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The inflammatory and infectious optic neuropathies are a broad, heterogeneous, and common group of diseases producing visual loss. Although many now-distinct syndromes have been previously combined as “typical or atypical optic neuritis,” recent developments highlight the importance of precision terminology as well as an individualized evaluation and treatment approach. In this episode, Gordon Smith, MD, FAAN speaks with Eric Eggenberger, DO, MS, FAAN, author of the article “Optic Neuritis” in the Continuum® April 2025 Neuro-ophthalmology issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Eggenberger is a professor of ophthalmology, neurology, and neurosurgery at the Mayo Clinic in Jacksonville, Florida. Additional Resources Read the article: Optic Neuritis Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @gordonsmithMD Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith. Today I'm interviewing someone who really needs no introduction, Dr Eric Eggenberger, about his article on optic neuritis, which appears in the April 2025 Continuum issue on neuro-ophthalmology. Eric, welcome to the podcast, and maybe you can introduce yourself to our audience. Dr Eggenberger: Thank you. Thanks for having me. So, my name is Eric Eggenberger. I work at Mayo Clinic Florida, and I am involved exclusively in neuro-ophthalmology. Dr Smith: I just had the pleasure, Eric, of talking yesterday with Lindsey De Lott about non-optic neuritis causes of optic neuropathy. And so, I'm going to kind of reference a little bit what I learned yesterday. She was great. I wonder if you might begin by talking a little bit about nomenclature. You talk about the need for use of precise terminology in your article. And yesterday she taught me a lot about the risk of misdiagnosis and other causes of optic neuropathy, and the two seem related. So, I wonder if you can maybe lay the foundation for our conversation by talking about terminology? Dr Eggenberger: I think that's a great point. So, we are in an era now where, instead of lumping all these different diagnoses together, we have learned to split apart some of these clinical entities. And so, I think it's really important that we focus on precise terminology and recognize that all optic neuritis is not the same. And we have very different, distinct clinical pathways for these imaging pathways, treatment pathways, for these different types of optic neuritis, whether that's MS related, whether it's MOG related or aquaporin-4 related. Dr Smith: So, I wonder maybe we can begin by just, you know, giving our listeners wisdom, pearls, and pitfalls about, how do you recognize when someone with a suspected optic neuropathy has optic neuritis versus a noninflammatory optic neuropathy? Dr Eggenberger: So, that's a really important issue because there's a lot of clinical overlap in terms of exam findings. So, for instance, in any optic neuropathy, let's say it's unilateral, you typically are going to see decreases in acuity and field and color, and you're going to see a relative afferent pupillary defect. And then it's really the context that that occurs in that helps us distinguish different disease entities. So, with optic neuritis, typically you're going to have pain. And that's oftentimes going to be in the younger populations compared to some of the other common optic neuropathies we see, like ischemic optic neuropathy, for instance. Dr Smith: Right. So maybe we can talk a little bit about, kind of, your overall diagnostic approach, right? A lot of this is, of course, based on age and context, but young people get ischemic lesions and older people can have inflammatory lesions. So, what's your overall approach to the patient you just described? Let's say it's a forty-eight-year-old woman who comes to the emergency department with subacute unilateral vision loss and there's dyschromatopsia, APD, reduced acuity. And, you know, let's just say a fairly, you know, benign-looking fundoscopic exam. What do you do to evaluate that patient? Dr Eggenberger: In that particular context, I think we're looking at other contextual clues. Is there other vascular risk factors or other things to point you in one direction or the other? One of the important parts you mentioned was the fundus exam. So, we know with ischemic optic neuropathy, 100% of the time with AIOM, you're going to see disc edema. And so, in the context of that story, we want to confirm on our exam an optic neuropathy, and then we can kind of focus on the retrobulbar courses or different types of optic neuropathies. From an exam perspective, in that particular patient we'd be looking to measure the acuity, quantify that. And in the ER, you're not going to be able to do a perfect field, but you'll get some sense of the field and how much field loss there is. And then as you mentioned, the afferent pupillary defect is critical. And we're going to get a little bit of the historical features in terms of pain. With typical retrobulbar optic neuritis, most of those patients are going to experience some pain, and usually it's pain on eye movements. And those would be the clinical things to focus on. Other exposures the patient may or may not have had, any other concomitant conditions, would all help point you in different directions, perhaps, and then we're probably on towards imaging. Dr Smith: Yeah, maybe you can talk a little bit about that? What's the appropriate use of imaging? I mean, presumably the patients, like the one I just threw out there, are pretty much all going to get neuroimaging. What's your approach to that? How do you protocol the study? What should we be looking for? Dr Eggenberger: In our clinic, we would typically be ordering an MRI orbit and brain, and each of those has a specific purpose. The orbit is going to show us the extent of the optic neuropathy. So, we're particularly looking for a longitudinally extensive optic nerve lesion or more than half of the optic nerve involved. And most patients acutely, if it isn't an “itis" situation, we'll see enhancement. And then the MR brain is going to be useful for looking for other evidence of demyelination within the central nervous system. We may at some point get down to doing an MR cord, but I think acutely it's going to be brain and orbit that most of our patients are getting. Dr Smith: Let's say that we did the scan and, sure enough, there's sort of a shorter segment, so less than half the length of the nerve region of enhancement. What's the rest of your diagnostic evaluation look like for that patient? Dr Eggenberger: So, in that particular case, we would look at the remainder of the brain. So, we're looking for other evidence of demyelination and any other contextual clues, systemically that would point you one direction or another. But with a shorter segment involved, one of the more common things we might encounter would be multiple sclerosis-related optic neuritis. Dr Smith: Would you look for aquaporin-4 and MOG in a patient with what appears to be an isolated, uncomplicated short segment optic neuritis? Dr Eggenberger: So, I think it really depends a bit on the context. I would never fault anybody for looking at MOG or an aquaporin-4 in that context because those are really treatment-altering diagnoses, but the yield in this particular case with a short segment involved and depending on the acuity and other features is probably going to be pretty low. Dr Smith: I really liked as an aside- I wasn't going to go there next, but you kind of got me thinking about it, you have a really nice section in your article. Which, all of it's great, but talking about how to manage low titer MOG antibodies. I wonder if you could talk about that because I think that's a lesson, maybe, that is transferable to a lot of other testing that we do. in terms of pre-prior probability and titer and so forth. Dr Eggenberger: Yeah, that's really an important point. So, we've seen this come up a number of times where the MOG antibody is a very good test, but in low titer it has a relatively low positive predictive value, perhaps 50%. In those cases, particularly without a classic clinical context, you have to be extremely alert for some other diagnosis that could mimic what you think is inflammatory demyelinating optic neuritis, but in fact is infectious or some other cause. Dr Smith: Yeah, super, super important and helpful. In terms of aquaporin-4, how does that compare in terms of predictive values, lower titer positive results? Dr Eggenberger: So aquaporin-4, the test has a very high specificity. So, it's quite useful if positive. You have to keep in mind there can be some false negatives, but the test otherwise is quite specific. And that is a diagnosis, you know, we never want to miss. It's a vicious disease. It tends to be a blinding disease, particularly without treatment. Bad things happen when we miss that, and we want to get on that diagnosis early and do pretty aggressive early and prophylactic treatment. Dr Smith: Your article covers not only the common causes of optic neuritis and, you know, MS, isolated optic neuritis, MOGAD NMO, you talk about a bunch of other things. I wonder, in this patient that we've been discussing, in the absence of any other historical information that seems relevant---or maybe you can define what would seem relevant---would you do other evaluation in that individual, other serologic evaluation and so forth, just in terms of diagnosis? Dr Eggenberger: In that particular case, without other red flags, I don't think I would initially. And follow-up is going to give you a lot of this context. So, you'd be on the lookout for other systemic conditions. So, if the patient had some arthropathy, if the patient had any pulmonary disease hints, if there was anything else that could lead you on a broader expedition. But I think in the context of this case, acutely in the ER, I probably wouldn't do a big lab plug for this. I probably would kind of go down the most likely road and start our treatments, and then follow that patient up. Dr Smith: Yeah, I know your article does a really great job, I think, of outlining when do you need to think about some of these less common causes. Well, can we talk about treatment, Eric? Because I want to move on to some other things. But- so, we've got a patient with isolated optic neuritis, nothing else, you know, in terms of the other antibodies we've talked about. What state-of-the-care- or, state-of-the-art treatment for that patient? Dr Eggenberger: So, the acute treatment for these inflammatory, optic neuritis-type cases is very similar Initially. High dose steroids remains kind of the standard. And then, in MS-related optic neuritis, we may or may not see a taper. So many times it's just an acute treatment of three to five days high dose. Whether that's oral or PO, we could institute either depending on the particular case. And then the taper would depend on the potential cause. So, for instance, with these antibody-driven diseases---so with MOG- or particularly with aquaporin-4---if it's a longitudinally extensive region of optic nerve involved, we tend to use a longitudinally extensive taper. And so, we use prednisone in those cases for several months while we're getting everything else set and deciding what the overall course is going to bring. Dr Smith: What about IV versus oral? There must be something about my practice. I was telling this to Lindsey. Every time on our hospital service, we seem to have at least two patients with optic neuropathies, which I always enjoy, but I find it's a little weird to admit someone who's doing just fine otherwise to the hospital with three days of IV SOLU-MEDROL. So, I'm always trying to figure out, like, how can I get this patient home? And your article had the best term I've heard in a long time, which is “SOLU smoothies.” I mean, are there other strategies that you sometimes use, other than just high-dose IV methylprednisolone? Dr Eggenberger: So, I agree with you. It's sometimes hard to admit somebody for just an IV therapy. And we'll do this as an outpatient, high-dose IV, but we'll also use high-dose orals. And in times in the past when there's been methylprednisolone shortage, we've used high-dose oral or IV dexamethasone as well. I think the IV form, although it's the gold standard, the high-dose oral forms have pretty equivalent bioavailability and are pretty tolerable in my experience. And certainly more convenient. Dr Smith: I wonder if we should switch and maybe talk a little bit about aquaporin-4, I mean, you emphasized that this is a vicious disease---I love the way you describe that---and often blinding. What updates do you have in terms of our therapeutic approach to NMO? That's been rapidly evolving of late. Dr Eggenberger: Right, so these are cases we're always going to share with neuroimmunology. And it requires kind of a multidisciplinary approach, in my opinion, for ideal or for best outcomes. And so, all of these patients are going to get put on prophylactic medications. So, this is a disease you just can't leave untreated. Bad stuff will happen for sure. And we now, fortunately, have some approved, FDA-approved medications that can positively impact the course of this disease. So, that's been a welcome addition. Dr Smith: What are the FDA-approved medications at this point for NMO? Dr Eggenberger: So, there are several at this point, and this is an area that's in growth, fortunately. And again, these are cases we're going to be sharing with our neuroimmunology colleagues. So, these are IV medications typically aimed at complement or CD19. And they all are relatively effective at quieting the course of the disease. Dr Smith: Maybe we can talk a little bit about MOG? I think that most of our listeners are probably pretty familiar with aquaporin-4 and NMO, what- maybe you could describe MOG a little bit and the therapeutic approach for patients with MOG-associated disease? Dr Eggenberger: So, MOG has been a real interesting kind of condition to learn more about. We certainly see a lot of MOG, and I'm sure we saw MOG before it was formally described, but I think we just thought it was kind of a benign, maybe monophasic MS type of presentation. But MOG tends to come in with a loss of acuity that kind of rivals aquaporin-4. So, the acuity tends to be pretty, pretty depressed, but it's very steroid-responsive. So, a lot of times these are the patients, you'll see that their vision will start to improve even when they're on the initial few days of the high-dose steroids. And many times we can get their vision back to 20/20 or very close to that. Dr Smith: And do these patients need chronic management? Dr Eggenberger: So, that's an area of controversy to some degree. About 50% of the optic neuritis MOG-related cases are going to have a relapsing course. And because the disease is steroid-responsive, many times we'll follow these patients after a first attack to see if this is the condition that's going to declare itself to be relapsing or if this is just going to be a monophasic kind of presentation of optic neuritis. We don't have great biomarkers to separate patients who are going to be in that 50% monophasic course versus the other half. It'll be relapsing. And so, it depends on the patient. If there's somebody that's, as many of these patients are, been very steroid responsive, they get back to 20/20, we can teach them about the disease so that if they do have a relapse, we can get them high-dose steroids in a relatively rapid fashion and they're otherwise healthy, we're probably going to watch that patient. And if it's somebody that doesn't recover 100%, there's other issues with treating them with high-dose steroids potentially in the future, then we may learn more towards an earlier prophylactic approach in that patient. Dr Smith: And what would that approach look like? Is it different from NMO or using more IVIG or B cell depletion as opposed to complement inhibition, for instance? Dr Eggenberger: In MOG, we know that the B cell depletion strategies don't work as well. And so most times we're turning to IVIG, and we found that pretty effective. That's kind of our go-to at this point. Dr Smith: Eric, it's a joy talking to you and I'd love to keep going about content, but I'll refer our listeners to your outstanding article. I mean, you're such a highly regarded neuro-ophthalmologist and educator. I wonder if you could talk to us about why you've done neuro-ophthalmology, and maybe this is an opportunity for you to convince all of our great residents that are listening or students what's great about being a neuro-ophthalmologist. Dr Eggenberger: I think neuro-ophthalmology is by far the most interesting part of neurology. So, it's an area that I think a lot of general neurologists, in my view, don't get enough of in their residency. But it's kind of the essence of neurology, where in neurology you're localizing down to the millimeter and in neuro-ophthalmology,  we're localizing down to the micron level. We have several new emerging diseases like these varieties of optic neuritis we're focused on. We're learning lots about those. You get to be involved in lots of different areas of neurology. So, we'll see not just demyelinating conditions, we'll see trauma as it relates to the visual system. And we'll see tumor, and we see all different flavors, stroke, and in any piece of neurology, commonly we'll have some vision aspect that we that we get involved in. So, we see a wide variety of conditions. So, I think it's been a really exciting place to be within neurology. And it's rapidly changing at this point. We're getting new therapeutics. So, it's, I think it's a great time to be a neuro-ophthalmologist. Dr Smith: Yeah, listening to you talk and just reflecting on it, it's really true. Neuro-ophthalmology does cover the entire span of neurology, right? I'm a neuromuscular guy and we see a lot of ocular myasthenia, which is another super exciting area. But we've been talking about optic neuritis, and your article talks about infectious causes and the paraneoplastic and a whole host of things. So, you're a great advocate and salesperson for your field. You convinced me. Dr Eggenberger: Efferent neuro-ophthalmology we love, we could talk about ocular myasthenia and other aspects for another hour. And we get involved in all kinds of cases: third nerve palsies, ocular myasthenia, trauma that involves the efferent system, all different aspects. It's really a great subspecialty, and you get to see a bit of all of neurology. Dr Smith: I'm trying to remember who it was, Eric. It was an attending of mine at medical school. I went to medical school at the Mayo Clinic in Rochester, and I want to say it was Manny Gomez, who was a very famous tuberous sclerosis person, who told me that neuro-ophthalmology was the most elegant specialty within neurology. That stuck with me. Thank you so much for joining me today. I really appreciate it. Dr Eggenberger: Thank you. I appreciate it as well. Dr Smith: So again, today I've been interviewing Dr Eric Eggenberger about his really wonderful article on optic neuritis, which appears in the most recent issue of Continuum on neuro-ophthalmology. Be sure to check out Continuum audio episodes from the neuro-ophthalmology and other issues. And listeners, thank you very much for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

