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Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease.  I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida.  Our full disclosures are available in the transcript of this episode.  James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary.  But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting.  So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important.  Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission.  In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults.  I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate.  The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it.  The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting.  The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work.  Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved.  One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now.  So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field.  Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it.  And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't.  A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that.  I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results.  There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that.  John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets.  I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can.  I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that.  And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. John Sweetenham  Dr. James Foran Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn  Disclosures:    Dr. John Sweetenham:    No relationships to disclose Dr. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview

Welcome back to the Oncology Brothers podcast! In this episode, we dive into the highlights from ASH 2024, focusing on key studies in leukemia. Join hosts Drs. Rahul and Rohit Gosain as they discuss groundbreaking research with Dr. Uma Borate from The Ohio State University. Episode Highlights: •⁠  ⁠KOMET 007 Study: An in-depth look at the Phase 1 study on the Menin inhibitor Ziftomenib, exploring its promising results in frontline settings for patients with NPM1 mutations and KMT2A rearrangements. •⁠  ⁠CPX351 vs. 7+3 Induction: A discussion on the liposomal formulation CPX351 and its effectiveness compared to the traditional 7+3 induction therapy, particularly in patients with myelodysplasia-related AML. •⁠  ⁠Venetoclax Combinations: Insights into the use of Venetoclax in combination with various therapies, including its role in treating patients without actionable mutations. Key Takeaways: •⁠  ⁠The importance of NGS testing in identifying targetable mutations in AML. •⁠  ⁠Promising response rates and manageable toxicities associated with Menin inhibitors. •⁠  ⁠The ongoing debate regarding the best induction therapy for AML patients. Don't miss this informative discussion that sheds light on the evolving landscape of leukemia treatment! Subscribe for more updates on oncology topics, including lymphoma, CLL, and myeloma discussions from ASH 2024. Thanks for tuning in! We are the Oncology Brothers. Website: http://www.oncbrothers.com/ X/Twitter: https://twitter.com/oncbrothers Contact us at info@oncbrothers.com

In this week's episode we'll discuss how CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia; learn more about the effect of ATM germline pathogenic variants on the outcomes in children with ataxia-telangiectasia and hematological malignancies; and discuss the preclinical efficacy of a potent, selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias.Featured Articles:CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemiaATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematologicalmalignanciesPreclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) inKMT2A- and NPM1-altered leukemias

In this week's episode we'll learn about iron, HFE hemochromatosis, and infections. In this large, population-based study, both high and low levels of plasma iron and transferrin saturation were associated with increased risks of infection. Then, we'll discuss how bispecific antibodies improve CAR T-cell response in B-cell malignancies. In-vitro and in-vivo data demonstrate enhanced therapeutic efficacy when a CD20-directed bispecific antibody is given in combination with CD19-directed CAR-T cells. Finally, we'll hear about determinants of outcome in NPM1-mutated AML. In a large series of patients with NPM1-mutated AML, investigators identified several variables beyond FLT3-ITD that adversely impacted outcomes. Featured Articles:Iron, hemochromatosis genotypes, and risk of infections: a cohort study of 142 188 general population individualsMolecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AMLCD20-bispecific antibodies improve response to CD19-CAR T cells in lymphoma in vitro and CLL in vivo models

Dr. Mollie Leoni, Executive Vice President for Clinical Development of Kura Oncology, discusses the company's ziftomenib program, a menin inhibitor for acute myeloid leukemia (AML). The company initially allowed all AML patients to participate in the clinical study, but later found that specific subtypes, such as those with NPM1 mutation or KMT2A rearrangement, were more likely to respond to the menin inhibitor. They also discovered other subtypes that were responsive, expanding the potential patient population. Understanding the role of menin and menin inhibitors in addressing abnormal gene expression and promoting healthy cell development opens the door to potential combination therapy, where menin inhibitors could be layered onto existing treatments for various cancers related to menin independence. Mollie explains, "In oncology, we have gotten good at treating the end state, but cancer has many, many causes with a common final endpoint to the way the cells look. So, it's many, many different diseases all at once. We've learned and are learning that with better technology and a better understanding of cancer in general we can identify not just how to stop the end state but how to stop it from starting." "That's where ziftomenib comes in. Ziftomenib addresses key mutations that when they occur, are what cause the development of cancer. So you're able to shut down the development and force the cells to develop normally rather than waiting until they're already diseased and killing them with chemotherapy or some other cytotoxic agent." "There is a protein complex that we refer to as the menin MLL complex, which goes rogue when something unusual happens in the cell. For example, that could be an NPM1 mutation. That could be a KMT2A rearrangement. Those are two things that are well-known to happen within AML diseases. It could also be a SETD2 RUNX1 mutation. So many types of mutations could happen that could cause this machinery to go rogue within the cell. And that complex causes genes to become active at levels and at times that are abnormal." #KuraOncology #Ziftomenib #MeninInhibitors #PrecisionMedicine #BTD #AML KuraOncology.com Download the transcript here

Dr. Mollie Leoni, Executive Vice President for Clinical Development of Kura Oncology, discusses the company's ziftomenib program, a menin inhibitor for acute myeloid leukemia (AML). The company initially allowed all AML patients to participate in the clinical study, but later found that specific subtypes, such as those with NPM1 mutation or KMT2A rearrangement, were more likely to respond to the menin inhibitor. They also discovered other subtypes that were responsive, expanding the potential patient population. Understanding the role of menin and menin inhibitors in addressing abnormal gene expression and promoting healthy cell development opens the door to potential combination therapy, where menin inhibitors could be layered onto existing treatments for various cancers related to menin independence. Mollie explains, "In oncology, we have gotten good at treating the end state, but cancer has many, many causes with a common final endpoint to the way the cells look. So, it's many, many different diseases all at once. We've learned and are learning that with better technology and a better understanding of cancer in general we can identify not just how to stop the end state but how to stop it from starting." "That's where ziftomenib comes in. Ziftomenib addresses key mutations that when they occur, are what cause the development of cancer. So you're able to shut down the development and force the cells to develop normally rather than waiting until they're already diseased and killing them with chemotherapy or some other cytotoxic agent." "There is a protein complex that we refer to as the menin MLL complex, which goes rogue when something unusual happens in the cell. For example, that could be an NPM1 mutation. That could be a KMT2A rearrangement. Those are two things that are well-known to happen within AML diseases. It could also be a SETD2 RUNX1 mutation. So many types of mutations could happen that could cause this machinery to go rogue within the cell. And that complex causes genes to become active at levels and at times that are abnormal." #KuraOncology #Ziftomenib #MeninInhibitors #PrecisionMedicine #BTD #AML KuraOncology.com Listen to the podcast here

The process of identifying which patients with acute myeloid leukemia (AML) can benefit from allogeneic stem cell transplantation in first complete remission (CR1) has taken a step forward thanks to analysis of the UK NCRI AML17 and AML19 studies, reported at the 65th ASH Annual Meeting and Exposition. Patients who achieved molecular residual disease (MRD) negativity in their peripheral blood were at low risk of relapse, and had no benefit from allogeneic transplant in CR1, including those with the FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication mutation of the NPM1 (nucleophosmin 1) gene, that is generally considered to be a marker of poor risk. Peter Goodwin spoke with Jad Othman, MBBS, from King's College London and the Guy's and St Thomas' Hospital in London, and now based at the Royal North Shore Hospital in Sydney, Australia. Othman explained how testing for the FLT3 mutation of the NPM1 gene can be used along with assessment of molecular MRD to help choose patients who can benefit from transplant and spare those for whom the risk/benefit ratio is adverse.

