Podcasts about idh2

Dr. Nimish Mohile and Dr. Jaishri Blakeley share the new rapid recommendation update to the therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline. They review the evidence from the INDIGO trial that prompted this update, and how to incorporate the use of vorasidenib into clinical practice. They discuss the importance of molecular testing, particularly for IDH1 or IDH2 mutations and outstanding questions for treatment of patients with oligodendrogliomas and astrocytomas. Read the latest update, “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline Rapid Recommendation Update.” Transcript This guideline, clinical tools, and resources are available at http://www.asco.org/neurooncology-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in Journal of Clinical Oncology.   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine and Dr. Nimish Mohile from the Department of Neurology and Wilmot Cancer Institute at the University of Rochester Medical Center, co-chairs on “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: American Society of Clinical Oncology-Society for Neuro-Oncology Guideline Rapid Recommendation Update.”  Thank you for being here today, Dr. Blakeley and Dr. Mohile.  Dr. Jaishri Blakeley: Thank you.  Dr. Nimish Mohile: Thank you for having us.  Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Blakeley and Dr. Mohile who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.   So then, to jump into the content here, Dr. Mohile, could you start us off by describing what prompted this rapid update to the ASCO-SNO therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline, which was previously published in 2021?  Dr. Nimish Mohile: Yeah. So the key reason for this update is the publication of a study in 2023. And this was a study called the INDIGO study that looked at a new class of therapies, something called IDH inhibitors. And in this study with a drug called vorasidenib, changed how we think about the treatment of oligodendrogliomas and astrocytomas, so particularly the grade 2 oligodendrogliomas and grade 2 astrocytomas. Because of the results of that study, we decided that we needed to do an update to inform clinicians about some of these changes and how we might approach these tumors differently today.  Brittany Harvey: Great. I appreciate that background. So then, based off the new data from the INDIGO study, what are the updated and new recommendations from the expert panel?  Dr. Nimish Mohile: So the key findings from the INDIGO study involved people who had grade 2 astrocytomas and grade 2 oligodendrogliomas. And in the setting after surgery, they were treated with vorasidenib, and what they found is that this delayed the time to next intervention. And the key aspect of that is that it delayed when we could start radiation and chemotherapy in these patients.   So what we did in the guidelines is that for both low grade oligodendrogliomas and low grade astrocytomas, we added one additional guideline statement. Our previous guideline in 2021 offered the options for observation or treatment with radiation and chemotherapy. And now in this guideline, we have options for observation, treatment with vorasidenib in those in whom we feel it is safe to defer radiation and chemotherapy, and then treatment with radiation and chemotherapy. So we've added in an additional option here. And the key message of the guideline is really on how, as clinicians, we think about using the vorasidenib and what the ideal setting for using the vorasidenib is.  Brittany Harvey: Excellent. It's great to hear about this new option for patients. So then you were just talking about how we think about who to offer this IDH inhibitor to. So, Dr. Blakeley, what should clinicians know as they implement these new recommendations into practice?  Dr. Jaishri Blakeley: Yes. So, first and foremost, let's go back to 2021, and a key note from those guidelines was the importance of molecular testing. And at that point, the importance of molecular testing, which in large part was focused on IDH1 or IDH2 mutations, was prognostic. We could say there's a difference in an IDH1 mutant astrocytoma and an IDH1 wild type astrocytoma, but we didn't have a specific therapeutic recommendation attached to that, like Dr. Mohile just said. And the big shift here is now we have a specific therapeutic for that population with IDH1 or IDH2 mutant glioma.   So for clinicians, we hope that they've been getting molecular testing on newly diagnosed glioma already, but now there's an additional motivation to do so because it may change your treatment plan in the right circumstance. So since the publication of the phase III INDIGO study that Dr. Mohile mentioned, and the FDA approval of vorasidenib, if you meet the specified criteria in the clinical trial - which the guidelines point out is a little different than what's on the FDA label, so clinicians might want to dig into that a little bit - then there is a treatment option that is new and different than combined chemoradiation or radiation alone or observation.  Brittany Harvey: I appreciate those clarifications there.   So then also, Dr. Blakeley, how does this update impact patients with astrocytic or oligodendroglial tumors?  Dr. Jaishri Blakeley: So first, patients also should know if they have IDH mutant gliomas. And this update only applies to people with IDH1/2 mutant glioma. Perhaps, we're not sure, it might only apply to people who are in the newly or newly-ish diagnosed category because the INDIGO study required that people were within the first five years of their surgical diagnosis and had not had other treatment. So there are a lot of people who have astrocytoma or oligodendroglioma who may or may not know their IDH1/2 status and may have already had another therapy - this update doesn't apply to them. We hope that future research will teach us about that. This update is for people who are newly diagnosed and just starting the journey to figure out the best therapy. It does say that if you do have that IDH1/2 alteration in your tumor, there is a drug therapy that is different from the drug therapies we would offer gliomas that do not have the IDH1/2 mutation.  Brittany Harvey: Absolutely. I think both that emphasis on molecular testing is very important and also thinking about that study inclusion criteria and how it impacts who's eligible for this treatment.   So then finally, Dr. Mohile, what are the outstanding questions about vorasidenib or other interventions for gliomas in adults?  Dr. Nimish Mohile: I think the key question for clinicians is exactly who we're going to use this in. The challenges with inclusion criteria in clinical trials is they don't actually always match what we're seeing in the clinic. And I think it brings up the question of, in low grade oligodendrogliomas which we think of as very slow growing tumors, do we have the option outside of the strict inclusion criteria to use that drug in other settings? I think it brings up the question for some clinicians in some of the higher grade tumors, in the grade 3 tumors, we don't yet have data in that area and our guideline doesn't address that. But I think some will be asking what the clinical activity of vorasidenib is in that setting. There are some suggestions that the IDH inhibitors may impact seizure control, and I think that that's data that we're continuing to wait on.   So I think that there's several outstanding questions there that we will have answers for hopefully in the next several years. I think the big question that we don't have an answer for and that will take a long time to know is whether the addition of vorasidenib in this setting actually improves how long people live. And given how long people with low grade oligodendrogliomas and low grade astrocytomas live today, we probably won't have an answer to that question for more than a decade.  Brittany Harvey: Definitely. We'll look forward to these ongoing developments and eventually longer term data on overall survival on these agents.   So, I want to thank you both so much for your work to rapidly include this information from this new trial. And thank you for your time today, Dr. Blakeley and Dr. Mohile.  Dr. Jaishri Blakeley: Thank you so much.  Dr. Nimish Mohile: Thank you Brittany.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/neurooncology-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    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. 