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 this week's episode we'll learn more about the significance of hypercalcemia in monoclonal gammopathy of undetermined significance, the role of neutrophil gelatinase-associated lipocalin in hemostasis, and the feasibility of combining CD19-targeted NK- or T-cell therapy with anti-CD19 monoclonal antibodies.Featured Articles:Approaching Hypercalcemia in Gammopathy of Undetermined Significance: Insights from the iStopMM study Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder Anti-CD19 antibody cotreatment enhances serial killing activity of anti-CD19 CAR-T/-NK cells and reduces trogocytosis 

Imugene Ltd chief operating officer Brad Glover and managing director and CEO Leslie Chong talked with Proactive's Tylah Tully about the company's latest Appendix 4C quarterly report, which provided several key updates for shareholders and investors. The pair also discussed the recent $20 million received from CVI Investments, ongoing clinical trials and financial outlook for 2025. Chong provided updates on Imugene's metastatic advanced solid tumour study (MARS), highlighting that a cholangiocarcinoma patient has been in full remission for over two years. She also shared news on the company securing a patent for its CF33 oncolytic virus technology, which extends until 2040. Glover discussed progress in Imugene's oncolytic virus program, stating that the company has initiated a combination trial with a CD19-targeting bispecific antibody. He also detailed the expansion of the Azer-cel trial, noting that the first Australian site has opened, and initial results from US sites have been promising. Financially, Chong reported that Imugene has approximately $65.4 million in cash, ensuring funding through 2025. Looking ahead, Glover emphasised the company's focus on clinical execution and data generation in 2025. #Imugene #CancerResearch #Biotech #ClinicalTrials #OncolyticVirus #Immunotherapy #StockMarket #ASX #MedicalInnovation

The global oncology drug market, valued at USD 231.56 billion in 2024, is expected to grow to USD 532.91 billion by 2031, driven by demand for targeted therapies, biomarker-based treatments, and immunotherapies. Several ASX-listed companies are contributing to this innovation: Arovella Therapeutics Ltd: Developing its invariant Natural Killer T (iNKT) cell therapy platform to treat blood cancers and solid tumours. Lead product ALA-101 uses CAR19-iNKT cells to target the CD19 antigen. The company recently raised $20 million to fund a phase 1 trial for CD19-positive blood cancers. Race Oncology Ltd: Focused on its lead asset, bisantrene, a small-molecule chemotherapeutic with reduced cardiotoxicity. A reformulated version, RC220, is being developed to meet unmet oncology needs. Imugene Ltd: Advancing immuno-oncology therapies, including azer-cel, an off-the-shelf CAR T therapy targeting CD19 for blood cancers, B-cell vaccine candidates, and CF33 oncolytic virotherapy, which combines engineered viruses with immunotherapies for solid tumours. Prescient Therapeutics Ltd: Developing personalised cancer treatments with technologies from institutions like Yale and Oxford. Lead drug PTX-100 has FDA Orphan Drug Designation for T-cell lymphomas. Its OmniCAR and CellPryme platforms enhance CAR-T therapies for improved efficacy and adaptability. These companies exemplify the growth and innovation occurring within the oncology sector. #ProactiveInvestors #ASX #OncologyMarket #ASXCompanies #ArovellaTherapeutics #RaceOncology #Imugene #PrescientTherapeutics #CancerResearch #ImmunoOncology #CellTherapy #TargetedTherapies #CAR_T #PersonalisedMedicine #CancerCare #BiotechNews #OncologyInnovation #GlobalHealthcare #ClinicalTrials #FDAApproval #SolidTumours #BloodCancers

Proactive's Tylah Tully breaks down ‘Just the Facts' of the latest news from Arovella Therapeutics Ltd (ASX:ALA). The company has raised $20 million, including a $15 million cornerstone investment, to fully fund its Phase 1 clinical trial for ALA-101, a CAR-iNKT cell therapy targeting CD19-positive blood cancers. The funding will also support the company's invariant Natural Killer T (iNKT) cell therapy pipeline and solid tumour programs. The capital raise was executed through a placement of 117.6 million shares at $0.17 each, attracting strong support from institutional investors like Pengana Capital Group and a $15 million commitment from an unnamed Australian private investor. Post-raise, Arovella holds $30.6 million in cash and cash equivalents, enabling it to secure IND approval from the US FDA for a Phase 1 trial targeting CD19-positive non-Hodgkin's lymphoma and leukaemia, commence and gather clinical data from the trial, and advance proof-of-concept data for its solid tumour programs focused on gastric and pancreatic cancers. The company emphasised that the raise demonstrates confidence in its CAR-iNKT platform and positions it as a leader in cell therapy innovation. #ProactiveInvestors #ArovellaTherapeutics, #ASX  #CARiNKT, #CellTherapy, #CD19, #BloodCancers, #CancerResearch, #Phase1Trial, #ClinicalTrials, #BiotechInvestment, #GastricCancer, #PancreaticCancer, #iNKTCells, #SolidTumours, #BiotechInnovation, #FDAApproval, #CARINKTTherapy, #CancerTreatment, #TherapeuticDevelopment, #InvestorSupport, #ASXBiotech

In today's episode, we had the pleasure of speaking with Paul J. Shaughnessy, MD, about the FDA approval of obecabtagene autoleucel (obe-cel; Aucatzyl) for patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Dr Shaughnessy is the medical director of the Adult Blood and Marrow Stem Cell Transplant Program at Methodist Hospital in San Antonio, Texas. On November 8, 2024, the FDA approved obe-cel for the treatment of adult patients with relapsed or refractory B-cell precursor ALL. This regulatory decision was supported by findings from the phase 1/2 FELIX trial (NCT04404660), in which 42% (95% CI, 29%-54%) of efficacy-evaluable patients with relapsed or refractory CD19-positive B-cell ALL who received the CAR T-cell product achieved a complete response (CR) within 3 months. The median duration of CR achieved within 3 months was 14.1 months (95% CI, 6.1-not reached). In our exclusive interview, Dr Shaughnessy discussed the significance of this approval, key efficacy and safety findings from the pivotal FELIX trial, and where obe-cel currently fits into the ALL treatment paradigm.

Imugene Ltd (ASX:IMU, OTC:IUGNF) CEO Leslie Chong and Professor Yuman Fong, chair of the Department of Surgery at the City of Hope and strategic advisor to Imugene, spoke with Proactive's Tylah Tully about the latest developments in Imugene's CF33 MAST (Metastatic Advanced Solid Tumours) VAXINIA study. Professor Fong, the inventor of CF33, described the approach behind the therapy, where genetically engineered viruses are designed to infect and kill cancer cells without harming normal cells. “In our lab, we prioritized creating a virus that could kill cancer of various types while remaining safe for humans,” he noted, explaining that this latest generation of the CF33 virus has shown positive results across a broad range of cancers, including melanoma and bile duct cancer. Chong and Professor Fong discussed the ongoing trials, where Imugene has received FDA orphan drug status and is seeing promising tumour responses in patients with advanced-stage cancers, including the challenging bile duct cancer. Chong highlighted the stability achieved in patients participating in the trial, some of whom previously exhausted other treatments. She explained, “Even at low doses, we're seeing disease stabilization, which is remarkable given that these patients have been through multiple other therapies before coming to us.” As CF33's clinical trials continue, Chong and Professor Fong are optimistic about the potential to offer a new option for patients with difficult-to-treat cancers. With the backing of a strong clinical and manufacturing team, Imugene is now expanding the trial to additional patients and combining CF33 with CD19-targeting drugs to further evaluate its impact on immune response and tumor reduction. #ProactiveInvestors #Imugene #ASX #CancerResearch #CF33 #OncolyticVirus #CancerTreatment #VAXINIA #ClinicalTrials #Immunotherapy #CancerInnovation #MetastaticCancer #ProactiveUpdates #LeslieChong #YumanFong #FDAApproval #OrphanDrugStatus #CancerScience

In the next episode of ASTCT's "Titans of Transplant," Dr. Shernan Holtan hosts Dr. Renier Brentjens, a pioneer in CAR T-cell therapy and a transformative leader in transplantation and cellular therapy. Dr. Brentjens discusses the challenges and breakthroughs behind developing the first chimeric antigen receptors (CARs), the pivotal discovery of CD19-targeting hybridomas, and the determination needed to turn bold ideas into clinical reality. Tune in for an insightful look at how early experiments paved the way for today's CAR T-cell advancements, capturing the passion, persistence, and pivotal moments that shaped a new era in cancer treatment.

Imugene Ltd (ASX:IMU, OTC:IUGNF) managing director and CEO Leslie Chong joins Proactive's Tylah Tully to provide a company update, including launching the first Australian site for the Phase 1b clinical trial of its azer-cel (azercabtagene zapreleucel) allogeneic CAR T-cell therapy. The Royal Prince Alfred Hospital in Sydney will lead Australian patient recruitment, with enrolment beginning in November 2024, marking Australia's only active trial for allogeneic CAR T-cell therapy in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL). This Australian expansion offers patients access to azer-cel, addressing critical treatment gaps for DLBCL, an aggressive form of non-Hodgkin's lymphoma. Chong emphasised the importance of local access to this innovative therapy. Imugene's US trials have shown promising results, with three patients achieving complete responses, two of whom received a combination of azer-cel with lymphodepletion and interleukin-2 (IL-2), showing durable responses extending beyond 90 and 120 days. The company has also dosed the first patient in the intratumoural (IT) injection combination arm of its OASIS Phase 1 clinical trial for onCARlytics (CF33-CD19). This trial aims to test the efficacy and safety of Imugene's CD19-expressing oncolytic virotherapy in advanced or metastatic solid tumours. The first colorectal cancer patient was treated at Northwestern University, and the trial is expected to enrol up to 40 participants with various advanced cancers. #ProactiveInvestors #Imugene #ASX  #Oncology #CAR_TCellTherapy #AzerCel #Vaxinia #ClinicalTrials #CancerResearch #Immunotherapy #DLBCL #HER2 #BileCancer #Biotechnology #ASX #FDAApproval #OrphanDrug #FastTrack #BiotechInvesting #OncolyticVirotherapy #CancerTreatment #CashPosition

In this week's episode, we'll learn about the role of a platelet-specific glycoprotein receptor in abdominal aortic aneurysm formation, the influence of TP53 mutations on outcomes for patients with 5q-deleted myelodysplastic syndrome, and a rational combination treatment intended to produce more durable responses in patients with refractory B-cell acute lymphoblastic leukemia who are treated with CAR T-cell therapy.Featured Articles:Soluble glycoprotein VI predicts abdominal aortic aneurysm growth rate and is a novel therapeutic targetInfluence of TP53 gene mutations and their allelic status in myelodysplastic syndromes with isolated 5q deletionA phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia

In a special co-branded episode between Oncology On the Go and the American Society for Transplantation and Cellular Therapy (ASTCT)'s program ASTCT Talks, Rahul Banerjee, MD, FACP, and Noopur Raje, MD, discussed the risk of secondary malignancies in patients with multiple myeloma who receive CAR T-cell therapy. Banerjee is an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington. Raje is the director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center and a professor of medicine at Harvard Medical School. Banerjee and Raje spoke in the context of prior advisories from the FDA on the potential development of secondary T-cell malignancies in patients who receive CAR T-cell therapy for hematologic cancers. Specifically, the agency required a boxed warning for secondary T-cell malignancy risks for BCMA- or CD19-targeting therapies in April 2024.1 The conversation also touched upon reports of secondary malignancies in cases and trials such as CARTITUDE-1 (NCT04181827), in which second primary cancers were highlighted in 9 patients who received treatment with ciltacabtagene autoleucel (Carvykti).2 Considering these reports and warnings, Banerjee and Raje emphasized shared treatment decision-making with patients after assessing the risks and benefits of CAR T-cell therapy compared with other agents like bispecific antibodies. They also reviewed optimal strategies for monitoring and referring patients based on the incidence of certain toxicities. “[Treatment with] CAR T cells requires planning, and we need to have good control of the disease. We need to have 4 to 6 weeks of a lead time to get these effective treatments to our patients, so early referral is a good idea,” Raje said. “[For example], if you see chronic diarrhea in someone that is way out of the window of what you would expect, referring back to the CAR T-cell center is important so that we don't miss some of these toxicities.” References FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. April 18, 2024. Accessed August 22, 2024. https://tinyurl.com/5n8pm5ca San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379

In a special co-branded episode between Oncology On the Go and the American Society for Transplantation and Cellular Therapy (ASTCT)'s program ASTCT Talks, Rahul Banerjee, MD, FACP, and Noopur Raje, MD, discussed the risk of secondary malignancies in patients with multiple myeloma who receive CAR T-cell therapy. Banerjee is an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington. Raje is the director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center and a professor of medicine at Harvard Medical School. Banerjee and Raje spoke in the context of prior advisories from the FDA on the potential development of secondary T-cell malignancies in patients who receive CAR T-cell therapy for hematologic cancers. Specifically, the agency required a boxed warning for secondary T-cell malignancy risks for BCMA- or CD19-targeting therapies in April 2024.1 The conversation also touched upon reports of secondary malignancies in cases and trials such as CARTITUDE-1 (NCT04181827), in which second primary cancers were highlighted in 9 patients who received treatment with ciltacabtagene autoleucel (Carvykti).2  Considering these reports and warnings, Banerjee and Raje emphasized shared treatment decision-making with patients after assessing the risks and benefits of CAR T-cell therapy compared with other agents like bispecific antibodies. They also reviewed optimal strategies for monitoring and referring patients based on the incidence of certain toxicities. “[Treatment with] CAR T cells requires planning, and we need to have good control of the disease. We need to have 4 to 6 weeks of a lead time to get these effective treatments to our patients, so early referral is a good idea,” Raje said. “[For example], if you see chronic diarrhea in someone that is way out of the window of what you would expect, referring back to the CAR T-cell center is important so that we don't miss some of these toxicities.”  References 1. FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. April 18, 2024. Accessed August 22, 2024. https://tinyurl.com/5n8pm5ca  2. San-Miguel J, Dhakal B, Yong K, et al. CIlta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379 