In this week's episode, we'll discuss the association between occupational exposure to anticancer agents in a parent and subsequent cancer in a child. Then we'll learn about deciphering and disrupting the activation of PIEZO1 in hereditary xerocytosis. Finally, we'll hear about the assessment of measurable residual disease, or MRD, in patients with NPM1-mutated AML, or acute myeloid leukemia, receiving venetoclax-based NON-intensive therapy.

La Dra. Nidia Paulina Zapata Canto, hematóloga adscrita al Instituto Nacional de Cancerología en la Ciudad de México, México, tiene como invitado especial en este episodio de “Preguntémosle al experto…” al Dr. Gustavo A. Rivero, hematólogo en Georgetown University en Washington, EE.UU, para abordar un caso clínico sobre trasplante alogénico en leucemia aguda mieloblástica (LAM) de bajo riesgo. Los expertos responderán con base en evidencia científica y en su experiencia a varias interrogantes. El caso trata de una mujer de 22 años con LAM ETO t(8;21) y NPM1 positivo. Inició tratamiento con 7+3 y se reportó una enfermedad mínima residual (EMR) de 1.3%, posteriormente se inició consolidación con 1.5 g de citarabina con EMR no detectable (ND) después del primer ciclo. Se consolidó con dos ciclos más a 1.5 g con EMR ND y con un seguimiento a 3 meses se le realizó secuenciación de nueva generación para mutación NPM1 con un resultado positivo. Con base en este caso, las preguntas para el experto son las siguientes: ¿Cuál es la dosis actual del HIDAC? ¿En el grupo del core binding factor la dosis de 1.5 g sigue siendo ideal? ¿Cómo beneficia gemtuzumab al grupo del core binding factor? Entre otras... Fecha de grabación: 24 de mayo de 2023. Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In this week's episode, we'll learn how rare germline genetic variants in complement factor H (CFH) affect the course of paroxysmal nocturnal hemoglobinuria, discuss the role of coagulation factor XII in thrombotic complications and vaso-occlusion associated with sickle cell disease, and learn more about the overlapping features of therapy-related and de novo NPM1-mutated AML.

In this week's episode, new research shows that in children with sickle cell disease, stem cell transplantation normalizes blood flow in the brain. The improvements in cerebral hemodynamics seen in this study may help explain the stroke protection seen following transplant in this high-risk patient population. Next up, a research article providing new insights on thrombocytopenia related to the GALE gene, including the identification of several previously unreported variants. The findings highlight the importance of GALE in the glycosylation of proteins that play a role in the production and function of platelets. Finally, we'll review a brief report on NPM1-mutated AML with adverse cytogenetics in light of the updated ELN 2022 classification. In short, adverse-risk cytogenetics remain significantly associated with unfavorable prognosis under the refined definitions, supporting the recent categorization of this entity as adverse-risk.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.18.517150v1?rss=1 Authors: Potapova, T. A., Unruh, J. R., Conkright-Fincham, J. J., Banks, C. A. S., Florens, L., Schneider, D. A., Gerton, J. L. Abstract: Ribosome biogenesis is one of the most essential and energy-consuming cellular functions. It takes place mainly in the nucleolus. For cancer cells, the nucleolar function is especially important due to the high demand for ribosomes to support continuous proliferation. The goal of this study was to assess the effects of existing chemotherapy drugs on the nucleolar state. For this, we conducted an imaging-based screen for anticancer drugs that induce morphological re-organization consistent with nucleolar stress. For a readout, we developed a novel parameter termed "nucleolar normality score", which measures ratios of dense fibrillar center and granular component in the nucleolus and nucleoplasm. We show that multiple classes of drugs cause nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Different classes of drugs induced morphologically and molecularly distinct states of nucleolar stress. By applying phospho-proteomics and live imaging strategies, we characterized in detail the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that targets RNA Pol II. Inhibition of CDK9 dramatically reduced rRNA production, caused dissociation of RNA Polymerase I catalytic subunit POLR1A from ribosomal DNA and dispersal of the nucleolar granular component, a stress we refer to as the "bare scaffold" state. We identified multiple nucleolar CDK phosphorylation substrates, including RNA Pol I - associated protein Treacle, and demonstrated that CDK9 can phosphorylate Treacle in vitro. This implies that transcriptional CDKs coordinate the action of RNA pol I and RNA pol II. Furthermore, molecular dynamics analysis of the endogenous nucleolar protein NPM1 demonstrated that CDK inhibition vastly increased its mobility, consistent with the loss of nucleolar integrity. We conclude that many classes of chemotherapy compounds directly or indirectly target nucleolar structure and function, and recommend considering this in anticancer drug development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Featuring a slide presentation and related discussion from Dr Eytan Stein, including the following topics: Historical paradigms for treating newly diagnosed acute myeloid leukemia (AML) (0:00) Long-term findings and emerging results with venetoclax-based therapies for newly diagnosed and relapsed/refractory (R/R) AML (1:19) Efficacy and tolerability of oral decitabine/cedazuridine for patients with AML (19:27) Mechanism of action, activity and safety of magrolimab-based therapies for newly diagnosed and R/R disease (23:34) Sabatolimab: Mechanism of action and efficacy in combination with a hypomethylating agent (32:01) Therapeutic targeting of Menin and NPM1 mutations in AML; activity of entospletinib in combination with induction chemotherapy (37:29) CME information and select publications

In this week's episode we'll learn more about the prognostic impact of NPM1 and FLT3 mutations in AML, discuss the progression and survival of monoclonal B-cell lymphocytosis, and learn more about the use of red blood cells derived from pluripotent stem cells in transfusion medicine.