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

In a conversation with CancerNetwork®, Shewetal Mehta, PhD, spoke about her research team's focuses in moving novel brain cancer therapies down the pipeline as part of an early phase clinical trials program at the Ivy Brain Tumor Center. Mehta, the deputy director and pre-clinical core leader at the Ivy Brain Tumor Center of Barrow Neurological Institute in Phoenix, Arizona, underscored a scientifically rigorous, patient-driven philosophy that drives her team members to deliver timely answers to those with brain cancer via work in a clinical lab and a pre-clinical arm. This collaboration helps identify therapeutic agents that may demonstrate activity in the brain while determining patient populations who are suitable to enroll on clinical trials. As part of her institution's early phase trial program, Mehta specifically highlighted work associated with a phase 0/1 clinical trial (NCT06072586) evaluating BDTX-1535, a brain-penetrant fourth-generation EGFR inhibitor, for those with recurrent high-grade glioma harboring oncogenic EGFR alterations or fusions.1 Investigators are incorporating liquid biopsy, sampling cerebrospinal fluid from patients on treatment to monitor potential evolutions or changes in brain tumors. Regarding biomarker testing, Mehta described the roles that gene sequencing and immunohistochemistry can play in identifying targetable alterations in patients with brain cancer. She mentioned vorasidenib (Voranigo), which received approval from the FDA in August 2024, as an example of a targeted therapy that may be suitable for use in patients who are found to have actionable IDH mutations. “Over the last year, we've seen that we were capable of not just doing these early phase clinical trials [but of entering] this phase of moving drugs into phase 3 [studies]. That's exciting,” Mehta stated regarding her outlook on the current state of brain cancer treatment. “Right now, we are excited about these new classes of agents that are within the space, like the proteolysis targeting chimeras, protein degraders, and antibody-drug conjugates, which have shown amazing promise in the rest of the oncology space.” References 1.        Study of BDTX-1535 in recurrent high-grade glioma (HGG) participants with EGFR alterations or fusions. ClinicalTrials.gov. Updated January 15, 2025. Accessed January 15, 2025. https://tinyurl.com/m6kwr2b3 2.        FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed January 20, 2025. https://tinyurl.com/25r9fkvy

This week Jonathan is joined by Joshua Zeidner, Associate Professor of Medicine, University of North Carolina School of Medicine, USA. Together, they discuss findings from recent research and treatment options for acute myeloid leukaemia and myelodysplastic syndrome. Timestamps:     (00:00)- Introduction    (01:57)- Joshua's love for the New York Giants  (04:28)- Treatment outcomes in IDH1 and IDH2-mutated acute myeloid leukaemia (AML)  (08:05)- Safety and efficacy of new agents in AML  (17:00)- Treatments for patients with AML with a TP53 mutation  (22:02)- Reliance on transfusion in myelodysplastic syndrome (MDS)  (25:44)- The time from research lab to bedside in drugs to treat AML and MDS  (30:50)- Joshua's three wishes for healthcare   (35:13)- Outro   

In today's episode, supported by Servier Pharmaceuticals, we had the pleasure of speaking with Jennie W. Taylor, MD, MPH, about the FDA approval of vorasidenib (Voranigo) for patients with IDH-positive grade 2 astrocytoma or oligodendroglioma. Dr Taylor is an associate professor of clinical neurology at the University of California, San Francisco (UCSF), as well as the community engagement liaison in the Neurologic Oncology Program at the UCSF Helen Diller Family Comprehensive Cancer Center. On August 6, 2024, the FDA approved vorasidenib for the treatment of adult and pediatric patients at least 12 years of age with grade 2 astrocytoma or oligodendroglioma harboring susceptible IDH1 or IDH2 mutations who have previously undergone surgery including biopsy, sub-total resection, or gross total resection. This regulatory decision was backed by findings from the phase 3 INDIGO trial (NCY04164901), in which, at a median follow-up of 14.0 months (interquartile range [IQR], 10.1-17.9), vorasidenib (n = 168) produced a median progression-free survival of 27.7 months (95% CI, 17.0-not estimated) vs 11.1 months (95% CI, 11.0-13.7) in the placebo arm (n = 163) at a median follow-up of 14.3 months (IQR, 10.0-18.1; HR, 0.39; 95% CI, 0.27-0.56; P < .001). In our exclusive interview, Dr Taylor discussed the significance of this approval, key data from INDIGO, and where vorasidenib fits into the astrocytoma or oligodendroglioma treatment paradigms.

Featuring perspectives from Dr Stephen T Oh, including the following topics: Introduction: ASH 2023 Update (0:00)  Case: A woman in her early 70s with symptomatic primary myelofibrosis (MF) receives ruxolitinib — Rao Mushtaq, MD (15:41) Case: A woman in her late 60s, a Jehovah's Witness with multiple comorbidities, presents with splenomegaly and anemia and is diagnosed with primary MF — Bhavana (Tina) Bhatnagar, DO (27:16) Case: A woman in her mid 70s who received pacritinib for 4 years on trial now experiences disease progression with massive splenomegaly and thrombocytopenia (20K-30K) — Neil Morganstein, MD (31:50) Case: A woman in her late 50s with symptomatic primary MF has normal cytogenetics and JAK2 and DNMT3A mutations — Jeanne Palmer, MD (35:45) Case (continued): A woman in her late 50s has progressive MF after ruxolitinib and fedratinib; repeat next-generation sequencing shows JAK2, DNMT3A, IDH2 and TET2 mutations — Dr Palmer (41:09) Case: A woman in her late 60s with primary MF who discontinued ruxolitinib due to onset of congestive heart failure now has possible acute myeloid leukemia transformation — Dr Bhatnagar (50:38) Case: A woman in her late 60s with well controlled MF who has received 10 mg of ruxolitinib twice a day for 3 years develops increasing anemia and splenomegaly — Dr Palmer (52:38) CME information and select publications