Chimeric antigen receptor (CAR)-T cell therapy has made impressive advancements in treating patients with blood cancers, such as leukemia and lymphoma, for more than a decade now. In this episode, we traverse the challenges and innovations of cell immunotherapy and better understand the design behind these logic-gated, genetically engineered cytotoxic cells with Dr. Yvonne Chen, a leading expert in the field. Dr. Chen is an incredibly accomplished Professor of the MIMG and CBE departments at UCLA and currently leads a Phase 1 Clinical Trial (NCT04007029) using bispecific anti-CD19/anti-CD20 CAR-T cells to treat patients with B cell malignancies. For more information on Dr. Chen's research: http://yvchen.bol.ucla.edu/. Music: https://pixabay.com/music/id-112777/ Episode Team:Guests - Dr. Yvonne ChenHost - Brenda JiScript Writers - Brenda JiAudio - Daniel NguyenProducers - Artin Allahverdian, Sonali JoshiDirector - Vy Han, MD

Audio roundup of selected biopharma industry content from Scrip over the business week ended 16 August 2024. In this episode: Merck & Co. steps into CD19 bispecific space; gene therapy patients rise, but slowly; Madrigal's Rezdiffra plans; Korean biopharma financing recovering?; and approvals to watch out for in Q3. https://scrip.citeline.com/SC150765/Quick-Listen-Scrips-Five-MustKnow-Things Playlist: soundcloud.com/citelinesounds/sets/scrips-five-must-know-things

Welcome back to the Oncology Brothers podcast! In this episode, hosts Drs. Rahul and Rohit Gosain dive into the world of diffused large B-cell lymphoma with special guest Dr. Carla Casulo from the Wilmot Cancer Institute in Rochester, New York. Key Points Covered: •⁠  ⁠Understanding the importance of accurate diagnosis through excisional biopsy in diffused large B-cell lymphoma. •⁠  ⁠Exploring the significance of cell of origin in guiding treatment decisions. •⁠  ⁠Initial treatment approaches for stage 1 and 2 disease, including the use of Polatuzumab based on the POLARIX trial. •⁠  ⁠Treatment options for relapsed or refractory disease, including CAR-T therapy, BiTE therapy, and anti-CD19 antibody agents. •⁠  ⁠Managing toxicities associated with different treatment regimens, such as cytopenias, infections, and neurotoxicity. Join us as we unravel the complexities of diffused large B-cell lymphoma and discuss the latest advancements in treatment options with Dr. Carla Casulo. Stay informed and up to date with the Oncology Brothers podcast! Don't forget to like, share, and subscribe for more insightful discussions on oncology topics. Thank you for tuning in to the Oncology Brothers podcast. Website: http://www.oncbrothers.com/ Twitter: https://twitter.com/oncbrothers Contact us at info@oncbrothers.com