Featuring perspectives from Dr Amir Fathi, including the following topics: Introduction: Differentiation Syndrome (0:00) Case: A woman in her late 70s who received decitabine/venetoclax for acute myeloid leukemia (AML) — Bhavana (Tina) Bhatnagar, DO (14:24) Case: A man in his early 30s with AML harboring a FLT3-ITD mutation with an allelic ratio of 0.6 and NPM1 and IDH2 mutations — Jeanne Palmer, MD (24:04) Case: A woman in her late 70s with ovarian cancer who develops AML with a TP53 mutation and a complex karyotype — Dr Bhatnagar (33:37) Case: A woman in her mid-30s with inversion 16 AML — Dr Palmer (46:33) Faculty Survey (50:05) Journal Club with Amir Fathi, MD (57:25) CME information and select publications

Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia” by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King's College London and Consultant Hematologist at Guy's Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.   The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.   In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.   Karol and colleagues from St. Jude's Children's Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.   In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.   The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.   The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.   Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.   On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.   The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.   Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.   This concludes this JCO Podcast. Thank you for listening.

Featuring Dr Mark Levis’s perspectives on his time spent speaking with patients with acute myeloid leukemia from the practice of community oncologist Dr Spencer Bachow, including the following topics: Case: A woman in her early 70s with acute myeloid leukemia (AML) and mutations in FLT3, NPM1 and IDH1 receives standard induction therapy and midostaurin followed by an allogeneic stem cell transplant (0:00) Perspective on the choice of allogeneic stem cell transplant versus venetoclax with a hypomethylating agent for older patients with AML; therapeutic options for post-transplant maintenance therapy (4:00) Selection of therapy for an older patient with AML with FLT3 and IDH mutations (15:13) Case: A man in his mid-70s with multiple comorbidities is diagnosed with AML with an SRSF2 mutation and receives azacitidine and venetoclax followed by venetoclax alone (24:47) Benefits and risks with the combination of venetoclax and azacitidine for patients with AML (34:49) Selection of patients for oral azacitidine; FDA approval of oral azacitidine as maintenance therapy for patients with AML in first remission (42:27) Case: A man in his late 40s with a history of primary myelofibrosis is diagnosed with secondary AML with del(5q) and del(7q) and mutations in JAK2 V617F, IDH2, DNMT3A and SRSF2 (45:55) Risk factors for the development of AML; therapeutic options for a patient with AML and mutations in JAK2 V617F, IDH2, DNMT3A and SRSF2 (51:08) Choice between venetoclax in combination with a hypomethylating agent and a clinical trial of CPX-351 (liposomal daunorubicin with cytarabine), each in combination with an IDH inhibitor, for patients with AML and an IDH mutation (55:36) Activity and tolerability of liposomal daunorubicin with cytarabine and its FDA approval for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (1:02:00) CME information and select publications

Featuring a discussion on recent clinical trial data on the use of FLT3 inhibitors in the management of acute myeloid leukemia with Dr Keith Pratz, including the following topics: Targeting FLT3 in Acute Myeloid Leukemia (AML) — Keith W Pratz, MD (0:00) Case: A man in his late 50s with AML and a FLT3-ITD mutation receives midostaurin and 7 + 3 chemotherapy followed by an allogeneic transplant and maintenance sorafenib (23:52) Case: A woman in her late 60s with hypertension and diabetes is diagnosed with AML and FLT3-ITD, IDH2, NPM1 and NRAS mutations (25:41) Case: A woman in her early 80s with AML with FLT3-TKD and NPM1 mutations receives single-agent gilteritinib (27:52) CME information and select publications

Featuring an interview with Dr Courtney D DiNardo on recent data on the management of acute myeloid leukemia not eligible for intensive induction therapy, including the following topics: Management of Acute Myeloid Leukemia in Patients Not Eligible for Intensive Induction Therapy — Courtney D DiNardo, MD, MSCE (00:00) Case: A woman in her mid-70s with AML and diploid cytogenetics with mutations in NPM1, IDH1 and FLT3-TKD who receives venetoclax with a hypomethylating agent (21:20) Case: A man in his late 60s with AML with del(5q), del(7q) and mutations in RUNX1 and SRSF2 (28:57) Case: A woman in her late 60s with relapsed/refractory AML with intermediate-risk cytogenetics (35:22) CME information and select publications

This week's episode will review efforts to improve the activity of CAR T cells, explore the impact of Protein C activator AB002 on thrombus development, and look at results from a UK study on minimal residual disease status and outcome after transplantation in NPM1-mutated AML.

Acute Leukemias Update — Part 2: Our interview with Dr Ravandi highlights the following topics as well as cases from his practice: Impact of genetic mutations and cytogenetic alterations on prognosis and therapy selection for patients with AML (00:00) Initial workup for patients with newly diagnosed AML (03:38) Biologic rationale for, activity of and approval of venetoclax in combination with hypomethylating agents for patients with AML who are 75 or older or have comorbidities (05:48) Integration of venetoclax with hypomethylating agents into the clinical algorithm for AML (10:50) Approach to therapy for older patients with AML and FLT3 mutations(12:43) Management of toxicities associated with venetoclax combined with a hypomethylating agent (15:08) RATIFY: Results of a Phase III trial evaluating midostaurin with 7 + 3 induction and high-dose cytarabine consolidation and as maintenance therapy for patients with newly diagnosed AML and FLT3 mutations (18:25) Efficacy of sorafenib, quizartinib or gilteritinib for patients with AML and FLT3 mutations (21:57) Side effects and spectrum of activity of gilteritinib, quizartinib and midostaurin (25:09) Case: A 70-year-old man with AML and NPM1 and FLT3 mutations receives azacitidine in combination with venetoclax and sorafenib as third-line therapy (29:06) Case: A 44-year-old woman with AML and an IDH2 mutation receives enasidenib (31:32) Perspective on the potential use of enasidenib or ivosidenib in the first-line setting (34:52) Mechanism of action and efficacy of CPX-351 in patients with therapy-related AML or AML with myelodysplasia-related changes (37:45) Clinical experience with CPX-351 (40:23) Role of gemtuzumab ozogamicin in the treatment of CD33-positive AML (42:57) Activity of the recently approved hedgehog inhibitor glasdegib in combination with low-dose cytarabine for newly diagnosed AML in patients aged 75 or older or those with comorbidities (46:27) Case: A 75-year-old woman with AML and significant comorbidities is enrolled on a clinical trial of decitabine with venetoclax (47:58) Case: A 76-year-old woman with ALL experiences a complete remission with blinatumomab as second-line therapy (51:46) Mechanism of action and efficacy of blinatumomab for ALL (55:52) Activity and tolerability of CAR T-cell therapy for ALL (57:50) Cytokine release syndrome and neurologic toxicities associated with CAR T-cell therapy and blinatumomab (59:52) Perspective on the role of tyrosine kinase inhibitors in the treatment of Philadelphia chromosome-positive ALL (1:02:09) Efficacy of gemtuzumab ozogamicin in patients with high-risk APL (1:04:46)   Select publications