Featuring perspectives from Dr Gail J Roboz, including the following topics: Introduction (0:00) Case: A man in his early 50s presents with fatigue and pancytopenia; bone marrow shows myelodysplastic syndromes (MDS) with 11% blasts; normal FISH MDS panel; next-generation sequencing shows BCOR, RUNX1 and UTAF1 mutations; normal metaphase cytogenetics — Warren S Brenner, MD (10:12) Case: An African American woman in her early 60s with high-risk MDS receives oral decitabine/cedazuridine — Henna Malik, MD (16:39) Case: A woman in her early 70s with anemia and low-grade MDS with ring sideroblasts experiences a poor response to erythropoietin and is now on luspatercept — Neil Morganstein, MD (22:15) Case: A woman in her early 60s with newly diagnosed acute myeloid leukemia (AML) and a FLT3-ITD mutation receives 7 + 3 induction with midostaurin induction, consolidation, allogeneic transplant and maintenance — Amany R Keruakous, MD, MS (35:23) Case: A man in his mid 60s with AML and an IDH1 mutation receives venetoclax/azacitidine/ivosidenib — Rebecca L Olin, MD, MSCE (53:23) Case: A woman in her late 30s with refractory leiomyosarcoma develops anthracycline-related secondary AML with an IDH2 mutation and is unable to obtain foundation funding assistance for enasidenib copays — Eric H Lee, MD, PhD (56:48) CME information and select publications

Featuring perspectives from Dr Richard F Riedel, including the following topics: Introduction: (0:00) Case: A woman in her late 20s with multiregimen-recurrent metastatic alveolar soft part sarcoma after treatment with multiple VEGF tyrosine kinase inhibitors and a single-agent PD-1 inhibitor receives axitinib/pembrolizumab — Nam Bui, MD (4:14) Case: A man in his mid 60s with metastatic dedifferentiated chondrosarcoma of the right femur undergoes resection and receives doxorubicin/cisplatin followed by maintenance pembrolizumab — IDH2 and TERT promoter mutations, PD-L1 2+ by IHC — Melanie B Thomas, MD (10:06) Case: A man in his early 30s with an asymptomatic “bulge on abdomen” found to be a 6.2-cm mass receives a diagnosis via biopsy of desmoid fibromatosis. Local treatment team recommends surgery — Dr Bui (22:20) Case: A woman in her early 40s with a history of familial adenomatous polyposis undergoes surgical excision of 3 colon cancer lesions followed by adjuvant capecitabine. On follow-up she is found to have a rapidly enlarging mass abutting the iliac and mesenteric vessels. Fine needle aspiration shows desmoid tumor — Dr Bui (29:37) Case: A man in his mid 30s with a protruding mass on his back diagnosed as a desmoid tumor receives sorafenib followed by second-line liposomal doxorubicin — Atif M Hussein, MD, MMM (33:29) Case: A man in his mid 50s with multiregimen-recurrent metastatic mediastinal liposarcoma receives resection, chemotherapy and eribulin — CDK4 amplification identified by next-generation sequencing (NGS) — Dr Thomas (39:31) Case: A man in his late 60s with abdominal pain and weight loss is diagnosed with metastatic high-grade myxoid liposarcoma of the retroperitoneum — Dr Hussein (43:06) Case: A woman in her late 50s diagnosed with Grade 2 leiomyosarcoma develops a recurrence 3 years after resection and adjuvant doxorubicin/ifosfamide — Dr Hussein (47:34) Case: A woman in her early 60s presents to the ER with shortness of breath and is diagnosed with unresectable leiomyosarcoma of the mediastinum — Dr Bui (51:48) Case: A man in his mid 40s diagnosed with gastrointestinal stromal tumor (GIST) receives neoadjuvant imatinib followed by resection, then adjuvant imatinib — KIT exon 9 mutation identified by NGS — Dr Bui (54:13) Case: A man in his mid 60s with mesenteric recurrence of abdominal GIST experiences transaminitis with imatinib — microsatellite stable, no actionable mutations by NGS — Dr Thomas (58:40) CME information and select publications

References Free Radical Biology and Medicine Volume 71, June. Pages 1-15 Cardiovasc.Res. 2012 May 1; 94(2): 379–390. Int. J. Mol. Sci. 2020, 21(7), 2578; https://doi.org/10.3390/ijms21072578 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

Rong He, M.D., explains how Mayo Clinic Laboratories' IDHQ test speeds therapeutic decision making for adults with acute myeloid leukemia, or AML. The standalone assay yields faster results than next generation sequencing.(00:32) Would you provide a brief background of yourself? (01:42) Could you give an overview of the IDHQ test? (02:25) Is there anything more you'd like to touch on about the droplet digital PCR approach and high sensitivity? (03:09) Why are IDH1 and IDH2 important in disease diagnosis, prognosis, or therapeutic management? (05:00) Is there anything else you'd like to say about this particular assay? (06:56) Would you describe the specific group of patients where testing is recommended?

