT3 inhibitor. We've certainly talked or there are certain clinical trials looking at starting people up on menin inhibitors post-transplant. Many of our FLT3 inhibitor trials have used maintenance post-transplant. Generally in those post-transplant settings, the maintenance is given for up to two years. It's hopefully just an oral pill. There are some of us that are also trying to give sort of low dose chemotherapy for patients that don't have target bone mutations. Generally that period of time post maintenance therapy starts about 30 to 90 days after the transplant. And I tend to leave it on for at least up to two years after which point there may be a discussion about whether it can be discontinued. There also is some patients will say, well what if I can't go to allogeneic stem cell transplantation? Is there maintenance for me after I get upfront therapy? And I think that there was a question in the queue about a drug called on onureg. Onureg is a pill that is being utilized as maintenance therapy for patients who've received intensive chemotherapy but can't go on to undergo an allogeneic stem cell transplantation, but have high risk disease. And onureg taken as a pill 14 days on, 14 days off has been shown to decrease the relapses post-transplant for a period of up to a few years in the clinical trials with onureg patients, however, had to continue to take Onureg potentially for the rest of their lives. And there was a continuing risk despite the fact of taking onureg that over time the disease may come back. And so that it's difficult to know, I think at, onureg is useful, it does prevent relapse as opposed to taking nothing in that setting. But, but certainly it's something that's effective. I've had one patient that took, has taken onureg for almost four years, has had no signs of disease and the discussion is whether we can stop it at some point. But it is a continuing risk.

 

- Great. And actually on that topic, one person asked, she's a 46-year-old healthy female at diagnosis with NRAS and EZH two went into remission after seven plus three and immediately to stem cell transplant. Now she's two years post-transplant. How does her future look?

 

- I think her future looks good if she's two years post-transplant, that's an excellent landmark to have. I think most of us would consider at that point potentially the risk of disease coming back would be less given the fact she's had no recurrence. I would however be cautious. I think most of us when we look at long-term survivors of AML are still looking at that five year time point to be a little bit more conservative. But I think that, I think up until now it sounds like she's doing well and I would have continued maintenance and I am, she's been through a lot and I would say that we would just carefully monitor her at this time. That's when some of that testing that I mentioned briefly, minimal residual disease testing can be very useful for those patients who look like they have no disease and it's hard to know whether the disease has been cured or not. And those are when those minimal residual disease tests are really important to perform to see whether we can detect any amount of disease prior to, that might predict for an overt relapse.

 

- Okay. I had one here that was, do you have thoughts about Imatinib or sirolimus for RUNX1? One, I'm three years post bone marrow transplant. Not relapsed, but planning ahead.

 

- Yeah, so I don't know. Certainly Sirolimus is an immunosuppressive agent that has been used in the post-transplant setting to prevent that complication graft versus host disease. Imatinib also has been used, it's a tyrosine kinase inhibitor that has been used along with other tyrosine kinase inhibitors such as Jakafi or ruxolitinib in the post-transplant heading for graft versus host disease. Those agents, I don't know if they have any direct activity against the AML in general. They're more in my mind for preventing complications of the transplant itself. So I think that the plan, I would hope would be that those drugs eventually could be tapered off if the graft versus host disease could be managed.

 

- Okay. I think this may be the last question, and this is regarding an older patient who is under decitabine and Venetoclax treatment in the sixth 28 day cycle and in remission since cycle four, searching the web, they see that maintenance results only last to 24 months. Is there research survivability beyond that 24 month period?

 

- Yeah, so many of us, when we go out, when we think about maintenance, we don't know. So the upfront trials of Venetoclax and Azacitidine and Venetoclax and Decitabine listed that patients would have to take these drugs for the rest of their lives. There are now we think anecdotal data that some patients that are very sensitive to these drugs may be able to stop some of them. We also have older patients that just realistically cannot take those medicines forever. So typically what we do for those regimens is we taper the drugs down, the doses down sometimes the frequency of administration. But outside of a clinical trial or advanced toxicity, I like to keep patients on some medication continuously. So in some of my elderly patients, I've dropped either the Venetoclax or the hypomethylating agents, others I've reduced it. I've not yet stopped. I think that the data suggests that if you stop the disease would come back. So I think unfortunately for those regimens it right now the standard of care is to continue to receive some therapy with one or more drugs until the disease progresses, recurs or until there's toxicity. But I've had, I just wrote chemo for a 86-year-old patient of mine who is getting cycle 53 or something of chemotherapy. So certainly it can prolong life in certain individuals for quite some time.

 

- Okay, great. This, this person asked, have you ever seen a weekly positive MRD result on a PCR test? And this was a PCR from a bone marrow biopsy?

 

- So it depends. I think the, the MRD testing using molecular assays like PCR differs tremendously. So it depends on the sensitivity of your test. Some of the PCR tests are only sensitive down to like 1% or 0.1%. Some of them are very sensitive down to like 0.001%. I think a weekly positive test, I think the first thing I would do in that situation may be to repeat the test because some of these tests are highly sensitive, but that means that they could be a false positive. However, so I wouldn't want to alter therapy immediately based on a weekly positive test, my first instinct to repeat the test and if it's definitely positive or it's rising, then that would be a cause for concern and discussions with my oncologist about what the next steps were. So I don't know, the weekly positive, is it just a false positive? Is it just, the test is not great, but certainly some of these tests are highly specific. So I would repeat the test and then move on from there.

 

- And is it necessary in that case to have another bone marrow biopsy or can an individual get a different, have that same test done using a sample taken some other way?

 

- So the sensitivity of the test in the bone marrow is about 10 to a hundred fold more sensitive in the bone marrow than in the blood. So some national guidelines have said if you become negative in the bone marrow, then it might be okay to follow the peripheral blood. But if there's a question of whether it's truly positive or not, unfortunately the standard of care is going to be a bone marrow biopsy because if you're weekly positive in the marrow, then you do a peripheral blood test that may not be as sensitive as the marrow. So you still might get a negative from the blood, which then may or may not be true. So I think that unfortunately there still is some discrepancy for some of that testing from the blood and the bone marrow.

 

- Okay. Well I think this has been a really informative program. I am very grateful to you for everything that you shared here today. I'm just going to put the slides back up. I wanted to point out here that a great source for information is the NCCN guidelines, which I have here on the right-hand side of the screen. We also have a lot of information about some of the things that we've talked about on our website. So please visit our website if you would like some information, for example, about testing and about other resources. And I wanted to also point out that we have several programs coming up very soon in the spring we have two programs. One is focused on immunotherapy specifically and the other is focused on clinical trials. So if you're interested in learning about clinical trials and how to, you know, find out if you can be considered for one or ask some other questions, please make sure that you pay attention to our upcoming communications in email and on social media and you'll hear about that future program. And finally, I just wanted to say thank you again to Dr. Wang for her time and for the great information that she shared in this program. I think it was really, really, as I said, informative and I hope everyone else on this call has found it informative. And as I mentioned, we will be sending a link out to a survey to get some feedback on it and we would be grateful for that feedback. And also we will be sharing the link to the video so you can share that with others if you think others could benefit from this. So that's about it. Again, thank you to our sponsors and Dr. Wang. Any, any final things to share?

 

- No, thank you very much. I really do appreciate the opportunity and I appreciate everything the Leukemia Research Foundation is doing to support patients, their caregivers, and future research.

 

- Thank you so much.