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

Autoimmune neurology is a rapidly evolving subspecialty that focuses on neurologic disorders with atypical immune responses. In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sean J. Pittock, MD, an author of the article “Overview and Diagnostic Approach in Autoimmune Neurology,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California. Dr. Pittock is the director for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Overview and Diagnostic Approach in Autoimmune Neurology Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Transcript Full transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.    Dr Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Sean Pittock about his article, “Introduction to Autoimmune Neurology and Diagnostic Approach”, which he wrote with his colleague, Dr Andrew McKeon. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, Dr Pittock. Could you introduce yourself to our audience?    Dr Pittock: Well, thank you very much, Dr Berkowitz. So, yeah, I'm a neurologist at the Mayo Clinic. I direct the neuroimmunology laboratory with Dr McKeon and Dr Mills here, and I have also been very much involved in the autoimmune neurology section at the American Academy of Neurology.    Dr Berkowitz: So, many of you probably know Dr Pittock - or if you don't know, you've certainly diagnosed diseases that he has described and written about, and so it's a real honor to get to talk to you today and pick your brain a little bit about some of these complex diseases. So, autoimmune neurology is certainly one of the most exciting subspecialties of our field. I feel like when I talk to students and they ask me to make a case for why they should consider neurology as a career, I tell them, “Of course, I have many reasons I love neurology”, but one thing I mention is that, although many other fields of medicine may have made incredible advances as far as treatments, I can't think of too many other fields outside neurology where entirely new diseases have been described since I've been in training and come out of training - and many of those have been in your field of autoimmune neurology. I can think of cases where I've heard you or one of your colleagues on a neurology podcast describing a new antibody, new disease, and a few weeks later, we see that disease and give a patient a diagnosis that had been elusive from other physicians and hospitals. It's a very exciting, gratifying area. It's also daunting, like, every time I go to the AAN and hear one of your colleagues, there's a new disease, and we realize, “Oops! Was I missing that?” or, “Am I going to see this?” And so, hoping to pick your brain a bit today about some of the key concepts and how to keep them in mind so our listeners can recognize, diagnose, and treat these conditions, even if they can't remember every single antibody in your article and all the new ones you and your colleagues will probably discover between now and when this, um, podcast is released. So, before we get into some of the important clinical aspects of these conditions, could you just lay out sort of the broad breaststrokes, the lay of the land of cell-mediated versus antibody-mediated paraneoplastic versus nonparaneoplastic cell surface versus intracellular - how can we sort of organize this area in our minds?    Dr Pittock: Yeah. It's complex, and it's really an evolving story. But the importance, really, from the perspective of the reader and the perspective of the clinician is that we're talking about disorders where we can actually do something - we can actually impact patients.  And we think about the concept of stopping and restoring in neurology now. We're talking about disorders where we have the potential to stop these inflammatory immune-mediated disorders and, potentially, by stopping early, we may be able to restore function - so, a really important new and evolving field in neurology, because you don't want to miss these conditions. Trying to get your head around the complexity of these entities is difficult, but what we've done in this chapter is, really, to try and lay the groundwork for the following chapters, but provide somewhat of a simplistic approach, but a practical approach that really, I think, can help clinicians. So, the way I think of it, a lot of autoimmune neurology really has stemmed from the discovery of antibodies that cause neurological disease, and the examples of those would be going back to myasthenia gravis (with antibodies to the acetylcholine receptor), going back to Lambert-Eaton syndrome. And then, you know, even if you go back to the older traditional paraneoplastic disorders (the Hu, the Ri, the Yo), at the end of the day, you really have two essential entities, if you want to be very simple. The first is disorders that are caused by an antibody, and the second are disorders where the antibodies you detect are not causing the disorder, but they're telling you that there's predominantly a cellular or T-cell mediated attack of the nervous system. And I think thinking about the diseases in those kind of simple terms helps us when we think about what would be the best treatment to use in these types of cases.   Dr Berkowitz: Fantastic. I think that's very helpful. And just to make sure it's clear in the minds of our listeners when we're dividing into these sort of causative antibodies versus antibodies that might be, uh (I don't know if I'm using the word properly), but, sort of epiphenomena (or they're present, but they're not causative) as you said, can you just give some examples of the ones on either side and how making this distinction helps us in practice?    Dr Pittock: Yes. So, antibodies that are causative of disease - I think, you know, the one that I've done a lot of work on is in neuromyelitis optica, where you have antibodies that are targeting a water channel that sits on an astrocyte, and so it causes NMOSD, or what we consider an autoimmune astrocytopathy. And we know that when the antibody binds to the target, many things can happen. So, when aquaporin-4 antibodies bind to aquaporin-4, they can do a lot of things. They can cause internalization, they can activate complement that results in the killing of the cell - but there can be other situations. For example, when NMDA-receptor antibodies bind to the NMDA receptor, then a variety of different things can occur different to water channel autoimmunity - where, for example, the receptor (the NMDA receptor) is downregulated off the cell surface, and that results, to some extent, in the neuropsychiatric phenomenon that we see in NMDA-receptor autoimmunity. And, obviously, when you have a situation where the antibodies are causing the disease, removal of those antibodies, or the reduction in the production of those antibodies, is going to help patients. Now, on the other side, we have antibodies that we detect in the blood or in the spinal fluid, and those antibodies are targeting proteins that are inside the cell - so those antibodies we don't consider as being pathogenic. Now, remember, there are sometimes situations where proteins that are inside the cell occasionally can be available for antibodies to bind at certain situations. So, for example, in the synapse, amphiphysin or the septins, may at times become available. And so, sometimes, there are targets or antibodies that are somewhat in between those two simplistic concepts. But when we're talking about antibodies that are targeting proteins on the inside of the cell, remember that antibodies don't just suddenly occur. There's a whole process of presentation of target antigen at the lymph node, and then both a T- and a B-cell response. The B-cell response potentially produces the antibodies but also triggers and stimulates T-cells, and those T-cells then go on to cause the disease. And those T-cells are very problematic, because those classical paraneoplastic and the newer ones we've described (and many have described) - these are associated with quite severe neurological disability, and they're very, very difficult to treat. And if you ask me, “Where is the holy grail of autoimmune neurology therapeutic research?” It's in trying to actually figure out ways of treating the predominantly T-cell mediated paraneoplastic and autoimmune neurological disorders. We're making great headway in terms of the treatments of the antibody-mediated neurological disorders.   Dr Berkowitz: That's a helpful overview. So, sticking with this framework, you mentioned as sort of the “causative antibody” category and the antibodies that are predominantly for intracellular antigens, but not believed to be causative - I want to make sure I'm understanding this correctly and we can convey it to our listeners - I believe you said in your paper, then, that the antibodies that are predominantly causative are more likely to be associated with conditions that are very treatable, as compared to the intracellular antibodies that are not thought to be causative, as you just said the disability can be irrecoverable or very hard to treat. And I believe another theme in your paper that you brought out is the antibodies that tend to be causative tend to be cell surface and tend to be less likely to be associated with underlying cancer (although not a perfect rule), and the intracellular antigens more commonly associated with cancer in those cases to look very hard for a cancer before giving up. Are those themes that I understand them from your paper properly, or anything else to add there?    Dr Pittock: Yes, I think that that's exactly the message that we were trying to get across, so that's good news that you've picked up on the themes. I think, yeah, in simple terms, remember that when a cytotoxic T-cell identifies the peptide that its T-cell receptor will target, the ultimate outcome is poor, all right? T-cells are like the marines - they don't mess around. Once they find their target, they eliminate that target, and so, it's really difficult to treat those types of diseases if you get them late. And most patients with cytotoxic T-cell mediated paraneoplastic neurological disorders, oftentimes, by the time they get to a center of excellence, the boat has left the dock in many respects - in other words, it's too late. So, you know, I will often see patients, for example, with progressive cerebellar degeneration (say, in the context of Purkinje cell autoantibody type 1 antibodies and a breast cancer), and if those patients are in a wheelchair at the time that I see them, there's very, very little that we can do. So, you really want to try and get that patient into the office, you know, when they're using a cane (or not), and then, potentially, you have the opportunity - using very aggressive immunosuppressive medications - to make a difference. And that is quite different to other scenarios, where, for example, if you have NMDA-receptor encephalitis - as many of the readers will know, this is a condition that is very treatable, and most patients do very well, because the antibodies, they're disrupting function, but they're not killing the neuron, as we see in those more aggressive, paraneoplastic cytotoxic T-cell mediated diseases.   Dr Berkowitz: Also, in terms of searching for an underlying cancer, another theme in your paper as I understood (but want to make sure I'm understanding and conveying to our listeners and hear your thoughts), that the cell surface and treatable antibody-mediated syndromes, as you mentioned (NMO, NMDA) tend to be less associated with underlying cancers (although can be), whereas the intracellular antigens, um, a much higher percentage of those patients are going to end up having underlying cancers. Is that correct, or any notable exceptions to be aware of in that framework?    Dr Pittock: Yeah, I think the major exception to the rule for the antibodies that are targeting intracellular antigens is the GAD65 antibody story. We generally don't consider the stiff person syndrome, cerebellar ataxia, or other autoimmune neurological disorders associated with very high levels of GAD65 antibodies - those are generally not paraneoplastic. And then there are always exceptions on both sides. You know, one of the benefits of understanding the implications of certain antibodies is trying to understand, you know, what is the likelihood of identifying a malignancy, which antibodies are high-risk antibodies (in other words, high-risk paraneoplastological disorders), and which are low risk in terms of cancer? And, you know, age and the demographic of the individual is often important, because we know, for example, with NMDA-receptor antibodies, the frequency of ovarian teratoma varies with the age of the patient.   Dr Berkowitz: Fantastic. And we encourage our listeners to read your articles – certainly, some very helpful tables and figures that help to elucidate some of these broad distinctions Dr Pittock is making - but just to summarize for the antibody-related part of autoimmune neurology, we have one category of cell-surface antibodies and another of intracellular antibodies. Both can cause very severe and varied neurologic presentations, but the cell surface tend to be more treatable, less likely to be associated with the underlying cancer, and the intracellular less treatable, more likely to be associated with the underlying cancer - but, as with everything in neurology and medicine, exceptions on both sides. Is that a fair aerial view of some of the details we've discussed so far, Dr Pittock?    Dr Pittock: Yeah, I think so. I mean, I also think that, you know, not only, at least, for the antibody-mediated disorders (you know, as we discussed) we have drugs that will reduce the production of those antibodies, but we're also learning a lot more about the cytokine and chemokine signatures of these disorders. For example, NMO, water-channel antibody-mediated diseases are associated with elevated levels of IL-6. We know, for example, in LGI1 encephalitis and other encephalitides, that IL-6 also is elevated at the time of that encephalitic process. And so, the potential to target IL-6 with, you know, drugs that inhibit IL-6 and the IL-6 receptor, these potentially have, you know, a role to play in the management of these types of patients - whereas in the T-cell mediated disorders, you know, no advance has been made in the treatment of those conditions, I would say, in over 50 years. So, for example, the standard of treatment is steroids and then drugs that impact the bone marrow, and so we really haven't moved forward in that respect. And that, I think, is an area that really needs drive and enthusiastic out-of-the-box thinking so that we can try to get better treatments for those patients.   Dr Berkowitz: This has been a helpful overview. I look to dive into some of the scenarios that frontline practitioners will be facing thinking about these diseases. An important point you make in your article is that autoimmune and antibody-mediated neurologic syndromes can affect any level of the neuraxis. Even just our discussion so far, you've talked about anti-NMDA receptor encephalitis, you've talked about myasthenia gravis (that's at the neuromuscular junction), you've talked about paraneoplastic cerebellar degeneration - there can be an “itis” of any of our neurologic structures and that “itis” can be antibody-mediated. So, one of the key messages you give us is, one, that these are sort of in the differential diagnosis for any presenting neurologic syndrome, and, two, sort of one of the key features of the history, really, to keep in mind (since we could be anywhere along the neuraxis) is the subacute presentation when this should really sort of be top of mind in our differential diagnosis - so, many of these patients are going to be mystery cases at the outset. And one striking element you bring out in the paper is that, sometimes, the MRI, CSF, electrophysiology studies may be normal or nonspecifically abnormal, and although it's very helpful when we can send these antibody panels out, in some cases, resources are limited or institutions have certain thresholds before you can send these out (because neurologists love to send them in). Sometimes, they are not necessarily appropriate. So, love to hear your thoughts on when we should be sending these panels. What are some clues? Um we have a subacute neurologic presentation at any level of the neuraxis, and when it's not anti-NMDA receptor encephalitis, that is sort of a clear phenotype in many cases. How you would approach a patient, maybe, where the MRI is either normal or borderline abnormal (or people are squinting at the medial temporal lobe and saying, “Maybe they're a little brighter than normal”), CSF is maybe normal or nonspecifically, um, and the protein is a little high, but no cells? What clues do you use to say, you know, “These are the patients where we should be digging deep into antibody panels and making sure these are sent and not miss this diagnosis?”    Dr Pittock: Well, thank you. That's a good question. So, I think, you know, first of all, these are complex cases. So, the patient is sitting in front of you and you're trying to figure out, first of all, Is this a hardware or a software problem? Are we definitively dealing with an encephalitis or an organic neurological entity that's immune-mediated? And, you know, the way I think of it is, for me, you see a patient, it's a twenty-five-piece jigsaw puzzle and you've got two pieces, and you're trying to say, “Well, if I step back and look at those two pieces, do I have any sense of where we're going with this patient?” So, the first thing you need to do is to collect data, both the clinical story that the patient tells you (and I think you make the good point that that subacute onset is really a big clue), but subacute onset, also fluctuating course, sometimes, can be important. The history of the patient - you know, Is the patient somebody who has a known history of autoimmune disease? Because we know that patients that have thyroid autoimmunity are more likely to have diabetes, they're more likely to have gastrointestinal motility or dysmotility, they're more likely to have a variety of different immune-mediated conditions. So, is there a family history or a personal history of autoimmunity? Is the patient at high risk for malignancy? Are there clues that this potentially could be a tumor-initiated immune process affecting the nervous system? The neurological exam also is extremely important because, again, that helps you, first of all, kind of define and get some objectivity around what you're dealing with. So, does the patient have hyperreflexia? Are there signs that there is neurological involvement? And then, really, what I think we need to do is to try and frame the predominant neurological presentation. So, what is the major issue? Because a lot of these patients will have multiple complaints, multiple symptoms, and it's very important to try and identify the major presentation. And that's important, because the neural autoantibody tests are now presentation-defined - in other words, they're built around the neurological presentation, because the old approach of just doing, apparently, a plastic evaluation is gone, because we've got to a stage where we have now so many neural antibodies, you can't test every single neural antibody. So, if you're suspecting that there may be an autoimmune neurological component, then you really need to think about what would be the most appropriate comprehensive evaluation I need to do for this patient. So, for example, if a patient comes in with a subacute-onset encephalopathy, you're probably going to want the autoimmune encephalitis evaluation, and then you have to pick whether it's going to be serum or spinal fluid - and as we outlined in the paper, there are certain antibodies that are better detected in serum versus spinal fluid. So, for example, in adults over the age of 50, LGI1 is much more accurately detected in serum than spinal fluid, and the absolute opposite is true for NMDA-receptor antibody detection. One of the most important components of the neurological evaluation is the spinal fluid, but actually looking at the white cell count - and in fact, sometimes, it's quite interesting to me that I'll often see patients referred with a diagnosis of encephalitis and autoimmune encephalitis, and yet they haven't had a spinal fluid examination. So, the presence of a white cell count, you know, greater than five is hugely helpful - it's like two pieces of that twenty-five-piece jigsaw, because that really tells you that there is something inflammatory going on. And now, in terms of imaging, you're right - some patients will have normal MRI. And if you really do think that there's evidence of - you know, for example, you do an MRI, but you're getting a good sense that there's a temporal lobe seizure occurring, MRI looks normal, the EEG shows some abnormalities in the mesial temporal area - you know, considering additional imaging modalities (like PET scan of the brain), I think, is reasonable. We know that in NMDA-receptor encephalitis cases, 30% of patients will have normal MRI but they'll often have abnormalities on the PET scans. So, I think, what we do is we try to gather data and gather information that allows us to add in pieces of that jigsaw so that, eventually, after we've done this evaluation, we can see now we have ten pieces. If we step back, we say, “Yes, now we know what this condition is”, and then we essentially plan out the therapeutic approach dependent on what we've found. In terms of identification of underlying malignancy, you know, different people have different approaches. Our approach generally has been to try to get a PET-CT scan of the body as our first go-to test, because, actually, we found that CT chest abdomen and pelvis really actually delivers the same amount of radiation - and from a cost perspective, it's about the same - and we have found that PET-CTs really do provide a higher sensitivity for cancer detection.   Dr Berkowitz: Perfect. A lot of very helpful clinical pearls there. So, in closing, Dr Pittock, I've learned a lot from you today. I'm sure our listeners will as well. What does the future hold in this field? What's coming down the pipeline? What are we going to be learning from you and your colleagues that are going to help us take care of patients with these diseases going forward?    Dr Pittock: Well, thank you, Dr Berkowitz, for that question. I think the future is very bright and very exciting, and, hopefully, some of the more junior members will be enthused by this Continuum series, and, hopefully, we'll go into this area. So, let's talk about the future. The future, I think, is going to be of great interest. Firstly, there's going to be continued discovery of novel biomarkers, and the reasons for that is because of the technical and technological advances we've seen. So, for example, there have been many, many antibodies discovered by us and others that have been discovered on the basis of, for example, phage technology. In fact, the Kelch 11 biomarker discovery in collaboration with UCSF and our group was done on the basis of Joe DeRisi and Michael Wilson's phage approach. And we're actually using that now at Mayo Clinic, and we've discovered about three or four new antibodies just in the last couple of years using this technology (and that here is led by John Mills and Div Dubey). And then, we're also going to see, I think, the evolution of protoarrays much more in biomarker discovery, so, we'll have more antibodies, and again, I think, generally, those antibodies will fall into the two categories we kind of described - so, you know, in terms of the approach to those conditions, maybe not so much change. I do think, though, that the introduction and the utility of comprehensive cytokine and chemokine analysis in the future will assist us in making diagnoses of seronegative encephalitis, but also potentially will direct therapy. So, for example, cytokine A is elevated - maybe that would be a potential target for therapy that's available for these patients with rare and potentially very disabling disorders. Then, when we look at the cytotoxic T-cell mediated disorders, I think the major areas of advance are going to be in better understanding the immunophenotype of cytotoxic T-cell mediated diseases, and then the potential development of tolerization strategies using the specific targets, those specific epitope targets that are involved in paraneoplastic and nonparaneoplastic diseases, and seeing if we can vaccinate patients, but move that immune response into more of a tolerogenic immune response rather than a cytotoxic killing response. And then I think, lastly, we're going to see a dramatic revolution in CAR-T therapeutic approaches to these types of disorders moving forward - and not just, you know, CAR-T therapies that are targeting, you know, CD19 or CD20, but CAR-Ts that are actually personalized and developed so that they can target the specific B- and T-cells in an individual patient and actually do a very fine removal of that autoimmune pathologic process that I think would have significant benefit for patients not only in stopping progression, but also in significantly reducing the potential of side effects - so, a much more targeted approach. So, that's where I think the next ten years is going to be. I think it's very exciting. It's going to require the collaboration of neurologists with, you know, immunologists, hematologists, you know, across the board. So, a very exciting future, I think, for this field.    Dr Berkowitz: Exciting, indeed. And we have learned so much from you and your colleagues at the Mayo Clinic about these conditions, and I definitely encourage our listeners to read your article on this phenomenal issue that really gives us a modern, up-to-date overview of this field and what's coming down the pipeline. So, a real honor to get to speak with you, pick your brain about some of the clinical elements, pitfalls and challenges, and also hear about some of the exciting signs. Thank you so much, Dr Pittock, for joining me today on Continuum Audio.   Dr Pittock: Thank you very much.    Dr Berkowitz: Again, today, I've been interviewing Dr Sean Pittock, whose article with Dr Andrew McKeon on an introduction to autoimmune neurology and diagnostic approach appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining us today.    Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/audioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Eoin P. Flanagan, MBBCh, FAAN who served as the guest editor of the Continuum® August 2024 Autoimmune Neurology issue. They provide a preview of the issue, which publishes on August 1, 2024. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Flanagan is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Continuum website: ContinuumJournal.com Subscribe to Continuum: shop.lww.com/Continuum More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Guest: @EoinFlanagan14 Transcript Full episode transcript available here   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based  neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.    Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Eoin Flanagan, who recently served as Continuum's guest editor for our latest issue on autoimmune neurology. Dr Flanagan is a neurologist at Mayo Clinic in Rochester, Minnesota, where he's a professor of neurology. Eoin, why don't you introduce yourself to our listeners?   Dr Flanagan: Yeah, it's a great pleasure to be here today. I'm a neurologist. I'm originally from Ireland – I did my medical school training over there, and then came over to the Mayo Clinic to train in neurology and in neuroimmunology. And delighted to be able to edit this exciting issue of autoimmune neurology of Continuum. I think, um, it's a really fascinating area that's moving very quickly, and I'm hoping that we can educate listeners to be able to feel comfortable when they come to see these patients and to realize how much of a growing specialty it is and how we're getting treatments, and we can really help these patients.     Dr Jones: Yeah, it's a pretty exciting area. And, so, not only are you the Guest Editor for our latest issue of Continuum, this is the first-ever Continuum issue dedicated to autoimmune neurology, so I want to thank you for taking it on. This is something that our readers have been asking for for many years. I hope the topic wasn't too daunting.   Dr Flanagan: No, absolutely, it's a pleasure to be able to do it, and it's just great when you read all the articles to kind of feel where the field is going and how much of  a benefit we can now make for our patients. So, that's been a real joy to do.   Dr Jones: Well, congratulations, and it's a magnificent issue. You have a lot to be proud of putting this group of authors together. So, for a few of our issues now, we've had the opportunity on the Continuum Audio podcast to interview the Guest Editor, which is really fun for me. I have to confess it's really a joy to talk to someone who is up to the minute not only in their narrow area of expertise at the article level, but, really, across the entire breadth of the subspecialty. And so, you've had an opportunity to delve into all relevant topics in autoimmune neurology. When you look at the issue as a whole, or the field as a whole, what do you think the biggest debate or controversy in the world of autoimmune neurology is right now?     Dr Flanagan: Yeah, I think there's some changes happening. You know, initially, people used to recognize a disease called Hashimoto's encephalitis, where patients would have a presentation of encephalitis in the setting of thyroid antibodies. And what we're now realizing is that many of these patients actually have antibodies to neural-specific targets, because we know that the antibodies that target the thyroid don't really impact the brain. And what we're now realizing is that there's many antibodies out there that bind to different receptors in the brain (the NMDA receptor, for example, AMPA receptor), so we're really trying to refine the field towards these different antibody-associated disorders - and each different disorder may behave very differently. A patient with NMDA receptor encephalitis, for example, may be in the ICU, in hospital, may take them six, nine months to recover. On the other hand, a patient with LGI1-antibody encephalitis may get five days of steroids and be almost back to normal within a few weeks. So, it's a really broad spectrum. And, I think, what we're now learning is that each antibody has a role in helping define the disease, guide your treatment, guide your search for cancer - but, also, they behave differently - so these neural-specific antibodies are really important, while the older antibodies (like the thyroid antibodies) may just be a bystander and something that's happening in the background in a patient who's more prone to autoimmune disease.   Dr Jones: Very helpful, and I think that resonates with our listeners who have taken care of patients with autoimmune neurologic disorders, and it really is, I think, a great prototype in our specialty, maybe (for lack of a better word) of how observations start at the bedside, and then discoveries are made at the bench, and those benefits are brought back to patients. You know, there's been a recognition of autoimmunity in neurology for a long time, right - responsiveness to immunosuppression, even before the biomarkers were discovered - tell us a little story about how that works for our listeners.    Dr Flanagan: Yeah, so, I think one of the first steps is defining a clinical syndrome. So what you'll find is that some of these syndromes (for example, neuromyelitis optica spectrum disorder, where they have longitudinally extensive lesions within a spinal cord) provoked people to be interested that these looked different to MS, and then that went to the lab, and the aquaporin-4 antibodies were discovered - or, more recently, MOG antibodies were discovered. The aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder is a good prototype, because that went to the laboratory. Initially, they saw complement deposition on the pathology of these patients, they saw antibody deposition - the antibody was then discovered to aquaporin-4. And then, many labs around the world went to their own labs and they tried to delve in to determine what the pathogenesis was, and they found that complement was important in cell killing, that interleukin-6 elevation was important, and that complement appeared to be important. So, then, what they did was they tried to find treatments that would target those pathways. So, and now, we have treatments that are successful for this disease that can target complement, target interleukin-6, and target B cells (be it CD19 or CD20). So, we now have many different treatments, and this disease used to be very severe (so, had a 33% mortality at five years), and now these patients can live a long life with these treatments. So, I think that gives you an example of how you can follow the immunology of the disease and use targeted treatments to help our patients, and I think we can use that as a good prototype for many of   the other antibodies, because every year we discover two to three new antibodies, and each disease is a bit different in its mechanism. So, there are now clinical trials in NMDA receptor encephalitis starting up. There's clinical trials in MOG antibody-associated disease. And I think we're going to see that as we move forward, that these treatment trials will come and we'll be able to help our patients better with proven treatments that we know work, rather than a history of we would just use five days of steroids and then we didn't know exactly what to do in the long term - and we could manage some of the relapse as well, but we couldn't really take care of the disease in the background - so, I think the NMO is a good model for moving forward, and the pharmaceutical companies are supporting moving forward with different trials for the disease.   Dr Jones: So, a key message there is understanding the biology so we can be a little more targeted and less indiscriminate in the immunomodulation we're going to use. And we have parallels to that in the neuromuscular world, right, like using B-cell depletion for MuSK-associated neuromuscular junction disorders, as opposed to the trial-and-error approach, right? That's got to be a little more patient-centric and you get to a therapeutic response faster, right?   Dr Flanagan: I think so. Yeah, and I think, in the future, that might be something where, you know, a different patient, if they had elevated cytokines that pointed more to an IL-6 elevation, then maybe, in that patient, you would target IL-6, while the next patient with the same disease has more prominent complement activation, maybe you would target complement, or another patient has more prominent B-cell markers elevated, that you would target B cells. So, I think, we're really moving towards a more individualized treatment in some of these disorders. So, it's a very exciting time, but we've only really made that breakthrough in one of the antibodies, and we have probably sixty, seventy antibody-mediated disorders now. So, it's going to get complicated, but it's also going to be, really, an exciting time for our patients, and I think an exciting time for neurology trainees and people who see patients in practice that we can now make diagnoses and guide their treatment that, previously, you know, these patients were told they might have presumed infectious encephalitis or we didn't know the exact cause.   Dr Jones: So targeted not only to the diagnosis, but to the individual.   Dr Flanagan: Yeah.   Dr Jones: So, that's a level of complexity that I think is going to blow a lot of our minds, right? And it's exciting, but I think it also is a little daunting, right?   Dr Flanagan: Absolutely. Yeah. Yeah, it's going to be complicated, and these are rare diseases, so they're difficult to do clinical trials in. But I think we can be guided, and our experience tells us that if you follow the mechanisms, that you can find targeted treatments. Now, you can also find targeted treatments in MS - you know, it took us a longer time to find successful high-efficacy treatments, but now we're doing much better with many high-efficacy treatments available. But, I think in these autoantibody-mediated diseases, really looking at the mechanisms and trying to figure out that and then targeting the treatment in that direction makes the most sense and is the most likely to be successful.   Dr Jones: So, one of the purposes of Continuum is to educate our readers and our listeners, and because neurology is so broad, because it is evolving so quickly,   it's really hard to stay current. And so, again, that's part of the purpose of the journal. I think one of the challenging areas is autoimmune neurology, because it changes fast, and it's complicated, and the treatments are high stakes and complicated to administer - so, I think this is an important topic. I know from my own experience in clinical practice, one of the challenging scenarios is you see   a patient who may have an autoimmune neurological disorder, you obtain some serum or CSF markers of neurologic autoimmunity, right? And of the ten antibodies you check, one of them comes back, and it's a low titer-positive antibody. I know that's something that you get a lot of questions about. How do you approach that?     Dr Flanagan: Yeah, I think, you know, we're all neurologists, and, you know, it's immediately back to the history, the examination, and the investigations, and what do they support - so, are you really dealing with an antibody-mediated disorder? And I think, from a neuroimmunology laboratory standpoint, we're always trying to get better tests, remove those less-specific tests (so, move away from the thyroid peroxidase antibodies) and really hone in on the exact targets and their mechanisms. So, I suppose, when you find a low-positive result, it's really important to go back to that clinical. And, I think, you know, that is job security for neurologists, right? Because you really have to interpret these in context. And, I think when you're seeing autoimmune cases, you need to have a good, broad understanding of differential diagnosis, because there are many different disorders that can present in a similar way, and you don't want to get distracted by that low-positive antibody and then put a patient on long-term immunosuppression that has many different risks. So, there is a potential for misdiagnosis, and I think that's an emerging area that we're recognizing that we always have to put the antibodies into clinical context. And, you know, there are more and more studies coming out that will help guide you, and I think the issue in Continuum will help guide you in terms of your understanding of, you know, what does a positive antibody mean? And it'll give a little bit on the methodology of how the antibodies are tested and how that can help you – or, sometimes, be it the titer may be very high that can help you. So, different aspects of the antibody test results can also help guide you in the likelihood of that being kind of a true positive versus a false positive. But I think always back to the history, exam, and the investigations, too.   Dr Jones: You're being very gracious there, and I'm glad you bring it up that it's really not just about the laboratory performance of the test, right? It's about the pretest probability of the clinical syndrome if it doesn't clinically resemble an autoimmune neurological disorder. So, I'm not going to pretend to be an expert in Bayesian statistics, but I think we should recognize that if we obtain any test when there's a low likelihood of the syndrome or the diagnosis being present, we're more likely to have false positives than in other scenarios or other settings. So, I think that is a charge to the clinician, where if we are obtaining these tests, we do really need to think about the likelihood of there being a clinical autoimmune neurology syndrome, right?   Dr Flanagan: That's exactly right. You know, one of the teachings that I sometimes give to the trainees is that, you know, if you have a ninety-year-old patient with mild cognitive impairment who comes into the emergency department with some worsened altered mental status, you know, you want to check for a urinary tract infection, you want to check a chest x-ray - you don't want to test neural antibodies upfront. So, you always have to consider the setting and avoid overtesting, because like any test, they're not perfect, and you can run into trouble if you order it too frequently - so, that's another thing that we try to educate people. And then if you do order the test, we like to educate people on, you know, what the positive test results mean, and is there any potential for false positives like we talked about?   Dr Jones: And I think, keeping in mind - obviously, there are exceptions - but the subacute onset of multifocal neurological disorder is really suggestive of autoimmunity. It doesn't mean that it can't happen in other contexts. And it has been exciting not only on the diagnostic side, but on the therapeutic side. There are so many exciting new treatments. What do you think is on the horizon beyond what we've seen in the last few years with small- and large-molecule therapies for these disorders?     Dr Flanagan: Yeah, I think there's new things. You know, people are always looking at different approaches. So, for example, there's a lot of interest in tolerance, and is there a way you could tolerize yourself out of some of these autoimmune conditions? There's a lot of work on CAR-T treatments, looking particularly in the field of lupus and other systemic autoimmune diseases, and I suspect that they will also be applied to autoimmune neurologic conditions. And then the other thing to mention is that we're seeing the more frequent use of immune checkpoint inhibitors in patients with lots of different types of cancers, including neuroendocrine tumor. So I think, in the future, everybody's going to have to learn about autoimmune neurology, because we're going to be seeing these patients more often, because there's going to be more neurologic immune-related adverse effects related to those immune checkpoint inhibitor treatments – so, I think we're going to continue to see autoimmune neurologic disorders pop up. And, you know, the immune checkpoint inhibitors are almost real-world laboratory experiments, because you're ramping up the immune system, and you can trigger many different types of autoimmune conditions. We're actually learning a lot from these patients that can help us in the way we diagnose and the way we treat these patients in the future, but I will say that, sometimes, they can cause a challenge, because some of these patients have difficult-to-control cancer - you need to up their immune system, but then they get autoimmune complications. We try and dampen down the immune system, and then we need to kind of ramp it back up to treat the cancer. And we've had some challenges where managing such cases can be difficult with that balance of cancer-directed immunotherapy versus immune-related adverse events, and, sometimes, that can pose a challenge for autoimmune neurologists when we see these patients.   Dr Jones: So, those are challenges, and I imagine it's a challenging and often rewarding field. What is the most rewarding thing about caring for patients with autoimmune neurological disorders?     Dr Flanagan: I think it's a few things. You know, one is that it's a multidisciplinary area,   so many of these patients will have different subspecialties of neurology involved. So, we'll get to work with our colleagues, and we may work with our oncology colleagues, we work with our ophthalmologist, and we work with our physical medicine and rehab team – so, it's a real team approach to help the patient. So, that's one aspect that's very enjoyable, because everybody needs to work together. And then, you know, these are treatable conditions. So we can have patients who are in the intensive care unit - you know, quadriplegic, in a coma - and then we treat them, we see them back, and they can be back close to normal. So, particularly, with some of these antibodies that target the cell-surface receptors (like NMDA receptor encephalitis, MOG antibodies), these patients can really go from being really, really sick in the ICU to coming back to normal – so, that's very satisfying, and much of that is related to the improvements we have in treatments, and then we can manage them in the long term with some of these newer treatments that are coming along for these diseases. So, I think it's a very exciting area and exciting time for our patients with these disorders, and we're getting more and more clinical trials, so we're hoping that we'll have more and more treatments available into the future.   Dr Jones: I think that has to be part of why the interest in autoimmune neurology has grown so much. I know as an educator - I hear this a lot from trainees - you know, the level of interest in MS and autoimmune neurology has really only grown over time. It must be because of better understanding of the pathobiology of disease, better treatment options, and something that our listeners may not know. Not only is Dr Flanagan an expert in autoimmune neurology - he's very well trained, he did fellowship in MS and autoimmune neurology, and behavioral neurology, right?   Dr Flanagan: That's correct. Yeah. Yeah.   Dr Jones: And, you know, it's going to sound like I'm trying to flatter Eoin here, but I'm really not (this is going to lead to a question). Eoin is, you know, very well recognized for his work in autoimmune neurology and discovery in this area. Uh, he happens to be one of the best doctors I know. And Eoin, you've won the Teacher of the Year Award several times. So, for our listeners who are looking into their careers and trying to manage multiple areas of interest, how do you do it? You do so many different things so well.   Dr Flanagan: Well, you know, I'm lucky to have had the opportunity to work here at the Mayo Clinic and in the neuroimmunology lab. So, we have a lot of resources, and it's an exciting area, you know? We need to bring up the next generation of leaders, so we need to be enthusiastic about these conditions, and we really can do a lot for these patients. So I think when I cover on the hospital service - you work with the residents or work with the fellows and clinic - you know, these cases (when they come around) are really enjoyable to see you can get an answer, we can figure out what type of treatment to do, and we can really help these patients. So, I think that makes it a very exciting area and an easy area to teach residents and to convey some of the excitement that's happening in the field. So, it's just a great honor to be able to work with trainees to kind of let them know the field. And, you know, there's more and more fellowship opportunities in different centers in neuroimmunology, and I think more residents are becoming interested in the field of autoimmune neurology because of so much happening. But, in saying that, with these challenges, it's very hard to keep up with all these antibodies - I find it hard. There's 70 different antibodies - it's hard to know every single thing about every single one. So, we need to continue to educate, to try and simplify, to try and help our younger people be able to manage these patients, because no matter who it is in neurology, you're going to encounter these patients - if you cover the hospital, if you see regular patients in clinic, if you do consult service, you'll come across these patients - and we're going to see them more and more with immune checkpoint inhibitors and other treatments coming along. So, I think it's an exciting area, and it's an important area for everyone to be aware of. So, it's just a great pleasure to be able to be involved in the field and see such enthusiasm in junior people.   Dr Jones: So, in addition to doing all those things well, you're also very humble. So, that's a great answer, and I think it is important - even though these are collectively rare - the opportunity to treat these patients and have wonderful outcomes is great, and I think the ability to recognize and feel comfortable. And, hopefully, Continuum has a place in that. I think your issue, Dr Flanagan, is a stellar issue and, uh, will be a benchmark for a generation of neurologists and how to approach these disorders. So, I want to thank you for being our Guest Editor for that topic and joining us today for such a thorough and fascinating discussion on autoimmune neurology.   Dr Flanagan: Thanks so much. And thank you to the Continuum team for highlighting autoimmune neurology. It's an exciting field, and I think, really, there is a great group of authors that cover neuroimmunology comprehensively, and I think, hopefully, people will enjoy the edition.   Dr Jones: Again, we've been speaking with Dr Eoin Flanagan, Guest Editor for Continuum's most recent issue on autoimmune neurology. Please check it out. And thank you to our listeners for joining today.     Dr Monteith: This is doctor Teshamae Monteith, Associate Editor of Continuum Audio.   If you've enjoyed this episode, you'll love the journal, which is full of in-depth   and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Arovella Therapeutics Ltd (ASX:ALA) CEO and managing director Dr Michael Baker joins Proactive to recap a busy quarter of development for the biotech company, which is focused on developing its invariant Natural Killer T (iNKT) cell therapy platform for cancer treatment. During the quarter, Arovella finalised a clinic-ready manufacturing process for ALA-101 and the CAR-iNKT cell platform at Cell Therapies Pty Ltd. This semi-automated process, crucial for large-scale Good Manufacturing Practice (GMP) production, ensures a high yield and purity of CAR-positive iNKT cells. The process is designed to be reproducible and aligns with regulatory expectations, enhancing the product's potential for approval and reducing technology transfer risks. Key milestones expected in the next 12 months include manufacturing clinical batches of ALA-101, securing regulatory acceptance for Phase 1 clinical trials in CD19-positive blood cancers, and presenting preclinical data for gastric cancer and IL-12-TM programs. The company holds $12.7 million in funding as of 30 June 2024, ensuring financial stability to obtain preliminary data in its planned first-in-human trials. Arovella's preparations for its Phase 1 clinical trial to treat CD19-positive blood cancers include the recent presentation of preclinical data at the AACR Annual Meeting, detailing the distinct phenotypes and cytotoxic abilities of CD4+ and CD4- CAR-iNKT cells. The company also strengthened its team with notable appointments, including Dr Michelle Ferguson and Dr Kelvin Yip, and added Professor Gianpietro Dotti to its Scientific Advisory Board. #ProactiveInvestors #ArovellaTherapeutics, #ASX #ALA #CancerTreatment, #iNKTCellTherapy, #ClinicalTrials, #ALA101, #CARiNKT, #GMPManufacturing, #CD19, #FDAApproval, #BiotechNews, #CellTherapy, #Immunotherapy, #PreclinicalData, #AACR, #BloodCancer #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews

Visit learnAMAstyle.com for free downloads in writing in medicine and the life sciences.    The FDA has approved blinatumomab (Blincyto) for treating adult and pediatric patients one month or older with CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) in the consolidation phase. This bispecific T-cell engager (BiTE®) therapy targets CD19 surface antigens on B cells, allowing T cells to recognize and eliminate malignant B cells. The approval was based on the Phase 3 E1910 trial showing improved overall survival with blinatumomab plus chemotherapy compared to chemotherapy alone.   The FDA has approved roflumilast cream 0.15% (Zorvye) for treating mild to moderate atopic dermatitis (AD) in patients aged 6 years and older. This steroid-free, once-daily topical treatment is a selective, highly potent phosphodiesterase 4 (PDE4) inhibitor designed for long-term disease control. The approval was based on phase 3 studies showing significant improvements in disease clearance, itch reduction, and overall skin condition compared to the vehicle group.   The FDA has approved a new 6mg single-dose prefilled syringe for faricimab-svoa (Vabysmo), facilitating easier administration for neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO). Faricimab-svoa is a VEGF and Ang-2 inhibitor, now available in a ready-to-use format. This approval provides an alternative to the existing single-dose vial and is granted to Genentech.   The FDA is set to decide on OX124, a high-dose naloxone nasal rescue medication designed to reverse opioid overdoses, with the PDUFA date set for July 15, 2024. Developed by Orexo, OX124 offers rapid absorption, high bioavailability, and enhanced stability, addressing the critical need for potent rescue medications due to the high rate of synthetic opioid overdoses. If approved, OX124's launch is anticipated later in 2024.   The FDA accepted an NDA for vonoprazan (Voquezna) tablets for treating heartburn associated with Non-Erosive gastroesophageal reflux disease (GERD) in adults, with the PDUFA date set for July 19, 2024. Vonoprazan is a potassium-competitive acid blocker (PCAB) offering an alternative to traditional proton pump inhibitors (PPIs). Non-Erosive GERD, affecting 38 million U.S. adults, is characterized by reflux-related symptoms without esophageal mucosal erosions, impacting quality of life with symptoms like heartburn and chest pain.  