Acute Leukemias Update — Part 1: Our interview with Dr Levis highlights the following topics as well as cases from his practice: Molecular profiling in the diagnosis and treatment of acute myeloid leukemia (AML) (00:00) Management of AML with p53 mutations (03:13) Efficacy of hypomethylating agents with venetoclax in older patients with AML (06:41) Therapeutic options for patients with AML and FLT3 mutations (10:31) Monitoring and management of venetoclax-associated tumor lysis syndrome (13:06) Case: A 62-year-old woman who presents with fatigue and bleeding gums is diagnosed with AML with FLT3 and NPM1 mutations (16:08) Role of the FLT3 pathway in myeloid cell development and types of FLT3 mutations (17:10) Impact of FLT3 mutations on therapeutic decision-making (21:01) Activity of midostaurin in newly diagnosed AML with a FLT3 mutation (23:48) BMT CTN 1506: A Phase III trial of gilteritinib as maintenance therapy after allogeneic transplant for patients with AML and FLT3-ITD mutations (25:20) Case: A 60-year-old man with AML and a FLT3-ITD mutation receives gilteritinib with standard 7 + 3 chemotherapy induction followed by allotransplant and maintenance gilteritinib on a clinical trial (27:20) Similarities and differences among midostaurin, quizartinib and gilteritinib (28:58) Case: A 63-year-old man with refractory AML and an IDH2 mutation receives enasidenib and develops differentiation syndrome (31:46) Biologic rationale for targeting IDH1/2 mutations and activity of ivosidenib or enasidenib in patients with relapsed/refractory AML (35:57) Efficacy and side effects of CPX-351 (liposomal cytarabine/daunorubicin) in patients with AML (40:46) Case: A 28-year-old obese man with acute lymphoblastic leukemia (ALL) and an MLL rearrangement develops hepatic toxicity after treatment with the Berlin-Frankfurt-Munster pediatric-inspired regimen containing L-asparaginase (43:01) Mechanism of action, activity and tolerability of blinatumomab for ALL (46:38) Neurologic side effects associated with blinatumomab (49:03) Use of blinatumomab for minimal residual disease-positive ALL (51:53) Optimal use of tyrosine kinase inhibitors in the management of Philadelphia chromosome-positive ALL (53:30) Case: A 41-year-old woman receives chimeric antigen receptor (CAR) T-cell therapy for relapsed ALL (58:37) Role of CAR T-cell therapy in the management of ALL (1:01:31) Use of the antibody-drug conjugates gemtuzumab ozogamicin and inotuzumab ozogamicin for acute leukemias (1:07:42) Activity of gemtuzumab ozogamicin in patients with high-risk acute promyelocytic leukemia (APL) (1:10:30) Select publications

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a moment to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands, lead author on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline.” Thank you for being here today, Dr. de Haas. Thank you. So first, can you give us a general overview of what this guideline covers? Well, yes. The laboratory evaluation of patients who are suspected of having acute leukemia is very complex, and it has evolved significantly with the incorporation of advanced laboratory techniques. The traditional backbone of initial workup of AL, of acute leukemia, is composed of ctyomorphology, cytochemistry, immunophenotyping, and molecular cytogenetics. These techniques are the backbone of the initial diagnostic workup of acute leukemia. This is leading to risk stratification and fine tuning of the therapy by molecular signatures. The advanced molecular diagnostics, such as next-generation sequencing, has become more important in the diagnosis and in the risk stratification of acute leukemia. This guideline is meant for both pediatric and adult patients, and it was initially published in 2017. This year, we reviewed this guideline, and we have taken into account two important developments. First, since 2017, we've seen that there are major advances in molecular techniques and also that we can identify and validate new molecular markers. And those two events have contribute to a better risk stratification. And the second development is the effect that the WHO classification was revised in 2017 which also has led to new risk recoveries and refined subclassifications. So what are the key recommendations of this guideline? Well, in total, we have reviewed 27 guideline statements by the ASCO endorsement expert panelists. And discussion points are used to summarize issues that were identified from the updated literature. The ASCO expert panel determined that the recommendations from the guideline as published in 2016 are clear, thorough, and they are based upon the most relevant scientific evidences. We fully endorse the CAP-ASH guideline on initial diagnostic workup of acute leukemia. And we decided to include some discussion points according to clinical practice and according to the updated literature. In fact, we identified four categories of key recommendations. The first one is the initial diagnostics focusing on basic diagnostics and determination of risk parameters. This concerns, in total, about 11 guideline recommendations, and they give an overview of the initial workup varying from the collection of the clinical history of the patient to initial basic diagnostics by cytomorphology, flow cytometry and molecular cytogenetic analysis of peripheral blood, bone marrow, and cerebrospinal fluids. Secondly, the second category were molecular markers and MRD detection, and they were addressed by 10 of the recommendations. And these recommendations give a structural overview of the molecular and cytogenetic workup for acute lymphoblastic leukemia versus acute myeloid leukemia identifying different prognostic markers. Also, the detection of MRD is taken into account in this recommendation. There is a major difference between children and adults, and this part is given most attention in the discussion part as the developments have been major during the past few years. The third one is the context of referral to another institution with expertise in the management of acute leukemia. This is addressed by four recommendations, emphasizing the point that referral to an institution with specific expertise is of major importance for the central workup of acute leukemia. And finally, the final reporting and report keeping is reflected in three recommendations, mainly supporting conclusions from 2017 which were describing the fact that the complete report with basic diagnostics in one central report should be available within 48 to 72 hours. And this should be followed by complete, final, comprehensive report in one or two weeks. So can you tell us about those discussion points that were made and why the panel decided to include these? The discussion points include mostly issues regarding diagnostics that involve flow cytometry and molecular techniques as addressed in part one and two of the guidelines. We think that the cytomorphologic assessment is essential for initial diagnosis of acute leukemia. Multicolor flow cytometry using 8 to 10 colors has led to a better distinction between myeloids, lymphoid, and mixed lineage blast origin. Even when the number of cells are limited, for instance in CNS involvement, fine needle aspirate of extramedullary leukemic infiltration, or skin biopsy for leukemic cutis. Also, it was suggested to better assess the central nervous system involved in leukemia. The expert panel recommends the immunophenotyping studies as an additional detection technique next to the cytomorphological examination of cytospins and particularly for those with a low level involvement of acute leukemia that cannot be well addressed by a morphologic examination only. The TDT immunohistochemistry staining of cytospins has alternatively been used for detection of CNS disease in AML and evaluation of CSF by multicolor flow cytometry has been recently adopted in some centers. Flow cytometry, using at least six, but we now use in some laboratories, even 8 to 10 colors has led to a much more specific in tentative diagnosis. And this has improved the detection of CNS involvement. The use of molecular tools, for instance, polymerase change reaction, PCR, NGS for low-level CSF involvement is still under study, and therefore, we did not recommend this in our discussion. Regarding the molecular markers and MRD detection, the discussion here was mainly based upon the results of translational research supported by better molecular detection techniques. And those molecular diagnoses have been developing in the past few years with the inclusion of many more molecular markers. And they included one of the key diagnostic criteria in the revised WHO classification, which was revised in 2017. And we made substantial changes that have been made in the ASH-CAP guidelines concerning molecular diagnostics. Those newly identified targets by advanced molecular techniques give possibilities for better risk stratification. Some examples of better molecular characterization of acute lymphoblastic leukemia are, for instance, additional testing for MLL translocations. Furthermore, we can look in patients with T-ALL for NOTCH1, and FBXW7 mutations. The Ikaros family zinc finger gene, the IKZF1 gene is frequently deleted in adults as well in children with B-ALL. And it was shown to have an independent prognostic significance and was also associated with poor clinical outcome. In the current text of the current risk that the protocols IKZF1 should be regularly included in the screening panels for all ALL patients. If we look for examples for better characterization of AML, acute myeloid leukemia, we have found an increasing number of additional cytogenetic aberrations, like for instance FLT3 ITD which is associated with poor outcome. Another example is appropriate mutational analysis for kids, which can be detected both in adult patient as pediatric patients with a confirmed core binding factor acute myeloid leukemia. So this is myeloid leukemia with a translocation A21, RUNX1, or inversion 16. This recommendation is very strong in adults, whereas in children, this prognostic fact impact remains unclear. So there have been proven several publications which refer to a similar prognosis for children and others who refer to a poor prognosis in comparison to known mutated genes. So we suggest to test for this mutation in adults, especially, but also in children to learn from it. Finally, emerging evidence supports molecular studies as principle test for monitoring minimal residual disease of acute leukemia. And there are several key molecular markers that are included in the initial workup, which will be carried on for monitoring MRD, for instance, PML- RAR-alpha, RUNX1-RUNXT1, CBFB-MYH11, and NPM1, CEBP-alpha and others. Beside those aforementioned markers, it's very important to screen for other molecular markers that have predictive or prognostic value in the individual. And it is possible to use them for MRD. We have found a recent consensus from the European Leukemia Net MRD Working Group, who was proposing that for detection of molecular MRD, and they refer the RT PCR platform to NGS and digital PCR platforms. Although all those molecular techniques have been developed very quickly and it is very tempting to use them for initial diagnostics, currently, not all laboratories will have all those techniques available. So the expert panel strongly advises understanding to make distinction between diagnostic that are needed in the first phase to start treatment and subsequently, treatment stratification, in contrast to the usual dose findings in a broader research. For instance, available karyotyping, FISH, PCR techniques, if possible, NGS can be used in the initial start of treatment, whereas techniques like whole exome sequencing, whole genome sequencing, RNA sequencing, and epigenomic studies are meant for a broader research. And finally, how will these guideline recommendations affect patients? Well, in the end, the patients will receive better and especially, more personalized treatment. If we have results available within two weeks from diagnosis, it will be possible to better identify which basis will better benefit from more intensified and more personalized treatment, whereas others may need less intensive treatment with less toxicity. If you use traditional techniques to do this supported by molecular techniques like karyotyping, FISH, and PCR techniques, and in the end, following MRD to see which patients are responding to treatment, MRD detection will help to identify these patients and stratify them finally to the best treatment. Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. de Haas. OK. Thanks a lot. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