Featuring perspectives from Drs Courtney DiNardo and Mark Levis, including the following topics: Introduction (0:00) Case: A man in his early 80s with newly diagnosed acute myeloid leukemia (AML) with significant comorbidities receives decitabine/venetoclax — Rebecca L Olin, MD, MSCE (7:36) Cases: A man in his mid 50s after 7 + 3 and allogeneic stem cell transplantation (SCT) presents with myeloid sarcoma; a man in his late 70s after 7 + 3 and allogeneic SCT presents with myeloid sarcoma — Spencer H Bachow, MD and Ranju Gupta, MD (12:16) Case: A man in his late 30s with core binding factor AML after induction CLAG-M with gemtuzumab ozogamicin followed by high-dose cytarabine x 4 — Anna Halpern, MD (18:10) Case: A woman in her mid 60s with newly diagnosed del(5q) AML with monocytic differentiation and multiple mutations (GATA2, BCOR, NF1 and RUNX1) receives azacitidine and venetoclax — Bhavana (Tina) Bhatnagar, DO (31:05) Selection of Therapy for Patients with AML (35:20) Cases: A man in his early 50s with therapy-related AML with an MLL mutation who receives CPX-351; a man in his early 70s with secondary AML with an IDH mutation — Amany R Keruakous, MD, MS and Priya Rudolph, MD, PhD (41:42) Case: A man in his early 70s with recurrent AML with an IDH2 mutation receives enasidenib and develops differentiation syndrome/disease progression — Dr Halpern (50:00) CME information and select publications

In this week's episode, we'll discuss new research revealing that the mechanosensory ion channel Piezo1 is the elusive carrier molecule of the Er blood group antigens, thus establishing a new blood group system. Next, we review results of a randomized phase 3 trial of enasidenib versus conventional treatment in late-stage mutant-IDH2 relapsed or refractory AML. Although the primary endpoint of overall survival was not met, investigators say the risk benefit ratio remains positive. Finally, we'll review a study showing a clinically significant risk of breakthrough COVID-19 infections in patients with B-cell malignancies despite vaccination and pre-exposure prophylaxis with tixagevimab-cilgavimab during the Omicron era. However, hospitalization rates in the study were low and no deaths were reported.

La Dra. Leticia Vázquez Cortés, oncóloga médica adscrita al Instituto Mexicano del Seguro Social en Morelia, Michoacán, México, nos comenta sobre lo más destacado en tumores del sistema nervioso central (SNC) presentados durante el Congreso Anual de ESMO 2022 en París, Francia. Resumen 2770: Estudio fase I/IIa, ReSPECT-GMB, de escalación de dosis, para determinar la seguridad y la dosis recomendada de rhenium-186 nanoliposomal en pacientes con glioma recurrente. Resumen 2780: Resultados preliminares del estudio fase II de retifanlimab (inhibidor de PD-1) con o sin epacadostat (inhibidor de IDO1) en combinación con bevacizumab y radioterapia hipofraccionada para pacientes con glioblastoma recurrente. Resumen 2790: Estudio prospectivo y multicéntrico con secuenciación de última generación de alto rendimiento con un panel de genes personalizado (8 genes: IDH1, IDH2, ATRX, Tp53, PTEN, PIK3CA, EGFR, BRAF) para detección de ADN tumoral circulante en líquido cefalorraquídeo y concordancia con el tumor primario en pacientes con glioma. Resumen 2800: Resultados finales del estudio fase II sobre farmacocinética y farmacodinamia de paxalisib en pacientes con glioblastoma recién diagnosticados con estado de promotor del gen MGMT no metilado. Fecha de grabación: 15 de septiembre de 2022. 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.

Featuring perspectives from Prof Ghassan Abou-Alfa, including the following topics: Introduction (0:00) Case: A woman in her early 50s with metastatic hepatoid carcinoma of the ovary with an FGFR fusion — Syed M Ahmed, MD, PhD (2:56) Key recent data sets (5:59) Case: A man in his mid 60s with a history of Child-Pugh B cirrhosis and Grade 1 esophageal varices who is receiving atezolizumab/bevacizumab for multifocal HCC — Raji Shameem, MD (22:28) Case: A man in his late 60s with previously treated HCC cirrhosis who is now diagnosed with potentially resectable HCC — Syed F Zafar, MD (29:30) Case: A woman in her late 70s receiving adjuvant anastrozole for Stage I breast cancer who is now receiving atezolizumab/bevacizumab for metastatic HCC — Sunil Gandhi, MD (33:41) Case: A man in his late 70s with metastatic HCC and portal vein thrombosis receiving atezolizumab/bevacizumab (NGS [next-generation sequencing] with PIK3CA mutation, PD-L1 50%) — Susmitha Apuri, MD (35:47) Management of Biliary Tract Cancers (40:18) Case: A man in his late 50s with resected Stage IIB gallbladder cancer s/p adjuvant capecitabine who now has metastatic disease (HER2-positive; MSS, PD-L10) — Nasfat Shehadeh, MD (44:01) Case: A woman in her early 40s with a history of ductal carcinoma in situ and family history of breast cancer, now with metastatic cholangiocarcinoma (NGS with IDH2 mutation) — Joanna Metzner-Sadurski, MD (53:41) CME information and select publications

Featuring perspectives from Dr Rebecca Olin, including the following topics: Introduction: Journal Club with Rebecca L Olin, MD, MSCE — Evaluation of the older patient with acute myeloid leukemia (AML) (0:00) Case: A woman in her late 80s with transfusion-dependent AML secondary to myelodysplastic syndrome — Raman Sood, MD (7:52) Case: A frail man in his mid 70s with newly diagnosed poor-risk AML with FLT3-ITD and IDH1 mutations — Amany R Keruakous, MD, MS (12:46) Case: A woman in her late 60s with relapsed AML and a FLT3-ITD mutation — Prashant Sharma, MD (18:23) Case: A man in his late 50s with AML receives 7 + 3 induction prior to discovery of complex cytogenetics — Rachel J Cook, MD (22:04) ASH 2021 review — Part 1 (25:07) Case: A man in his early 70s with relapsed AML and an IDH2 mutation — Erik J Rupard, MD (29:13) Case: A man in his late 50s with therapy-related AML and an IDH2 mutation — Bhavana (Tina) Bhatnagar, DO (32:28) Case: A woman in her mid 40s with newly diagnosed poor-risk AML and an ejection fraction of 35% — Dr Keruakous (32:28) ASH 2021 review — Part 2 (39:28) Faculty survey (58:32) CME information and select publications

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

Featuring perspectives from Dr Naval Daver, including the following topics: Introduction (0:00) Case: A man in his late 70s with acute myeloid leukemia (AML) and a TP53 mutation — Shaachi Gupta, MD, MPH (22:20) Case: A woman in her early 40s with relapsed AML — Rebecca L Olin, MD, MSCE (27:34) Case: A woman in her early 30s with therapy-related core binding factor AML — Prashant Sharma, MD (34:58) Case: A man in his early 70s with AML and an IDH2 mutation — Erik J Rupard, MD (45:54) Faculty Survey (57:05) CME information and select publications