Drs. John Sweetenham and Shaji Kumar discuss the emergence of CAR T-cell therapy for multiple myeloma, its benefits and challenges for patients, and its potential role earlier in the treatment of disease. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Multiple myeloma is the second most common hematologic malignancy, and the American Cancer Society estimates that there will be more than 35,000 new cases of the disease diagnosed in the United States this year. The emergence of several novel therapies over the last decade has transformed the therapeutic landscape for multiple myeloma, and chimeric antigen receptor – or CAR T-cell therapy – is one of the newest treatments for this disease, which has created a great deal of buzz.  Dr. Shaji Kumar is an internationally renowned investigator of novel therapeutics and next-generation treatment options for patients with multiple myeloma, and I'm delighted to welcome him to the podcast today to discuss innovations in CAR T-cell therapy in this space. Dr. Kumar is a professor of medicine and chair of the Myeloma Group, as well as chair of research in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota. He is also the editor-in-chief of The Hematologist.  You'll find our full disclosures available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Shaji, it's great to have you on the podcast today. Dr. Shaji Kumar: Thanks, John. Dr. John Sweetenham: Shaji, to begin with, maybe we could ask you for an overview of where CAR T-cell therapy sits in multiple myeloma right now. We know that CAR T-cell therapy has improved the survival for some patients with myeloma in recent years. But of course, relapse still remains a problem. Can you tell us a little about the therapies that are currently approved for multiple myeloma in the CAR T-cell space, and what are the potential benefits and challenges of these products? Dr. Shaji Kumar: Absolutely. It has been a revolution, I think, in terms of therapies for multiple myeloma during the past decade. We have seen so many new treatments approved for myeloma, and consequently, the survival of patients with myeloma has significantly improved. Two decades ago, we used to tell patients a median survival of 3 years, and today we tell patients a median survival of 8 to 10 years, a number that is continuing to go up. And it is all because of the new treatments that have become available for patients, especially over the past decade, and CAR T-cell therapy has been a game changer.   Now, the main treatments that we were relying on for the past 2 decades have been the immunomodulatory drugs, the proteasome inhibitors, and more recently, the anti-CD38 monoclonal antibodies. Unfortunately, what we see in the clinic is that patients go through these therapies and various combinations of these agents, and often over the 6 to 10 years after the diagnosis, they often become refractory to these drugs. And then we are left with very few choices, if any, for controlling the disease. And that's where the CAR T cells have really made an impact.  Over the past several years, clinical trials have shown that CAR T-cell therapy is highly effective. In fact, when we look at the initial trials that have been done in this space, the majority of these CAR T cells have been targeted towards what we call BCMA, or a B-cell maturation antigen that is present on both normal and abnormal plasma cells. Now, the concept of CAR T cells has been around for a while, and we have already seen success in other hematological malignancies, but it has been a little late compared to the other diseases in terms of its arrival in the myeloma field. But over the past few years, we have seen some dramatic progress. We currently have two different CAR T cells that are approved and available in the clinic. We have idecabtagene vicleucel (ide-cel) and also ciltacabtagene which is also called cilta-cel. Both of these CAR T cells are targeted towards BCMA.   In the early trials conducted with both of these CAR T cells, we've seen patients who have become refractory to all the available therapies, and now upwards of 90% of these patients are responding to these CAR T cells. We are now seeing responses that we had typically not seen previously in any of the other therapies – not only the high response rates but also the depth of response. What we are seeing is a significant number of these patients – nearly half – of these patients can actually be minimal residual disease (MRD)-negative in the bone marrow after the CAR T-cell therapy. And this is clearly unprecedented in this myeloma space. Now, the approval for both these CAR T cells has been based on the experience in patients who have become refractory to the currently available therapies. And the ‘line in the sand' that the FDA has drawn for approval for these drugs has been at least 4 prior therapies. In those patients, when you look at the studies that have been done both for the ide-cel and the cilta-cel, it clearly demonstrates the advantages. And we can look at the data that's available in 3 groups. So we have the single-arm studies, the early phase I and phase 2 trials that have been done with both these CAR T cells. For ide-cel, we have the KarMMa trial, and for the cilta-cel, we have the CARTITUDE trials. In the initial studies, as I previously mentioned, we are seeing responses upwards of 90%, and we are seeing disease control that is lasting at least a year or more with these CAR T cells.   Now, of course, the question is, we do need randomized phase 3 trials to demonstrate that this is indeed true. Even before the phase 3 trials came along, there have been multiple case-control studies that have been done where the outcomes of patients getting these CAR T cells were compared to real-world controls or cohorts of patients who did not get these therapies. And these studies demonstrated that the outcomes of patients getting CAR T cells were significantly better than what has been shown in the real-world controlled population. And then finally, we have, of course, the phase 3 trials that have read out in patients with relapsed myeloma, in fact, in a group of patients in an earlier stage of the disease than who were studied in those single-arm studies. Now, based on the results from the single-arm studies, we got the approval from the FDA for the use of CAR T cells in this late stage of the disease. And with the phase 3 trials that have read out, both the KarMMa-3 trial and the CARTITUDE-4 trial again clearly demonstrate that these CAR T cells are much more effective than what we would have seen with the conventional therapies if those patients were assigned to those treatments. Now, clearly, it's not only a question of efficacy. We also know that they do come with some toxicities, and we have a good sense of the toxicities from those initial phase I and phase 2 trials. Now, as we have seen with the other diseases, the 2 major categories of toxicities that we see are the cytokine release syndrome and the neurological toxicity associated with CAR T-cell therapy.  In terms of the clinical features and the presentations, they are not different than what we have seen with the CAR T cells used in other hematological malignancies, but we do see different frequencies of these in the myeloma patient population. The cytokine release syndrome is something that is seen in a majority of the patients, at least in the lower grades. And over the time since we have been using CAR T-cell therapy, I think we have all become a lot more familiar with the management of the cytokine release syndrome, and we have very effective therapies to manage, and to some extent, maybe even prevent the onset of the cytokine release syndrome in patients undergoing CAR T-cell therapy.  The neurological toxicity is another toxicity that is unique to these immunological therapies, known as the ICANS, or the immune cell effector-associated neurological syndromes. And these, again, thankfully, are much less frequent than what we see with the cytokine release syndrome. But even with the ICANS and other neurological toxicities associated with CAR T-cell therapy, we have a better understanding of the biology behind it, and we also have better modalities to monitor the patients for these toxicities and intervene in an appropriate and timely manner to take care of them.  In addition to the ICANS and the cytokine release syndrome, we certainly do see other toxicities as well. We do see hematological toxicities, which are common for many of the treatments we use for hematological malignancies. Thankfully, these other toxicities can be easily managed. They often reverse themselves over time and haven't really posed any major hurdles in terms of the utilization of these modalities of therapy for patients with myeloma. Dr. John Sweetenham: Okay, that's great. Thank you very much, Shaji. I'll return to some of the potential late effects of CAR T-cell therapy in a moment. But before we get to that, as you know, in other hematologic malignancies, there has been a trend in recent years to moving CAR T-cell therapy further up the therapeutic algorithm, as it were. So there is consideration being given to using this as a first-line or second-line therapy. Do you think there is a potential role for CAR T cell earlier in the treatment of multiple myeloma? For example, could you see a time when it may be used as second-line treatment for this disease? Dr. Shaji Kumar: Absolutely. I think that's a very good point. And I think, just as with other cancers and as with myeloma, too, with many of the therapies we use for myeloma in the newly diagnosed setting or the time of first relapse, were all initially tested in these later relapses. We are following the same script even for the CAR T cells. In fact, the 2 phase 3 trials, the KarMMa-3 trial and the CARTITUDE-4 trial, enrolled patients in the earlier lines of therapy, either 1 prior line or 2 prior lines for these trials. And what we have seen with both phase 3 trials is that the outcomes, both the progression-free survival outcomes and the response rates, are significantly better compared to the standard-of-care therapies that these patients would have otherwise received.  Now, what is unclear at this point is, does every patient at the time of the first relapse need a CAR T-cell therapy, or can we be more selective in terms of deciding which particular subgroup of patients can benefit more from this CAR T-cell therapy in different lines or different relapses? The bottom line is, I think the data that we have right now clearly points towards the utility of CAR T-cell therapy at earlier lines of treatment. The question now is, which patients do we need to do at which stage? In fact, when you look at the newly diagnosed setting, there are ongoing clinical trials that are looking at replacing autologous stem cell transplant with CAR T-cell therapy. Those phase 3 trials are currently enrolling where patients are being randomized to either the autologous stem cell transplant, which is considered a standard of care for eligible patients, or giving them a CAR T-cell therapy. Similarly, even in transplant-ineligible patients, trials are exploring the possibility of using CAR T-cell therapy instead of giving patients a prolonged course of maintenance and consolidation.  One of the beauties with the CAR T-cell therapy right now is that it's a one-time treatment. You get the treatment and you do not get any additional therapies after that. It's a protocol that is being debated – whether we will need maintenance therapies after CAR T-cell therapy, but I think that is something that will have to be explored in the context of clinical trials. But certainly, I think over the next 5 years, we will see the CAR T-cell therapy moving to earlier and earlier lines of therapy. My guess is in 5 years, there will be a subset of patients where we would offer them CAR T-cell as part of the first-line therapy, some others, maybe based on disease and patient characteristics, we might use it at the time of first or second relapse.   Dr. John Sweetenham: Great, thank you. Just to return to toxicities and some of the potential late effects. As you know, last November, the FDA launched an investigation to determine whether CAR T-cell therapy can, in rare cases, cause secondary cancers. You may remember that this was in response to reports of T-cell malignancies in patients who had received various types of CAR T-cell immunotherapies. The FDA determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies. Could you care to comment on this whether you have seen any evidence of this in your own work, and whether the events and the FDA investigation have impacted your clinical research or your clinical practice in any way in terms of patient monitoring or maybe in terms of trial approval? Dr. Shaji Kumar: This has been an important observation. As with all new therapies, whenever the question of long-term toxicities is brought up, especially second malignancies, it is something that needs to be looked into very carefully, and I think the FDA is doing exactly that. There have been reports of second cancers, particularly T-cell cancers. In fact, there were some statements that came out recently from the FDA where they commented on the fact that they had seen 22 cases of T-cell cancers by the end of 2023. And, in fact, in 3 of those cases where genetic sequencing was performed, they did notice that the genetic material or the chimeric antigen receptor was inserted into these cancer cells as part of the process. So I think there is a lot more work that needs to be done in terms of understanding the mechanism and probably also understanding how prevalent these instances are.  But I think, based on what we know as of now, these cases form a very tiny fraction of the total number of CAR T-cell therapies that have been used in patients with lymphoma and myeloma. In our own day-to-day practice, this has not really affected how we view this therapy. It clearly has made a significant impact for patients with no other treatment options. So in our daily practice, we continue to use CAR T-cell therapy as we have done before these reports came out. But we do inform patients about the risk and what we know about the risk of these T-cell malignancies.   In addition to T-cell malignancies, there have also been reports of myelodysplastic syndromes in patients undergoing CAR T-cell therapy. Again, it is important to remember that, at least in the myeloma setting, many of these patients have had multiple lines of therapy, often with drugs that can cause second malignancies, particularly myelodysplastic syndrome. So I think a lot more work needs to be done in terms of understanding what is the direct impact of CAR T-cell therapy versus what was lurking underneath because of the treatments that these patients had previously received. So I think it is important for us to continue to be very diligent, as with any new therapies that we introduce for the treatment of our patients. But at the same time, understand that, in the context of the benefits that these therapies bring to our patients, especially when they have no other treatment options.  Dr. John Sweetenham: Absolutely. So, at least for now, and probably in the longer term, the benefits of the therapy certainly appear to outweigh the risks, although it is important not to underestimate or minimize those risks.   I wanted to change direction a little bit and talk a little bit in the final question about care disparities and CAR T cell. Of course, CAR T-cell therapy is typically offered at large cancer centers and is very expensive. This means that there are issues of access to treatment. In addition, the literature shows us that non-Hispanic Black individuals are twice as likely to develop multiple myeloma compared to their White counterparts. Furthermore, at least right now, Black patients are less likely to receive these novel CAR T-cell therapies and continue to be underrepresented in clinical trials. So, this is a big, complex question, but can you talk a little bit about how outcomes differ between racial and ethnic groups who actually receive CAR T-cell therapy for multiple myeloma? And could you address what you think are the most appropriate strategies for minimizing the disparities in access? Dr. Shaji Kumar: That's a very, very important question, particularly in the context of multiple myeloma, where African American individuals are at a higher risk of getting plasma cell malignancies. I think we need to think about this in the context of what we know about disparities even before the CAR T cell came along. There has been a good amount of literature that has looked at the outcomes based on the types of therapies that could be impacted by this. There have been studies that have looked at cooperative group trials, which often have a good representation of minorities and have shown that if patients have equal access to advanced therapies that we have, their outcomes are comparable or sometimes even better for African American patients compared to Caucasian patients. So I think it's very important that the treatment strategies that we develop are equally accessible to everyone.  In terms of CAR T-cell therapy or immunotherapies, I don't think we have any concrete evidence to suggest that there is any difference in outcomes. And I think it's reasonable to assume that if patients are exposed to similar therapies, they will have similar outcomes, even in the context of immunotherapies. But at the same time, I think we must continue to study this diligently, and the only way to do that is to ensure that clinical trials include patients reflective of society in general. This will allow us to understand if any differences exist. In addition, I think there is a serious risk that with these expensive therapies, this gap can only widen. And I think that is one reason that we must be proactive, particularly with therapies like CAR T-cell therapy, which not only are expensive but also require quite a bit of logistical support for patients to go to larger centers to get these therapies, stay around these larger centers for upwards of a couple of months, which means they are living outside of their usual societal structure, and ensure there is access to the resources that are needed to enable them to do that. So I think there is a lot that is still unknown, but I think we really need to be proactive in ensuring equal access to these therapies. Dr. John Sweetenham: Yes. Thanks for a very thoughtful response to that question, also for the work that you are obviously doing to help address this extremely important issue.  I'd like to thank you for sharing your insights with us today and for the extraordinary work that you're doing and your team are doing to advance care for patients with multiple myeloma. Dr. Shaji Kumar: Thank you, John. Dr. John Sweetenham: And thank you also to our listeners for joining us today. If you value the insights 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 inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements do not necessarily reflect the opinions of ASCO. Mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's guest:    Dr. Shaji Kumar @myelomaMD   Follow ASCO on social media:       @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:      Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness     Dr. Shaji Kumar: Consulting or Advisory Role: Takeda, Janssen Oncology, Genentech/Roche, Abbvie, Bristol-Myers Squibb/Celgene, Pfizer, Regeneron, Sanofi, K36 Research Funding (Inst.): Takeda, Abbvie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, Carsgen Therapeutics Ltd., Allogene Therapeutics, GlaxoSmithKline, Regeneron, Bristol-Myers Squibb/Celgene Travel, Accommodations, Expenses: Abbvie, Pfizer