In this week's episode, Dr. Danielle Shafer, Medical Director of the Clinical Trials Office at Massey Cancer Center at Virginia Commonwealth University, explores the recent FDA approval of ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia. Dr. Shafer's primary clinical focus is leukemia & lymphoma in adult patients. Her research focus is limited to the same population, with a particular interest in relapsed/refractory AML. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [MUSIC PLAYING] Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Danielle Shafer, and I'm an assistant professor at the Massey Cancer Center at Virginia Commonwealth University. My area of specialty is leukemia and lymphoma. Today, we will discuss the approval of ivosidenib in patients with relapsed and refractory AML with a susceptible IDH1 mutation. As a background to today's discussion, somatic mutations of IDH have been identified in multiple tumor types, including AML and MDS. As a result of the mutation, there is impaired hematopoietic differentiation, as well as epigenetic alteration. IDH mutations occur in approximately 20% of adults with AML, and 5% of adults with MDS. IDH1 mutations occur in approximately 6% to 9% of adult AML patients. Enasidenib was approved by the FDA in 2017 for adult patients with relapsed and refractory AML with an IDH2 mutation. On July 20, of 2018, ivosidenib was approved by the FDA for the treatment of adult patients with relapsed and refractory AML with a susceptible IDH1 mutation, as detected by an FDA approved test. The approval of ivosidenib in the relapse to refractory setting was based on the results of a phase I dose escalation and dose expansion study published in the New England Journal of Medicine. The primary objectives of the study were to assess the safety, maximum tolerated dose, and recommended phase II dose. Of the 258 patients receiving study drug, 179 patients had relapsed and refractory disease. The median age was 67, with a range of 18 to 87 years. Patients had a median of two prior therapies, 24% had relapsed after transplant, and 59% were refractory to induction or re-induction. 59% had favorable cytogenetics. The most common co-occurring mutation was NPM1 in 26% of patients. A maximum tolerated dose was not defined, and ivosidenib 500 milligrams was selected for dose expansion. The most common adverse reactions were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, Q/T prolongation, rash, pyrexia, cough, and constipation. In the overall population, 30 day all-cause mortality was 7%. The majority of deaths were related to disease progression or complications of underlying AML. No treatment-related adverse events leading to death were seen in patients with a starting dose of 500 milligrams. IDH differentiation syndrome is of special interest, as early identification is necessary. It is similar to what has been described with ATRA and arsenic trioxide. In this study, IDH differentiation syndrome was reported in 19 patients, and was of grade 3 or higher in nine patients. Leukocytosis grade 2 or 3 accompanied differentiation syndrome in 7 of the 19 patients. Median time to onset was 29 days, with a range of 5 to 59 days. Treatment included glucocorticoids, diuretics, and hydroxyurea, if leukocytosis was present. With intervention, 17 of the 19 patients had resolution. The two remaining patients had differentiation syndrome at data cutoff. In the relapsed refractory population, the rate of complete remission or complete remission with partial hematologic recovery was 30.4%. The median duration of complete remission, or complete remission with partial hematologic recovery, was 8.2 months. The median time to response was 2.7 months. With a median follow-up of 14.8 months, the median overall survival was 8.8 months. ivosidenib is the first IDH1 inhibitor to enter the clinic for relapsed refractory AML, and clearly represents a step forward for this population. The drug is, overall, well-tolerated. Differentiation syndrome represents a unique toxicity, as early recognition is critical. Practicing physicians may encounter difficulties differentiating disease progression from differentiation syndrome in some patients. Given the success of the drug in the relapsed refractory setting, it is now being combined with other therapies and moving earlier in the treatment course. Based on the encouraging results of a phase I study, ivosidenib is currently being combined with intensive chemotherapy in a phase III study, for newly-diagnosed AML patients with IDH1 mutations. Although the drug is termed a success, the majority of patients are still dying of their disease. While some patients were bridged to transplant in the New England study, the benefit is not yet entirely clear. Additional questions emerge regarding co-mutations and IDH1 mutation clearance. Not surprisingly, in this study, there was some preliminary data to suggest that patients with IDH1 clearance had longer durations of remission and survival. We anticipate better understanding as more patients are treated with the drug. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the treatment of AML, visit the comprehensive e-learning center at university.asco.org. [MUSIC PLAYING]