In this podcast episode, Sarah M. Tinsley, PhD, APRN, AOCN, discusses targeted therapy with FLT3 and IDH1/2 inhibitors in AML, with a focus on the nursing perspective. Topics include:Approved and emerging treatment options for FLT3-mutated AMLManagement of adverse events associated with FLT3 inhibitorsTherapies for IDH1- and IDH2-mutated AMLIdentifying and managing differentiation syndrome associated with IDH1/2 inhibitorsPresenters:Sarah M. Tinsley, PhD, APRN, AOCNNurse PractitionerCourtesy Assistant ProfessorDepartment of Malignant HematologyMoffitt Cancer CenterUniversity of South FloridaTampa, Florida 

Featuring perspectives from Drs Krishna Gundabolu, Richard M Stone and Eunice S Wang, moderated by Dr Harry Paul Erba, including the following topics:   Introduction (00:00) Case: A man in his late 60s with acute myeloid leukemia (AML) and an IDH2 mutation — Wendy Stock, MD (01:13) Case: A man in his early 80s with AML and multiple comorbidities who receives up-front venetoclax and azacitidine — Mark Levis, MD, PhD (06:00) Management of newly diagnosed AML in patients ineligible for intensive induction therapy (12:22) Case: A man in his early 70s with newly diagnosed AML with poor prognostic features — Dr Levis (21:36) Case: A woman in her late teens with AML and complex cytogenetics — Dr Stock (25:56) Treatment of AML in adult patients eligible for intensive therapy (30:48) Case: A man in his late 40s with newly diagnosed AML with poor prognostic features — Dr Levis (43:06) Case: A man in his late 70s with AML and FLT3 and IDH2 mutations — Dr Stock (46:24) Clinical decision-making for patients diagnosed with AML and an actionable mutation (54:27) Case: A man in his late 60s with transfusion-dependent myelodysplastic syndrome with ringed sideroblasts — Dr Stock (01:05:24) Current and future treatment considerations for patients with myelodysplastic syndromes (01:11:33)   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 Courtney D DiNardo's perspectives on her time spent speaking with patients with acute myeloid leukemia from the practices of community oncologists Drs KS Kumar and Andrew C Rettew, including the following topics: Case: A woman in her early 70s with acute myeloid leukemia (AML) and an IDH mutation receives venetoclax and azacytidine (0:00) Selection of patients for treatment with venetoclax/azacitidine versus intensive 7 + 3 chemotherapy; optimal application of venetoclax/azacytidine (5:41) Tolerability and side effects of venetoclax/azacitidine; testing for IDH mutations and choice of therapy for patients with AML and an IDH mutation (14:24) Duration of therapy and long-term outcomes with venetoclax/azacitidine; clinical research on combination therapy with venetoclax and oral hypomethylating agents (HMAs) (23:08) Treatment options for patients with AML who experience disease progression on venetoclax/azacitidine; use of IDH inhibitors for AML (29:23) Case: A woman in her mid-50s with a complex medical history is diagnosed with AML and receives 7 + 3 chemotherapy and gemtuzumab ozogamicin (34:24) Case: A man in his early 70s with AML and a FLT3-ITD mutation receives 7 + 3 chemotherapy and midostaurin (47:36) Optimal approach to the management of AML with FLT3 mutations (51:20) Impact of COVID-19 on the clinical care of patients with AML (57:37) Case: A man in his early 70s with AML with myelodysplasia-related changes and mutations in RUNX1, SRSF2, ASXL1 and IDH2 receives liposomal daunorubicin and cytarabine (CPX-351) followed by enasidenib (1:07:10) Activity and tolerability of CPX-351 for AML; patient selection (1:11:19) Choice between a venetoclax/HMA combination and an IDH inhibitor for patients with progressive AML and an IDH mutation (1:17:53) Feasibility and efficacy of stem cell transplantation in patients with relapsed AML; use and tolerability of glasdegib and low-dose cytarabine for AML (1:25:52) CME information and select publications

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 an interview with Dr Harry Paul Erba, including the following topics: Improvement in overall survival in the VIALE-A trial with azacitidine/venetoclax compared to azacitidine alone for patients with previously untreated acute myeloid leukemia (AML) ineligible for intensive chemotherapy (0:00) Delay in time to deterioration of health-related quality of life for patients with AML receiving venetoclax in combination with azacitidine or low-dose cytarabine (2:26) Interim analysis of the Phase Ib/II study of venetoclax with FLAG-IDA for patients with newly diagnosed or relapsed/refractory (R/R) AML (4:12) High rates of minimal residual disease-negative complete remission and excellent tolerability with venetoclax added to cladribine and low-dose ara-C alternating with 5-azacitidine for newly diagnosed AML in older patients (7:14) Final results of a Phase III study evaluating CPX-351 versus 7 + 3 for older adults with newly diagnosed high-risk or secondary AML (8:39) Phase II study of CPX-351 with venetoclax for patients with AML (11:07) Results with venetoclax and azacitidine for chemotherapy-ineligible patients with untreated AML with IDH1/2 mutations (18:00) Improvement in overall survival with ivosidenib compared to standard therapies for relapsed or refractory AML with IDH1 mutation (22:26) Beat AML Master Trial: Enasidenib monotherapy with the addition of azacitidine for nonresponders is effective in older patients with newly diagnosed AML with IDH2 mutations (24:48) Efficacy of gilteritinib in patients with R/R AML harboring FLT3 mutations (26:46) Clinical outcomes for patients with R/R AML treated with gilteritinib who received prior midostaurin or sorafenib (30:17) Difference in patterns of secondary resistance between Type I and Type II FLT3 inhibitors in patients with AML (31:33) Final results of a Phase I study of gilteritinib in combination with induction and consolidation chemotherapy for patients with newly diagnosed AML (34:21) Phase III LACEWING study of gilteritinib, gilteritinib with azacitidine or azacitidine alone for patients with newly diagnosed AML with FLT3 mutations who are ineligible for intensive induction chemotherapy (35:28) Efficacy and safety of venetoclax in combination with gilteritinib in patients with R/R AML with FLT3 mutations in the expansion cohort of a Phase Ib study (38:27) Phase Ib results with the first-in-class anti-CD47 antibody magrolimab combined with azacitidine for AML (41:29) Results from the QUAZAR AML-001 maintenance trial of CC-486 for patients with AML (46:00) BMT CTN 1102 trial comparing reduced-intensity allogeneic hematopoietic cell transplantation to hypomethylation therapy or best supportive care for patients aged 50 to 75 with advanced myelodysplastic syndromes (MDS) (51:45) Health-related quality-of-life outcomes for patients with MDS with ring sideroblasts treated with luspatercept in the MEDALIST study (56:52) Interim analysis of the Phase III European SINTRA-REV trial of lenalidomide for patients with low-risk del(5q) MDS who are not transfusion dependent (1:01:26) Safety, efficacy and patient-reported outcomes with venetoclax in combination with azacitidine for patients with higher-risk MDS (1:04:38) Efficacy and safety of pevonedistat and azacitidine compared to azacitidine alone for patients with higher-risk MDS in the Pevonedistat-2001 trial (1:08:53) Conclusions in AML and MDS from 2021 Highlights of ASH® (1:11:19) CME information and select publications