輕食新時尚 我的新感覺 無論是濃情蜜意的甜美滋味-草莓夾心、可可夾心、花生夾心- 還是清爽不膩、經典鹹口味的雞蛋沙拉、鮪魚沙拉 新感覺隨時都能滿足味蕾，給你全新輕食選項 每一天都散發優雅時尚、自信向前 https://bit.ly/49es7mF -- 【00941】全台首檔鎖定半導體上游設備與材料廠的ETF，2/26稱王募集！ 半導體不是只有護國神山，想投資真正的隱形英雄，力爭「上游」就對了！中信上游半導體(00941)，帶你與科技王者中的王者同行：https://bit.ly/3Umqe2r －－－－以上訊息由 SoundOn 動態廣告贊助商提供－－－－ 飛碟聯播網《飛碟早餐 唐湘龍時間》2024.02.20 週二醫療保健單元 潘懷宗的醫學新知時間 《令人興奮！比化療友善的兒童抗血癌新藥出現》 英國倫敦「奧蒙德街醫院」 (Great Ormond Street Hospital；GOSH) 的醫生們領導完成一項在英國和愛爾蘭20多個中心的臨床試驗，近期公布了令人振奮與滿意的結果。此試驗是針對患有B急性淋巴細胞白血病(B-Acute Lymphoblastic Leukaemia；B-ALL)的兒童，在接受「引導性化學治療」後，若產生嚴重的副作用，就可以改用免疫治療新藥---百利妥注射劑(Blincyto；有效成分blinatumomab)，後期再合併其他治療，讓整個療程更加溫和友善。目前，此治療新藥在台灣，健保給付「治療無效」和「已復發」的B-ALL兒童病患，但從這次英國的試驗結果，等於是證明此藥的使用時機，可以考慮再往前擴大到第一階段就能使用。 這款免疫藥物，其副作用遠遠低於現階段所使用的化療藥物，因為此藥只針對癌細胞進行死亡狩獵，一般健康的細胞則不受影響。百利妥注射劑的藥物作用原理如圖1所示，它有兩隻手，第一隻手可以抓住血癌細胞的特異部分CD19，讓癌細胞無法逃走，另一隻手則是抓住殺手T細胞上面的特異部位CD3，亦即是把血癌細胞抓住後，同時吸引殺手T細胞過來將其殺死。英國病童家長稱這種療法為“一束溫暖的陽光”照進了難過黑暗的心靈，此藥除了有效，能讓病情緩解外，更重要的是，這款藥物的治療，不需要在醫院裡面進行，可以在任何場合，像是在家裡、在學校或者是在公園。 ▶ 《飛碟早餐》FB粉絲團 https://www.facebook.com/ufobreakfast/ ▶ 飛碟聯播網FB粉絲團 https://www.facebook.com/ufonetwork921/ ▶ 網路線上收聽 http://www.uforadio.com.tw ▶ 飛碟APP，讓你收聽零距離 IOS：https://reurl.cc/3jYQMV Android：https://reurl.cc/5GpNbR ▶ 飛碟Podcast SoundOn : https://bit.ly/30Ia8Ti Apple Podcasts : https://apple.co/3jFpP6x Spotify : https://spoti.fi/2CPzneD Google 播客：https://bit.ly/3gCTb3G KKBOX：https://reurl.cc/MZR0K4

ChatGPT4 in medical writing and editing at learnAMAstyle.com Nascentmc.com for medical writing assistance for your company. Visit nascentmc.com/podcast for full show notes Tricuspid Valve Replacement System for Tricuspid Regurgitation The FDA approved the Evoque tricuspid valve replacement system, a first in the U.S. for a transcatheter tricuspid device, after the TRISCEND II trial showed significant improvements in TR grade and patient symptoms. TR, where the heart's valve does not close properly causing blood backflow, can now be treated with this device, which also received CE Mark approval in Europe and is produced by Edwards Lifesciences. Afami-Cel for Synovial Sarcoma The FDA is prioritizing the review of afamitresgene autoleucel (afami-cel) for advanced synovial sarcoma, based on positive results from the SPEARHEAD-1 trial showing a 39% response rate and increased survival rates. Afami-cel targets MAGE-A4 in synovial sarcoma, a rare soft tissue sarcoma, offering a new treatment option for this aggressive disease. It's manufactured by Adaptimmune Therapeutics with a decision expected by August 4, 2024.  Pulsed Field Ablation for Atrial Fibrillation Boston Scientific's FARAPULSE PFA System has been FDA approved for treating intermittent atrial fibrillation, offering a non-thermal, tissue-selective ablation alternative with proven safety and efficacy. The approval was based on the ADVENT study and real-world data, highlighting shorter ablation times and no severe side effects. Boston Scientific plans an immediate U.S. launch. Shorter Turnaround Time for Axi-cel The FDA approved a manufacturing process change for axi-cel (Yescarta), reducing delivery time from 16 to 14 days, which is a CD19-directed CAR T-cell therapy for certain lymphomas. This change, granted to Kite, a Gilead Sciences subsidiary, aims to improve treatment accessibility by offering faster delivery of this personalized therapy. AI Algorithm for Cervical Cancer Screening Hologic's Genius™ Digital Diagnostics System with the Genius™ Cervical AI algorithm has been FDA approved, introducing the first digital cytology platform integrating AI for cervical cancer screening. This system digitizes traditional Pap test slides, applying AI to enhance detection of pre-cancerous and cancerous cells, improving sensitivity and enabling remote case review. It will be available in the U.S. in early 2024. Trastuzumab Deruxtecan for Solid Tumors The FDA granted priority review to trastuzumab deruxtecan for treating unresectable or metastatic HER2-positive solid tumors, potentially marking it as the first HER2-directed, tumor-agnostic therapy. Based on the DESTINY-PanTumor02 study, showing promising survival outcomes, a decision is expected in the second quarter of 2024. The drug is developed by AstraZeneca and Daiichi Sankyo.  

Last week, we saw some big headlines in the oncology space, from Dexter Scott King's death from prostate cancer and MLB Hall-of-Famer Ryne Sandberg announcing that he was diagnosed with the disease.  The FDA also requested a label update for CAR-T cell therapies that would warn patients and providers about secondary malignancies that have been reported from the treatment. Also, we took a look at laughter therapy, and how it could help patients and caregivers.  We've also been busy covering two conferences — ASCO's Gastrointestinal Cancers Symposium, as well as their Genitourinary Cancers Symposium, so tune in later this week for a special podcast episode highlighting some major research from those events.  Dexter Scott King Dies of Prostate Cancer, Ryne Sandberg Diagnosed With the Disease Last Monday, Jan. 22, we saw two big stories in the prostate cancer space. First, Dexter Scott King, the son of the Civil Rights activist, Martin Luther King, Jr., died of prostate cancer. He was 62 years old.  At the time of his death, King was the Chairman of the King Center, which is an organization focused on educating the world about the life and legacy of Dr. Martin Luther King Jr. Dexter Scott King was also the president of the King estate.  In a statement announcing King's death, his wife, Leah Weber said, “He transitioned peacefully in his sleep at home with me in Malibu. He gave it everything and battled this terrible disease until the end.”  And on the same day Dexter Scott King died, Major League Baseball Hall-of-Famer, Ryne Sandberg, announced that he was diagnosed with metastatic prostate cancer.  The 64-year-old — who was a 10-time All Star during his tenure for the Chicago Cubs, which ran from 1982 to 1997 — announced his diagnosis on Instagram. He said that received the diagnosis a week earlier and has started treatment. He asked that fans keep him in their thoughts and prayers.  FDA Requests Warnings on CAR-T Cell Therapies, Citing Secondary Cancers The investigation into CAR-T cell therapies continues. Recently, the Food and Drug Administration (FDA) requested that approved BCMA- or CD19-targeted CAR-T cell therapies update their labeling to include a warning of reports of T-cell malignancies, including CAR-positive lymphomas, which have been reported in patients who use this type of therapy.  Back in November, the FDA announced that it was investigating reports of secondary diseases in patients who underwent CAR-T cell therapy. The available data shows that these diseases are extremely rare, and researchers are still looking into what, exactly, is causing them.  Now, the FDA wrote letters to the manufacturers of five CAR-T cell therapies, requesting that they include a Boxed Warning — which is the highest safety-related warning for drugs — outlining the potential risks of CAR-T cell products. The companies must respond to the FDA within 30 days of receiving the letters, which were sent out on Jan. 19.  Laughter Therapy May Improve Mood, Decrease Pain in Patients With Cancer And on a much lighter note, we covered recent research showing that laughter therapy can decrease mood disturbances in patients receiving palliative care for late-stage cancer, as well as their loved ones. The findings, which were published in the journal, Cancer Nursing, also found that the laughter therapy reduced pain perception in patients and decreased levels of burnout in caregivers.  Laughter therapy refers to alternative and complementary therapy using humor to help relieve stress and pain, in addition to potentially improving a patient's sense of well-being, according to the National Cancer Institute. In this instance, it consisted of five 20- to 30-minute sessions held over five consecutive days. The participants introduced themselves using funny tools to relieve tension, and moved their bodies in laughing rhythms.  “This indicates that our palliative care patients and family caregivers would have a positive view of the use of laughter or humor in their palliative circumstances,” the researchers wrote.   For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.

Free course ChatGPT4 in medical writing and editing at learnAMAstyle.com ·       Nascentmc.com for medical writing assistance for your company.Visit nascentmc.com/podcast for full show notes Boxed Warning for CAR-T Cell Therapy: The FDA mandates a boxed warning on all CAR T-cell therapies due to increased secondary cancer risks, affecting six named treatments. This follows investigations into T-cell malignancies in patients treated with BCMA- or CD19-directed therapies. Manufacturers have 30 days to comply or challenge this requirement, reflecting the FDA's stance that benefits still outweigh risks.  Dupilumab for Pediatric EOE: The FDA has approved dupilumab for children aged 1-11 with eosinophilic esophagitis (EoE), expanding from its prior approval for older patients. Dupilumab, targeting interleukin-4 and -13, treats EoE, an allergic inflammation causing symptoms like heartburn and difficulty swallowing. The approval, based on the EoE KIDS trial, marks the first FDA-approved EoE treatment for this age group.  Wearable Device for Osteopenia: The FDA has cleared Osteoboost, a wearable belt for treating osteopenia, marking a non-drug medical device approach in this field. Developed by Bone Health Technologies, it uses low-intensity vibrations on the spine and hip, inspired by NASA's bone loss prevention methods. Clinical trials show its effectiveness in maintaining bone health, and it was reviewed under the FDA's De Novo process with Breakthrough Device Designation.  BSI-082 IND for Solid and Liquid Tumors: The FDA approved an IND application for BSI-082, a novel antibody targeting SIRPα and β to enhance tumor-associated macrophages' phagocytic activity. Developed by Biosion USA, Inc., BSI-082 covers over 90% of human populations and avoids broad toxicity typical in CD47-targeting therapies. Its in vivo efficacy, especially when combined with other antibodies, shows significant anti-tumor effects in animal models. VCA-894A for Charcot Marie-Tooth: The FDA approved an IND application for VCA-894A by Vanda Pharmaceuticals to treat Charcot-Marie-Tooth disease, axonal, type 2S (CMT2S). VCA-894A, an antisense oligonucleotide, targets the IGHMBP2 gene variant responsible for CMT2S. CMT2S, a rare condition with symptoms like muscle weakness and sensory impairment, currently has no available treatments; this approval represents a significant step in addressing this genetic disorder. Free course on ChatGPT4 for medical writers and editors learnAMAstyle.com

CME credits: 0.25 Valid until: 28-01-2025 Claim your CME credit at https://reachmd.com/programs/cme/expert-answers-to-common-questions-for-improving-the-road-to-remission-with-car-t-cell-therapies-in-large-b-cell-lymphoma-considerations-for-community-practice/15570/ CD19-directed chimeric antigen receptor (CAR) T-cell therapies are revolutionizing the treatment of aggressive non-Hodgkin lymphoma (NHL), offering patients with refractory/relapsed disease the chance for a potential cure after a single infusion. However, the widespread use of CAR T-cell therapies faces several challenges, from the production of the therapies to the management of toxicities to issues of inpatient vs outpatient administration. While CAR T-cell therapies have historically been given in the inpatient setting, interest in outpatient delivery is growing, and this option may become more feasible if logistical issues and lack of multidisciplinary collaboration between the community provider and the CAR-T cell therapy center can be overcome. AXIS routinely collects and analyzes data gathered from participants in our live activities. These questions provide incredible insight regarding the persistent challenges that clinicians face when trying to optimize treatment and management of patients with cancer, helping to verify where clinical practice gaps exist. This activity will provide expert answers to questions asked during a recent educational series on CAR T-cell therapies in large B-cell lymphoma regarding practical considerations for CAR T-cell therapies. =

In this week's episode we'll discuss the findings from a prospective trial of TCRαβ/CD19-cell depleted HLA-haploidentical transplantation to treat pediatric acute leukemia, learn more about the incidence, clinical characteristics, and survival of malignancy-associated hemophagocytic lymphohistiocytosis in Sweden, and discuss the bone marrow as the primary site of thrombopoiesis. 

In this week's episode we'll explore the role of fibrinogen polymerization in thrombosis. Then, we'll discuss preventing CD19-negative relapse after CAR T-cell therapy in acute lymphoblastic leukemia. Finally, we'll learn how increased levels of the RNA-binding protein FUS has been identified as an effector of hematopoietic stem cell aging. 

At the 2023 American Society of Hematology (ASH) Annual Meeting in San Diego, California, Oncology Data Advisor had the privilege of speaking with many distinguished clinicians and patient advocates about their research presented at the meeting. This podcast series features exclusive conversations on breaking data for novel therapies, technological innovations in hematology/oncology, efforts to reduce disparities and improve health equity, and more!