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands, lead author on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline.” Thank you for being here today, Dr. de Haas. Thank you. So first, can you give us a general overview of what this guideline covers? Well, yes. The laboratory evaluation of patients who are suspected of having acute leukemia is very complex, and it has evolved significantly with the incorporation of advanced laboratory techniques. The traditional backbone of initial workup of AL, of acute leukemia, is composed of ctyomorphology, cytochemistry, immunophenotyping, and molecular cytogenetics. These techniques are the backbone of the initial diagnostic workup of acute leukemia. This is leading to risk stratification and fine tuning of the therapy by molecular signatures. The advanced molecular diagnostics, such as next-generation sequencing, has become more important in the diagnosis and in the risk stratification of acute leukemia. This guideline is meant for both pediatric and adult patients, and it was initially published in 2017. This year, we reviewed this guideline, and we have taken into account two important developments. First, since 2017, we've seen that there are major advances in molecular techniques and also that we can identify and validate new molecular markers. And those two events have contribute to a better risk stratification. And the second development is the effect that the WHO classification was revised in 2017 which also has led to new risk recoveries and refined subclassifications. So what are the key recommendations of this guideline? Well, in total, we have reviewed 27 guideline statements by the ASCO endorsement expert panelists. And discussion points are used to summarize issues that were identified from the updated literature. The ASCO expert panel determined that the recommendations from the guideline as published in 2016 are clear, thorough, and they are based upon the most relevant scientific evidences. We fully endorse the CAP-ASH guideline on initial diagnostic workup of acute leukemia. And we decided to include some discussion points according to clinical practice and according to the updated literature. In fact, we identified four categories of key recommendations. The first one is the initial diagnostics focusing on basic diagnostics and determination of risk parameters. This concerns, in total, about 11 guideline recommendations, and they give an overview of the initial workup varying from the collection of the clinical history of the patient to initial basic diagnostics by cytomorphology, flow cytometry and molecular cytogenetic analysis of peripheral blood, bone marrow, and cerebrospinal fluids. Secondly, the second category were molecular markers and MRD detection, and they were addressed by 10 of the recommendations. And these recommendations give a structural overview of the molecular and cytogenetic workup for acute lymphoblastic leukemia versus acute myeloid leukemia identifying different prognostic markers. Also, the detection of MRD is taken into account in this recommendation. There is a major difference between children and adults, and this part is given most attention in the discussion part as the developments have been major during the past few years. The third one is the context of referral to another institution with expertise in the management of acute leukemia. This is addressed by four recommendations, emphasizing the point that referral to an institution with specific expertise is of major importance for the central workup of acute leukemia. And finally, the final reporting and report keeping is reflected in three recommendations, mainly supporting conclusions from 2017 which were describing the fact that the complete report with basic diagnostics in one central report should be available within 48 to 72 hours. And this should be followed by complete, final, comprehensive report in one or two weeks. So can you tell us about those discussion points that were made and why the panel decided to include these? The discussion points include mostly issues regarding diagnostics that involve flow cytometry and molecular techniques as addressed in part one and two of the guidelines. We think that the cytomorphologic assessment is essential for initial diagnosis of acute leukemia. Multicolor flow cytometry using 8 to 10 colors has led to a better distinction between myeloids, lymphoid, and mixed lineage blast origin. Even when the number of cells are limited, for instance in CNS involvement, fine needle aspirate of extramedullary leukemic infiltration, or skin biopsy for leukemic cutis. Also, it was suggested to better assess the central nervous system involved in leukemia. The expert panel recommends the immunophenotyping studies as an additional detection technique next to the cytomorphological examination of cytospins and particularly for those with a low level involvement of acute leukemia that cannot be well addressed by a morphologic examination only. The TDT immunohistochemistry staining of cytospins has alternatively been used for detection of CNS disease in AML and evaluation of CSF by multicolor flow cytometry has been recently adopted in some centers. Flow cytometry, using at least six, but we now use in some laboratories, even 8 to 10 colors has led to a much more specific in tentative diagnosis. And this has improved the detection of CNS involvement. The use of molecular tools, for instance, polymerase change reaction, PCR, NGS for low-level CSF involvement is still under study, and therefore, we did not recommend this in our discussion. Regarding the molecular markers and MRD detection, the discussion here was mainly based upon the results of translational research supported by better molecular detection techniques. And those molecular diagnoses have been developing in the past few years with the inclusion of many more molecular markers. And they included one of the key diagnostic criteria in the revised WHO classification, which was revised in 2017. And we made substantial changes that have been made in the ASH-CAP guidelines concerning molecular diagnostics. Those newly identified targets by advanced molecular techniques give possibilities for better risk stratification. Some examples of better molecular characterization of acute lymphoblastic leukemia are, for instance, additional testing for MLL translocations. Furthermore, we can look in patients with T-ALL for NOTCH1, and FBXW7 mutations. The Ikaros family zinc finger gene, the IKZF1 gene is frequently deleted in adults as well in children with B-ALL. And it was shown to have an independent prognostic significance and was also associated with poor clinical outcome. In the current text of the current risk that the protocols IKZF1 should be regularly included in the screening panels for all ALL patients. If we look for examples for better characterization of AML, acute myeloid leukemia, we have found an increasing number of additional cytogenetic aberrations, like for instance FLT3 ITD which is associated with poor outcome. Another example is appropriate mutational analysis for kids, which can be detected both in adult patient as pediatric patients with a confirmed core binding factor acute myeloid leukemia. So this is myeloid leukemia with a translocation A21, RUNX1, or inversion 16. This recommendation is very strong in adults, whereas in children, this prognostic fact impact remains unclear. So there have been proven several publications which refer to a similar prognosis for children and others who refer to a poor prognosis in comparison to known mutated genes. So we suggest to test for this mutation in adults, especially, but also in children to learn from it. Finally, emerging evidence supports molecular studies as principle test for monitoring minimal residual disease of acute leukemia. And there are several key molecular markers that are included in the initial workup, which will be carried on for monitoring MRD, for instance, PML- RAR-alpha, RUNX1-RUNXT1, CBFB-MYH11, and NPM1, CEBP-alpha and others. Beside those aforementioned markers, it's very important to screen for other molecular markers that have predictive or prognostic value in the individual. And it is possible to use them for MRD. We have found a recent consensus from the European Leukemia Net MRD Working Group, who was proposing that for detection of molecular MRD, and they refer the RT PCR platform to NGS and digital PCR platforms. Although all those molecular techniques have been developed very quickly and it is very tempting to use them for initial diagnostics, currently, not all laboratories will have all those techniques available. So the expert panel strongly advises understanding to make distinction between diagnostic that are needed in the first phase to start treatment and subsequently, treatment stratification, in contrast to the usual dose findings in a broader research. For instance, available karyotyping, FISH, PCR techniques, if possible, NGS can be used in the initial start of treatment, whereas techniques like whole exome sequencing, whole genome sequencing, RNA sequencing, and epigenomic studies are meant for a broader research. And finally, how will these guideline recommendations affect patients? Well, in the end, the patients will receive better and especially, more personalized treatment. If we have results available within two weeks from diagnosis, it will be possible to better identify which basis will better benefit from more intensified and more personalized treatment, whereas others may need less intensive treatment with less toxicity. If you use traditional techniques to do this supported by molecular techniques like karyotyping, FISH, and PCR techniques, and in the end, following MRD to see which patients are responding to treatment, MRD detection will help to identify these patients and stratify them finally to the best treatment. Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. de Haas. OK. Thanks a lot. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