Featuring an interview with Dr Andrew H Wei on the following topics: Treatment of acute myeloid leukemia (AML) in patients not eligible for intensive induction therapy (0:00) Case: A man in his late 70s with AML receives re-treatment with venetoclax and azacitidine after attaining a durable remission of 2.5 years with that regimen (21:23) Case: A woman in her late 70s initially diagnosed with AML with an IDH2 mutation receives gilteritinib as third-line therapy after detection of a FLT3-ITD mutation (23:16) 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

In this episode, Naval G. Daver, MD, discusses promising investigational agents and treatment combinations in clinical trials for patients with newly diagnosed and relapsed/refractory AML, including:FLT3 inhibitors crenolanib and quizartinibAnti-CD47 antibody magrolimabIMGN632, a CD123 antibody–drug conjugateAnti-CD70 antibody cusatuzumabAPR-246, targeting the TP53 mutationContent is part of an online CME program supported by an educational grant from Daiichi-Sankyo.Link to full program, including a ClinicalThought commentary:  https://bit.ly/2Y2uCG2

Oncometabolites and The Heart Dr RR Baliga 'Got Knowledge Doc' PodKasts for Cardio-Oncologists Baliga RR, Young JB. Energizing Diastole Heart Fail Clin. 2008;4(1):ix‐xiii. Energizing Diastole Sulkowski, P.L., Oeck, S., Dow, J. et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature (2020). Tumour metabolites hinder DNA repair   Krebs Cycle Nobel Lecture   Ivosidenib and Cardiogenic Shock   Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc Natl Acad Sci U S A.    D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev.   Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer. J Cardiovasc Transl Res.   Krebs Cycle Primer Khan Academy Taegtmeyer H, et al  Oncometabolic Tracks in the Heart. Circ Res. 2017      

A special video supplement to a CME conference held during the 61st ASH Annual Meeting featuring expert comments on the management of acute myeloid leukemia. Featuring perspectives from Dr Richard M Stone. Design and results of the QUAZAR AML-001 maintenance trial assessing CC-486 versus placebo for patients with AML in first remission (00:00) Mechanism of action of azacitidine in AML (04:09) Preclinical data on the use of anti-inflammatory agents for clonal hematopoiesis of indeterminate potential (CHIP) (05:56) Ongoing investigations of anti-CD47 antibodies, antibody-drug conjugates and immune checkpoint inhibitors for AML (07:40) Clinical relevance of CHIP mutations (11:05) Pathophysiology of CHIP mutations and cardiovascular disease (16:23) Composition of CPX-351; advantages and disadvantages in the management of AML (17:45) Efficacy and safety of CPX-351 for secondary AML; patient selection for treatment with CPX-351 (20:10) Investigation of venetoclax-based combination strategies in AML (23:27) Factors determining eligibility for intensive chemotherapy for older and younger patients with AML (26:10) Counseling patients on potential outcomes of intensive chemotherapy for AML (30:51) Duration of therapy with an HMA and venetoclax for patients with AML (34:27) Genetic alterations in AML; incidence and biology of FLT3 mutations (36:12) Clinical presentation of patients with AML with FLT3 mutations; activity of the FLT3 inhibitors gilteritinib and midostaurin (38:44) Role of FLT3 inhibitors as a bridge to transplant and in the post-transplant setting (42:12) Tolerability of FLT3 inhibitors for patients with AML and choice of agent in the post-transplant maintenance setting (45:18) Evidence with and ongoing investigation of the FLT3 inhibitor quizartinib in patients with AML with a FLT3 mutation (47:28) Incidence of IDH mutations in AML; treatment for AML with IDH1 and IDH2 mutations (49:45) Differentiation syndrome with IDH inhibitors: Incidence, presentation and management (54:20) Treatment options for patients with AML harboring IDH or FLT3 mutations who are unfit for intensive chemotherapy (57:02) Future developments in the management of AML (59:28) Long-term outcomes with HMA and venetoclax in AML (1:01:32) CME information and select publications