Die akute myeloische Leukämie (AML) ist aus genetischer Sicht eine sehr heterogene Erkrankung. Rezeptortyrosinkinasen (RTKs) wie FLT3 sind in der Leukämogenese von zentraler Bedeutung. Durch Mutationen aktivierte RTKs sind allerdings alleine nicht in der Lage eine AML zu induzieren. Die Kooperation mit anderen Mutationen ist hierfür notwendig. Zu den am häufigsten gemeinsam auftretenden Mutationen in der AML gehören NPM1- und FLT3-ITD- (internal tandem duplication) Mutationen. Klinische Daten zeigen, dass eine FLT3-ITD die gute Prognose von NPM1-mutierten (NPM1c+) Patienten in Abhängigkeit des FLT3-ITD-mRNA-Levels in negativer Weise beeinflusst. Dies lässt auf ein pathogenes Zusammenwirken beider Genmutationen in der AML schließen, welches im Rahmen dieser Arbeit untersucht wurde. Dazu wurde basierend auf der humanen AML-Zelllinie OCI-AML3 mittels stabiler, lentiviraler Transduktion das erste zelluläre Modellsystem etabliert, das die relevanten Genotypen (NPM1c+/FLT3-ITD; NPM1c+/FLT3-WT) sowie unterschiedliche Verhältnisse von FLT3-ITD zu FLT3-WT (ITD/WT) im NPM1-mutierten Hintergrund modelliert. Zunächst wurde die NPM1-Mutation sowie die Funktionalität des FLT3-WT- und FLT3-ITD-Rezeptors in den nativen und transgenen Zellen bestätigt. Mit Hilfe des Zellmodells konnte gezeigt werden, dass Zellen, die beide Mutationen tragen, in vitro wie auch in vivo einen Wachstumsvorteil besitzen. Dieser vergrößerte sich zudem mit zunehmendem ITD/WT-Verhältnis. Ab einem bestimmten ITD/WT-Verhältnis konnte dieser Wachstumsvorteil in vitro mit einem FLT3-Inhibitor über eine gewisse Dauer gehemmt werden. Diese Ergebnisse könnten auf ein Zusammenwirken der beiden Mutationen bei der Leukämogenese hinweisen und eine Ursache für die schlechteren Überlebenskurven von Patienten mit beiden Mutationen und zunehmender FLT3-ITD-Last darstellen. Der insgesamt jedoch nur schwach ausgeprägte Phänotyp des etablierten Zellmodells erfordert zum eindeutigen Nachweis der funktionellen Interaktion von NPM1- und FLT3-ITD Mutationen ein alternatives Modellsystem. In diesem Zellmodell zeigten Zellen, die den FLT3-WT-Rezeptor überexprimierten, ebenfalls einen schwachen Wachstumsvorteil gegenüber nativen Zellen mit endogener FLT3-WT-Expression. Neben aktivierenden FLT3-Mutationen wie einer ITD, führen auch hohe FLT3-WT-Expressionslevel zur konstitutiven Aktivierung der FLT3-Kinase und verschlechtern die Prognose der Patienten. Deshalb wurde in dieser Arbeit mit der Untersuchung der transkriptionellen Regulation von FLT3, als mögliche Ursache hoher FLT3-WT-Expressionslevel, begonnen. In silico wurden im proximalen FLT3-Promotor Bindestellen für die hämatopoetischen Transkriptionsfaktoren (TF) PAX5 und MYB identifiziert. Mit Hilfe des Dual-Luciferase® Reporter Assay Systems wurden PAX5 als schwacher Repressor und MYB als Aktivator des Flt3-Promotors bestätigt. Auch der Transkriptionsfaktor CEBPA verhielt sich auf gleiche Weise als Aktivator der Flt3-Promotoraktivität. Eine Punktmutation im CEBPA-Gen, die aus zwei AML-Fällen bekannt ist, führte zu einer erhöhten Flt3-Promotoraktivität. Die Identifizierung weiterer mutierter, FLT3-regulierender TF und ihre Korrelation mit der FLT3-Expression sollen zukünftig tiefere Einblicke in die transkriptionelle Regulierung von FLT3 als Ursache der FLT3-Überexpression in AML-Patienten gewähren. Für eine Reihe von in AML-Patienten gefundenen Mutationen ist deren Rolle in der Pathogenese der AML noch unbekannt. Dazu gehören Mutationen in den Rezeptortyrosinkinasen DDR1 und DDR2. In der vorliegenden Arbeit wurden DDR1- und DDR2-Mutationen stabil in Ba/F3 Zellen und transient in HEK-293T Zellen exprimiert, um ihr transformierendes Potential zu untersuchen und diese funktionell zu charakterisieren. Transgene, DDR1- und DDR2-exprimierende Ba/F3 Zellen zeigten keinen transformierenden Phänotyp. Weitere Untersuchungen zeigten eine konstitutive Phosphorylierung der extrazellulären DDR2-Mutanten (G222R, M291I) in HEK-293T Zellen und eine Adhäsion von Ba/F3 Zellen mit wildtypischem sowie mutiertem DDR1-Rezeptor in Anwesenheit des DDR-Liganden Kollagen. DDR1- und DDR2-Rezeptoren sind bisher vor allem in soliden Tumoren untersucht. Weitere funktionelle Analysen sind notwendig, um ihren Stellenwert bei der Entstehung von AML zu erfassen. Diese Arbeit zeigt, dass Rezeptortyrosinkinasen in der Leukämogenese auf unterschiedliche Weise eine wesentliche Rolle spielen können. Da Rezeptortyrosinkinasen zudem wichtige Zielmoleküle für therapeutische Ansätze darstellen, sind sie von besonderer Bedeutung.