Proceedings from a CME symposium held during the 61st ASH Annual Meeting. Featuring perspectives from Drs Mark Levis, Daniel A Pollyea, Richard M Stone and Andrew H Wei. Introduction Program Overview: Dr Neil Love (00:00) Evolving Paradigms in Up-Front Treatment for Older Patients or Those Ineligible for Intensive Chemotherapy          Case (Dr Pollyea): A woman in her mid-30s with acute myeloid leukemia (AML) who is unable to undergo intensive induction chemotherapy because of refusal to accept blood products on religious grounds achieves a complete response to venetoclax/azacytidine (11:28) Case (Dr Pollyea): A women in her late 60s with AML who is ineligible for intensive induction chemotherapy receives venetoclax/azacitidine as first-line therapy (15:18) Faculty Presentation: Dr Pollyea (19:39) Assessment, Incidence and Clinical Significance of FLT3 Mutations in AML Case (Dr Stone): A man in his mid-40s with AML with a FLT3-ITD mutation receives 7 + 3 induction in combination with midostaurin and undergoes allogeneic transplant (47:53) Case (Dr Stone): A man in his early 60s who underwent allogenic transplant 1.5 years ago for high-risk myelodysplastic syndrome (MDS) presents with AML with a FLT3-ITD mutation and receives gilteritinib (50:46) Faculty Presentation: Dr Stone (52:31) Long-Term Treatment for Patients with AML with IDH Mutations Case (Dr Levis): A woman in her mid-80s who previously received azacitidine and lenalidomide for MDS presents with AML with an IDH1 mutation and receives ivosidenib (1:13:52) Case (Dr Levis): A man in his early 60s who is receiving enasidenib for AML with an IDH2 mutation develops differentiation syndrome causing acute kidney injury (1:19:11) Faculty Presentation: Dr Levis (1:21:56) Other Novel Agents and Promising Strategies Under Evaluation for Patients with AML Faculty Presentation: Prof Wei (1:43:54) CME information and select publications

Proceedings from a roundtable discussion with Drs Courtney D DiNardo, Keith W Pratz, Richard M Stone and a group of 20 general medical oncologists and nurse practitioners on the optimal management of acute myeloid leukemia within a community-based setting. Initial Workup and Determination of Eligibility for Intensive Treatment; Integrating Venetoclax into the Treatment of Acute Myeloid Leukemia (AML) Faculty presentation — Dr DiNardo: Exploring the current management paradigm for AML in patients not eligible for intensive therapy (00:00) Case (Dr Marte): A woman in her early 80s who presented 7 years ago with t(8;21) AML is in complete remission 7 years after treatment with 7+3 chemotherapy (09:13) Therapeutic options for older patients with AML without targetable mutations (11:02) Genetic testing for patients with AML (16:21) Assessment of minimal residual disease status in patients undergoing treatment for AML; selection of patients who are eligible for intensive chemotherapy (19:40) Choice of therapy for a patient with AML and multiple comorbidities (23:36) Prophylaxis for patients receiving venetoclax in combination with azacitidine (26:57) Optimal duration of venetoclax therapy (29:05) Prevention and management of tumor lysis syndrome associated with venetoclax (30:58) Selection of therapy for a patient with AML with complex karyotype and a TP53 mutation (34:58) Case (Dr Dandamudi): A woman in her early 80s with AML attains an excellent response to venetoclax and azacitidine (38:11) Case (Dr Choksi): A woman in her late 70s with myelodysplastic syndrome (MDS)/myeloproliferative neoplasm develops neutropenia after treatment with venetoclax and azacitidine (43:13) Case (Dr Hussein): A man in his early 80s develops persistent neutropenia after receiving azacitidine for MDS, which resolves after treatment with pembrolizumab for metastatic melanoma (51:14) Choice of hypomethylating agent for patients with AML (52:42) Case (Dr Gandhi): A man in his mid-70s with AML receives venetoclax/decitabine (55:34) Perspective on the use of GCSF for the management of neutropenia associated with venetoclax/azacitidine for AML (57:49) Management of AML with FLT3 and IDH Mutations Faculty presentation — Dr Stone: Management of AML with a FLT3 mutation in older patients who are not eligible for intensive treatment (1:00:36) Therapeutic approach for elderly patients with FLT3-ITD AML and high allelic burden (1:08:08) Case (Ms Sanchez): A woman in her mid-60s with FLT3-ITD AML is enrolled on a clinical trial evaluating gilteritinib as maintenance therapy after allogeneic transplant (1:11:48) Activity and tolerability of gilteritinib and sorafenib in patients with AML (1:16:39) Ongoing investigation of venetoclax in combination with a hypomethylating agent for younger/fit patients with AML (1:19:26) Duration of response to therapy with venetoclax and a hypomethylating agent; investigation of approaches to overcome resistance (1:22:31) Case (Dr Sullivan): A man in his mid-30s with AML with mutations in FLT3, MPN1 and ROS1 experiences disease progression after chemotherapy and FLT3 inhibitors (1:24:46) Case (Dr Dandamudi): A man in his early 70s receives venetoclax and azacitidine for AML (1:32:43) Faculty presentation — Dr Pratz:Therapeutic approach for older patients with AML with IDH1/2 mutations who are not eligible for intensive treatment (1:35:52) Selection of first-line therapy for patients with AML with an IDH mutation (1:45:08) Side effects associated with ivosidenib; management of differentiation syndrome related to IDH inhibitors (1:48:41) Case (Dr Shah): A man in his late 80s with AML with an IDH2 mutation and multiple comorbidities receives enasidenib (1:54:41) Case (Dr Malhotra): A man in his early 60s with AML with an IDH2 mutation receives enasidenib (1:57:56) CME information and select publications

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

Go online to PeerView.com/YTB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The rarity and heterogeneity of biliary cancers (eg, cholangiocarcinoma, gallbladder cancer) make this group of malignancies a clinical challenge in GI oncology. Fortunately, recent scientific developments on the genetic and molecular level have led to the clinical testing of several targeted agent classes, including FGFR, IDH, HER2, TRK, and multikinase inhibitors, in patients with biliary cancers. This educational activity, based on a recent PeerView “MasterClass” symposium presented in collaboration with the Cholangiocarcinoma Foundation, provides an in-depth examination of the latest science on the biologic rationale for targeting biliary cancers and the important evidence that is validating potent therapies in a setting where conventional chemotherapy often has limited efficacy and value for patients. Each segment will conclude with expert insights on patient-centric care and strategies for translating new evidence and data into clinical practice for the optimal management of biliary cancers. Upon completion of this activity, participants should be better able to: Summarize the biologic rationale for targeting biliary cancers, including multikinase tumor pathways, NTRK gene fusions, IDH2 mutations, FGFR translocations, and immune checkpoint pathways, Examine the latest efficacy and safety evidence on the use of novel therapeutic strategies, such as multikinase, TRK, IDH, and FGFR inhibitors, in patients with biliary cancers, Describe ongoing clinical trials investigating novel approaches, such as chemotherapy platforms, targeted agents, and immunotherapy, that are recruiting patients with biliary cancers, Apply current and emerging therapeutic strategies into personalized treatment plans for patients with biliary cancers, including in the context of a clinical trial