Bei Patienten mit AML und MDS hat die Identifikation von zytogenetischen und molekularen Aberrationen eine herausragende Bedeutung. Als wichtige unabhängige Prognoseparameter nehmen sie einen entscheidenden Einfluss auf die Planung der Therapiestrategie und sind darüber hinaus zum genetischen Monitoring der Krankheitsaktivität geeignet. In der vorliegenden Arbeit konnte die Effektivität des FLAMSA-RIC-Protokolls in zytogenetisch und molekulargenetisch definierten Subgruppen herausgearbeitet werden. Im ersten Teil der Analyse wurden 141 Patienten mit normalem Karyotyp und bekanntem Mutationsstatus für NPM1 und FLT3 untersucht. Dabei konnten vielversprechende Resultate bei Transplantation im primären Induktionsversagen beobachtet werden. Bei Patienten, die jenseits der ersten kompletten Remission transplantiert wurden, konnte die prognostische Relevanz der molekularen Subgruppen bestätigt werden, was sich sowohl in den unterschiedlichen Eigenschaften der Patienten im Rezidiv und bei Transplantation als auch in den unterschiedlichen Ergebnissen der Patienten mit verschiedenen Genotypen zeigte. Bei Transplantation jenseits der ersten kompletten Remission, zeigten Patienten mit einem günstigen Genotyp (NPM1mut/FLT3wt) signifikant bessere Ergebnisse nach Transplantation als Patienten mit einem ungünstigen Genotyp (NPM1wt/FLT3wt und FLT3-ITD mit oder ohne NPM1-Mutation). Der prognostische Wert der günstigen molekularen Marker blieb auch bei Transplantation jenseits der ersten kompletten Remission erhalten. So waren die Ergebnisse in der Gruppe von Pateinten mit günstigem Genotyp bei einer Transplantation in erster kompletter Remission und jenseits der ersten kompletten Remission vergleichbar. Dagegen zeigten Patienten mit einem ungünstigen Genotyp signifikant schlechtere Ergebnisse, wenn die Transplantation jenseits der ersten kompletten Remission erfolgte. Im zweiten Teil der Arbeit wurden die Ergebnisse von 173 Patienten mit AML und MDS und einer Hochrisiko-Zytogenetik analysiert. Die Resultate unterstreichen die Bedeutung des FLAMSA-RIC-Regimes als hocheffektives Konditionierungsprotokoll bei der allogenen Stammzelltransplantation von Patienten mit MDS und AML und einer ungünstigen Zytogenetik. Für MDS-Patienten konnte eindrucksvoll gezeigt werden, dass eine Transplantation vor dem Übergang in eine sekundäre AML signifikant bessere Überlebensraten erzielt als nach der Transformation in eine akute Leukämie. Des Weiteren wurden zytogenetisch definierte Subgruppen innerhalb der klassischen ungünstigen Prognosegruppe identifiziert, die eine differenziertere Abschätzung der Prognose ermöglichen.

Exon 12 Nucleophosmin (NPM1) Mutationen stellen die häufigsten molekularen Aberrationen bei Erwachsenen mit akuter myeloischer Leukämie (AML) dar. Molekulare Detektion der Mutation Typ A (NPM1 A), welche 80% aller NPM1 Mutationen ausmacht, könnte für die Bestimmung von minimaler Resterkrankung (MRD) eingesetzt werden. Der molekulardiagnostische Nachweis minimaler Resterkrankung mittels RQ PCR ist von wesentlichem prognostischem Wert, um in Zukunft eine möglichst präzise Abschätzung des individuellen Rezidivrisikos, sowie eine risikoadaptierte Behandlung des Patienten zu ermöglichen. In dieser Arbeit wurde ein RT PCR-Test für die relative Quantifizierung von NPM1 Mutation A Expressionslevels im Vergleich zu Genlevels des Housekeeping-Gens ABL1 entwickelt. Die Expressionsratios wurden zusätzlich zur Normalisierung über das Referenz-Gen ABL1 über das Expressionsratio von NPM1 A zu ABL1 eines Calibrators normalisiert. Die PCR wurde mithilfe der Zelllinie OCI/AML3, welche positiv für die NPM1 A Mutation ist, etabliert. Der Calibrator entspricht einer Probe OCI/AML3 cDNA. Mithilfe einer Verdünnungsreihe von OCI/AML3 cDNA wurden getrennte Standardkurven für die Amplifikation von NPM1 und ABL1 erstellt. Der Assay hat eine Sensitivität von 10-5, das heißt die letzte nachweisbare Verdünnung von für die Mutation positive cDNA ist 1:100 000. Die Spezifität der PCR konnte mit mehreren Zelllinien, welche negativ für die NPM1 Mutation sind und keine Amplifikation gezeigt haben, nachgewiesen werden. Die Ergebnisse hinsichtlich Sensitivität und Spezifität konnten mit ausgewählten Patientenproben bestätigt werden. Die klinische Anwendung wurde mithilfe von Verlaufsmessungen von 51 NPM1 A positiven Patienten durchgeführt. NPM1 A mRNA Expressionslevel wurden in 154 Knochenmark- und Blutproben zu unterschiedlichen Stadien der Krankheit bestimmt. Bei 27 Patienten, die zum Zeitpunkt der Diagnose und nach Induktionstherapie analysiert worden sind, zeigten die NPM1 A Expressionsratios eine mittlere log10 Reduktion von 2,48. Dieses Ergebnis korreliert mit dem Erfolg der Behandlung, auch sichtbar in der Reduzierung der Blastenzahlen im Knochenmark. Von den 51 Patienten die zur Diagnosestellung untersucht worden sind, erlitten 21 ein Rezidiv. Zwei der 21 Patienten mit Rezidiv verloren die NPM1 A Mutation im Rezidiv, was durch eine Schmelzkurven-PCR bestätigt wurde. Die Beobachtung vom Verlust der Mutation durch klonale Evolution bei 9,5% der untersuchten Probenpaare von Diagnose und Rezidiv limitiert den Wert der NPM1 Mutation als molekularer Marker für MRD.