A diagnosis of acute myeloid leukemia (AML) was once an emergency, requiring immediate treatment. Today, the need to start treatment is still urgent, but many patients can benefit by waiting a few days for testing to reveal a fuller picture of the disease. That’s the advice of James M. Foran, MD, of the Mayo Clinic. He joins Blood & Cancer host David H. Henry, MD, of the Pennsylvania Hospital, Philadelphia, to walk through some patient scenarios and the newest treatment options. In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about what patients do and do not remember from their visits. Practice points: Rapid testing results can drive important choices in the initial treatment of AML. Adjunctive therapies may improve survival by 7%-20% in appropriate patients. Although a total work-up may take up to 2 weeks, new research suggests it is feasible to get rapid sequencing/cytogenetic testing and assign treatment within 7 days. Treatment varies: Daunorubicin and cytarabine (Vyxeos) are still central treatment strategies, but there may be survival advantages (7%-20% improvement) by adding adjunctive therapies, if indicated. A few are listed below: Liposomal formulations of daunorubicin-cytarabine (CPX351) can have survival advantages in therapy-related AML or AML with myelodysplastic syndrome (MDS)-related changes. Gemtuzumab (Mylotarg) may be indicated for core binding factor (CBF) AML. Midostaurin (Rydapt) may improve survival in patients with FMS-like tyrosine kinase (FLT) 3 Enasidenib (Idhifa) may be indicated in patients with IDH mutations. Options for elderly patients: In a recent study, CC 486 (oral azacitidine) showed a significant survival advantage and remission duration in elderly patients with AML. The drug is not yet available but could eventually be a maintenance therapy option for patients who do not go on to transplant. Azacitidine, plus or minus an IDH2 inhibitor, showed much higher remission rates in elderly patients, but did not translate into a survival advantage. AML in the outpatient setting: Many patients with AML are being increasingly managed as outpatients, which ultimately will require a different kind of support infrastructure in our hospitals and clinics. Show notes by Debika Biswal Shinohara, MD, PhD, resident in the department of internal medicine, University of Pennsylvania, Philadelphia. Dr. Henry and Dr. Yurkiewicz reported having no financial conflicts relevant to this episode. Dr. Foran reported advisory board membership with Pfizer, Jazz Pharma, and Novartis.  * * *  For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

Acute Leukemias Update, Issue 1, 2020 — Part 2: Our interview with Dr Wang highlights the following topics as well as cases from her practice: Case: A woman in her early 60s with previously treated metastatic triple-negative breast cancer is diagnosed with AML with a FLT3-ITD mutation (00:00) Molecular profiling in the diagnosis and treatment of AML (01:54) Activity and tolerability of midostaurin in combination with standard 7 + 3 chemotherapy for newly diagnosed AML with a FLT3 mutation (05:14) CPX-351 for secondary AML (07:16) Incidence and characterization of FLT3 mutations in AML; efficacy of midostaurin and gilteritinib (10:45) Clinical experience with and tolerability of gilteritinib (16:12) Activity of midostaurin in newly diagnosed AML with a FLT3 mutation (20:54) Ongoing Phase III trials of crenolanib, gilteritinib and quizartinib as first-line therapy for AML with a FLT3 mutation (24:17) Significance of allelic ratio in AML with a FLT3-ITD mutation (26:50) Therapeutic options for patients with relapsed/refractory AML and metastatic triple-negative breast cancer (31:01) Activity and safety of immune checkpoint inhibitors in patients with AML (32:58) Biologic rationale for and activity of venetoclax in combination with a hypomethylating agent for patients with AML (35:06) Case: A man in his early 40s with relapsed/refractory AML with an IDH2 mutation receives enasidenib (36:32) Similarities and differences between enasidenib and ivosidenib; recognition and management of treatment-associated differentiation syndrome (39:22) Integration of the FDA-approved IDH inhibitors enasidenib and ivosidenib into clinical practice (44:15) Approach to therapy for older patients with AML with FLT3 or IDH1/2 mutations (46:56) Integration of venetoclax in combination with a hypomethylating agent into community practice (51:23) Use of gemtuzumab ozogamicin for patients with low- to intermediate-risk AML with no adverse cytogenetics (55:33) Activity and unique side-effect profile of the hedgehog inhibitor glasdegib for AML (58:17) Results of the Phase III QUAZAR AML-001 trial: Overall survival benefit with CC-486 as maintenance therapy for newly diagnosed AML in first remission (1:00:34) Mechanism of action and activity of the first-in-class small molecule APR-246 in combination with azacitidine for patients with AML or myelodysplastic syndromes with TP53 mutations (1:04:19) Mechanisms of action and activity of blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin in patients with relapsed/refractory ALL (1:06:44) Tolerability and safety of blinatumomab and inotuzumab ozogamicin (1:09:51) CME information and select publications

MDS: Eliot shares his journey of diagnosis, treatment, transplant, and clinical trial for MDS with IDH1 and IDH2 mutations and AML. Myelodysplastic Syndromes, Acute Myeloid Leukemia, bone marrow transplant

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

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]

Dr. Eytan Stein provides a brief update on phase 1 arms of a trial studying the effectiveness of enasidenib in patients with relapsed and refractory AML and an IDH2 mutation.

Dr. Eytan Stein provides a brief update on patients experiencing differentiation syndrome in a larger enasidenib trial, detailing the creation of a Differentiation Syndrome Review Committee.

Dr Stein speaks with ecancer at EHA 2017 about the results of a phase 1/2 study looking at using enasidenib, an oral, selective, small-molecule inhibitor of mIDH2 proteins, to combat mutant-IDH2 relapsed or refractory acute myeloid leukaemia.