Drs. John Sweetenham and Fred Locke discuss the FDA investigation on the risk of cancer from CAR T-cell therapy and share insights on the known number of cases and the potential implications on clinical research and patient care. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. CAR T-cell therapies have been game changers for treating certain cancers including lymphomas and leukemias, as well as multiple myeloma, since the vast majority of patients who have received CAR-T do not have other curative options with conventional non-cellular, anti-cancer therapies. But on November 28, the U.S. Food and Drug Administration announced that it is investigating whether CAR T-cell therapy can, in rare cases, cause secondary cancers. The FDA launched the probe after receiving reports from clinical trials and other data sources of T-cell malignancies in patients who received CAR T-cell immunotherapies. Joining me to discuss the investigation and its implications for the field is Dr. Fred Locke, a medical oncologist and translational researcher and a senior member and chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center in Tampa, Florida. Dr. Locke is an internationally renowned clinical research leader in the field of CAR T-cell therapy. You'll find our disclosures in the transcript of this episode, and disclosures of all guests on podcasts are available at asco.org/DNpod. Fred, it's great to have you on the podcast today. Dr. Fred Locke: Thanks, John, I'm really glad to be here. Dr. John Sweetenham: So, T-cells are the backbone of CAR T-cell therapies, and there are currently 6 CAR-T products approved by the FDA. As our listeners will know, CAR T-cell therapies manipulate a patient's T-cells, enabling them to recognize and attack antigens on cancer cells and induce potential long-standing changes in the immune system. In its statement on November 28, the FDA said it determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA- and CD19-directed, genetically modified, autologous CAR T-cell immunotherapies. Fred, could you comment for us on the investigation: How many patients are reported to have developed second malignancies from CAR T-cell therapy, and whether there are likely to be more secondary cancers reported? Dr. Fred Locke: Yes, so the FDA and the reports are coming out that there are 19 cases of T-cell malignancy that we're aware of that have occurred after the current FDA-approved CAR T-cell therapies were administered for the treatment of leukemia, lymphoma, or multiple myeloma. The majority of those cases were reported through the FDA Adverse Event Reporting System. And we don't know a lot of details of those 19 cases. We think that there's probably about 13,000 to 14,000 patients who've been treated with the commercial CAR T-cell therapies. So if you kind of do some crude math, you can come up with 19 out of say, 13,500; we're at about 0.1% of patients who could have developed T-cell lymphoma after treatment with these CAR T-cell therapies. It's not entirely out of the realm of possibility that T-cell lymphoma could develop from gene-modified T-cells, and these are all the patient's own T-cells that have been modified outside of the body. But I would still posit that this is a really low incidence of T-cell lymphomas in these patients who really are without other great treatment options. Dr. John Sweetenham: Yeah, and I think that's a point that we'll return to a little bit later on in the conversation around the fact that you know, clearly, there are major benefits that have been associated with CAR T-cell therapy and hematologic malignancies so far. And of course over the years, I think that many of us have become familiar with and learned a great deal about how to manage some of the more serious side effects of CAR T-cell therapy. And you, of course, have led several pivotal national trials of anti-CD19 CAR-Ts for lymphoma. Can you comment at all on whether you've seen previous data from your own practice or others on the risk of second malignancy from CAR T-cell therapy? And can you share your insights on the data and any new emerging data that warrants our attention for the concern or risk of second malignancy? And I guess to round up that series of questions, is there anything currently in yours or others research into CAR-T to explain what's happening and why this is going on? Dr. Fred Locke: I think what may have prompted the FDA's announcement of this is that on the same date that they came out with announcing their investigation, there was the release of the abstracts for the American Society of Hematology Annual Meeting. And within those abstracts, and unfortunately it was not selected for poster or oral abstract presentation, but discovered within those abstracts was one on a CAR+ T-cell lymphoma after ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. And what these investigators and the company were reporting is that a patient with refractory multiple myeloma received the cilta-cel BCMA-directed CAR T-cell therapy and developed a stringent complete response, and about 5 months later developed a nasal facial plaque and PET+ cervical lymph nodes. And both the lymph nodes and the plaque were biopsied and showed a T-cell lymphoma in which 90% to 100% of the cells were positive by qPCR for the CAR construct and immunohistochemistry for the CAR protein. So this was a T-cell lymphoma growth where the cells were expressing the inserted protein, the chimeric antigen receptor protein, which is obviously not natural. And when they looked a little bit deeper at these patients, 91% of the cells have the same T-cell receptor sequence. So this was really a clonal sort of process. They did CAR integration analysis to see how the insertion of the CAR, the chimeric antigen receptor gene, could have potentially disrupted a gene within the T-cells. And what they found is that there were some dominant sort of insertions within certain genes suggesting monoclonality, but it wasn't within any sort of obvious activating genes that would be expected to lead to the T-cell lymphoma. They went on and did some additional analysis, and they showed that there was some existing TET2 mutations in the T-cells of this patient, prior to probably prior to the CAR T-cell manufacturer, and they weren't associated with clonal insertion. And I think, you know, it's possible that this patient who had a pre-existing mutation may have been susceptible to the development of a T-cell lymphoma prior to the CAR T-cell treatment. And TET2 was previously shown a number of years ago in a CLL patient treated with CD19 CAR T-cell therapy; it was shown that there was insertional mutagenesis, silencing the TET2 gene, and that associated with clonal expansion of the CAR T-cells in that patient and corresponded with remission of the CLL. However, the difference here is that that patient's T-cell clone went back down and contracted, and the patient remained in remission 5 years later with their T-cells still in the blood, but the minority of those T-cells had that that TET2 mutational insertional mutagenesis. All this is something we thought was theoretically possible, that T-cell lymphoma could develop after car T-cell therapy. And in fact, a prior trial using a different method of delivery of a CAR gene; instead of using a virus to insert the car into the into the T-cells, a transposon system called piggyBac was used. And in that trial, again, CD19 CAR trial, but in this case, it was allogeneic donor cells for patients who had relapsed after an allogeneic transplant. So it's sort of an autologous, you know, analogy, but it's using the donor cells. And in that trial, 2 out of like 10 patients developed clonal T-cell lymphoma, which was CAR+, but they weren't able to identify a clear insertional mutagenesis event in those cases. So, we've known this is possible, and it would have been great if this poster or if this abstract at ASH was presented as an oral or a poster so we could get more detail, but it's possible that that's the likely reason for the FDA's announcement. Dr. John Sweetenham: Thanks. The bottom line, I guess, is that for now, the jury's still out on exactly what's underlying these observations, but something which I'm sure is going to be the subject of a lot of discussion during the ASH meeting this year and moving forward. I'd like to inform our listeners that ASCO released a statement on the FDA investigation, stating that the risk of T-cell malignancies due to CAR T-cell therapy appears to be very low. And we've just heard from Dr. Locke that, of the several thousand patients who've received CAR Ts, there are 19 cases so far, it's been reported, which puts us into some type of proportion. The ASCO statement goes on to say that based on available data, and while such malignancies have occurred in patients who have received CAR T-cell therapy, the causal relationship, whether these cases are spontaneous or are caused by the therapy, needs to be investigated further, and we've just heard a little about the detail of that. ASCO added that by issuing a warning but not revoking approval of these therapies, the FDA clearly believes that the current available evidence suggests the overall benefits of these products, used within their approved label, continue to outweigh the potential risks. So Fred, the risk of secondary malignancies is already included as a class warning in the U.S. prescribing information for these CAR T-cell therapies. But do you think that the CAR-T products could eventually be taken off the market, and how would your research be impacted if this were to happen? And maybe finally, how long will patients on CAR T-cell therapy need to be monitored moving forward? Dr. Fred Locke: I don't believe that CAR T-cell therapy will be taken off the market. As we've already talked about, the incidence is extraordinarily low and the causality is unclear. It would certainly impact my research, as I'm doing clinical trials with CAR T-cell therapies, but it would more importantly impact the way we treat patients. We did over 300 CAR T-cell therapy treatments last year here at Moffitt Cancer Center. We're one of the busiest programs in the world giving CAR T-cell therapy, and it is truly a transformative therapy for all the diseases that we administer these FDA-approved therapies for. For example, in diffuse large B-cell lymphoma, we participated in the ZUMA-7 clinical trial and recently reported that patients randomized to CAR T-cell therapy had improved overall survival. They were living longer than patients randomized in the second-line setting to get conventional chemotherapy and autologous transplant. This is clearly a therapy that can work. I would also add that the risk of secondary malignancies is real, but that's a risk for all cancer patients, particularly patients with hematologic malignancies, and for example, lymphoma patients who've gotten an autologous stem cell transplant are at a relatively high lifetime risk of developing a secondary myeloid malignancy, most commonly, treatment-related MDS or AML. And that risk is also present after CAR T-cell therapy. The degree of attribution of CAR-T versus the condition of chemotherapy for CAR-T versus the previous chemotherapy is all unclear, and more analysis needs to be done. But the risk of developing treatment-related MDS or leukemia is certainly higher than the small number of T-cell lymphomas reported. The other thing I want to point out is that there was an analysis of the SEER database that patients with B-cell lymphomas are at about a 5-fold higher risk of developing a T-cell lymphoma than the otherwise healthy population; and vice versa, by the way, T-cell lymphoma patients are at risk for developing B cell lymphoma. And in fact, in that SEER database, it's not a wildly different percentage chance of developing a T-cell lymphoma after a B-cell lymphoma. And this data came out before the advent of CAR T-cell therapy. So I really think we need more science to be done to understand what's happening for these patients. Will this impact the field? Well, certainly, there are treatments that are not CAR T-cell therapy that compete with CAR T-cell therapy or could; I'm a strong believer that they don't offer the same outcomes for patients, but we will certainly see people talking about this for some time. Then the other place where this could be relevant, I think, is as we look at CAR T-cell therapy for autoimmune disorders, and we're starting to see studies of that for lupus and other diseases, the risk to benefit ratio could be different in those cases. So this is something we really need to consider as we move forward with CAR T- cell therapy. Dr. John Sweetenham: Yeah, thanks, Fred. And as a major clinical investigator in the field of CAR-T at the moment, do you see any potential concerns about difficulties in getting patients onto the trials of CAR T-cell in the light of this information? Dr. Fred Locke: No, I really don't. We're not seeing hesitancy, at least in the patients who are referred in for CAR T-cell therapy. Again, it may give ammunition for those who are already predisposed to not refer patients in for CAR T-cell therapy, but I don't think it should. I think that these are low risks, and these therapies clearly have benefits to patients. And we should give their patients an opportunity to get these therapies, and I don't see it impacting our clinical trials at this point. Dr. John Sweetenham: Yeah, and your comments address what was going to be my final question to you and that is, as a referring oncologist, how would you advise a referring oncologist to talk with their patients about these data and their implications moving forward? Dr. Fred Locke: If the patient brings it up, I think the response should be that these are very few cases of very low incidence and very low risk. There are other risks to CAR T-cell therapy that are greater, and really speaking with a cell therapist who administers the treatment is probably the best way to give the patient the option to get CAR T-cell therapy if they want to, knowing all the risks and benefits. So, I would leave it up to the CAR-T treatment center to discuss those risks with the patient.   Dr. John Sweetenham: Well, thanks, Fred, for sharing your insights with us on these concerning developments in CAR T-cell therapy, and I think also for putting them into context in terms of the sort of magnitude of this problem in the context of the overall number of patients who are benefiting from this therapy right now. We truly appreciate your time, and thanks for sharing your thoughts with our listeners. Dr. Fred Locke: Thanks, John, my pleasure. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights you hear on 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. Fred Locke @DrFredLocke     Follow ASCO on social media:         @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn         Disclosures:        Dr. John Sweetenham:    Consulting or Advisory Role: EMA Wellness     Dr. Fred Locke: Consulting or Advisory Role: Novartis, Celgene, Calibr, Allogene, Gerson Lehrman Group, EcoR1, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite (Gilean), Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol-Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Mittenyi Biotec, Caribou Biosciences, Takeda, Umoja Biopharma Research Funding: Kite Pharma, Allogene, Novartis, Bluebird Bio, Bristol-Myers Squibb/Calgene Patients, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 CAR T Cells with Enhanced Metabolic Fitness; Serial Number: 62/939,727 Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292. Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy.  Serial Number: 62/879,534. Travel, Accommodations, Expenses: Kite Pharma, A2 Biotherapeutics

Biopharma's latest pair of multibillion-dollar takeouts come in two of industry's hottest areas: ADCs and obesity. On the latest BioCentury This Week podcast, BioCentury's editors discuss the move by Roche into obesity via its acquisition of Carmot Therapeutics and the winding journey of ADC company ImmunoGen to its $10.1 billion buyout by AbbVie. BioCentury's editors discuss what FDA's statement on the risk of T cell malignancy following BCMA- or CD19-directed CAR T cell therapy means for companies operating in the space.

More than 70,000 U.S. veterans are living with MS. That's why the only federal funding specifically earmarked for MS research comes from the U.S. Department of Defense. It's why the U.S. Department of Veterans Affairs has established the Multiple Sclerosis Centers of Excellence. And it's why, in 2019, the National MS Society established a strategic partnership with the U.S. Department of Veterans Affairs. This week, we're saluting the men and women of our armed services, and we're highlighting some of the resources available to U.S. veterans who are living with MS. Izzy Abbass, the Co-Chair of the Paralyzed Veterans of America MS Committee, joins me to discuss all the ways the PVA assists U.S. veterans in obtaining their VA benefits. We're also sharing the results of a study that compared the efficacy of being treated with autologous hematopoietic stem cell transplantation (aHSCT) and being treated with a high-efficacy disease-modifying therapy.  We'll tell you about the results of a study that may begin to explain why African Americans who are living with MS often experience a more severe disease course. We'll give you the details about where and how to register for this Thursday's International Progressive MS Alliance's global webcast that's focused on treatments and new research for cognitive challenges in progressive MS. And actress Jamie-Lynn Sigler is also joining me this week to talk about her MS journey and to share some news about a new project that she has developed for people living with MS. We have a lot to talk about! Are you ready for RealTalk MS??! This Week: Resources for U.S. Veterans living with MS  :22 My guest, Izzy Abbass, explains how the PVA assists U.S. Veterans with MS in receiving their VA benefits  2:41 A study compared the efficacy of autologous hematopoietic stem cell transplantation (aHSCT) with a high-efficacy disease-modifying therapy  11:21 Results of a study may begin to explain why African Americans who are living with MS often experience a higher level of disease activity and faster disability progression  14:36 This Thursday, the International Progressive MS Alliance is hosting a global webcast exploring treatments and research focused on cognitive challenges in progressive MS  17:31 Jamie-Lynn Sigler discusses her new guide for people living with MS  19:13 Share this episode  30:25 Have you downloaded the free RealTalk MS app?  30:45 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/323 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com National MS Society: Resources for U.S. Veterans with Multiple Sclerosis https://nationalmssociety.org/Resources-Support/Find-Support/Veterans-with-Multiple-Sclerosis U.S. Department of Veteran Affairs: Multiple Sclerosis Centers of Excellence https://www.va.gov/ms Paralyzed Veterans of America: Multiple Sclerosis Resources https://pva.org/research-resources/multiple-sclerosis STUDY: Autologous Hematopoietic Stem Cell Transplantation is Superior to Alemtuzumab in Patients with Highly Active Relapsing Multiple Sclerosis and Severe Disability https://sciencedirect.com/science/article/pii/S2211034823005977 STUDY: African American Patients with Multiple Sclerosis (MS) Have Higher Proportions of CD19+ and CD20+ B-Cell Lineage Cells in Their Cerebrospinal Fluid than White MS Patients https://sciencedirect.com/science/article/abs/pii/S2211034823005485 REGISTER for Thursday's Global Webcast on Cognitive Challenges in Progressive MS https://msif.org/cognitive-webcast Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 323 Guests: Izzy Abbass and Jamie-Lynn Sigler Privacy Policy

Brian Yang interviews Nasdaq-listed cell therapy developer Gracell Bio Founder and CEO William Wei Cao who discussed the plan to enter the US market through quicker turnaround, faster delivery, cost-effective and safety profile. He also discussed taking the Shanghai-based firm's CD19 and BCMA-dual targeted therapy to the first-line treatment, allogenic CAR-T therapies, combinations, Chinese biotech going global and surviving in the current “capital winter” environment.

Brian Yang interviews Nasdaq-listed cell therapy developer Gracell Bio Founder and CEO William Wei Cao who discussed the plan to enter the US market through quicker turnaround, faster delivery, cost-effective and safety profile. He also discussed taking the Shanghai-based firm's CD19 and BCMA-dual targeted therapy to the first-line treatment, allogenic CAR-T therapies, combinations, Chinese biotech going global and surviving in the current “capital winter” environment.

Did you know that noncellular CD19-targeted therapies represent a new therapeutic option in both transplant eligible and ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL)? Credit available for this activity expires: 10/18/2024 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/997427?ecd=bdc_podcast_libsyn_mscpedu

Featuring an interview with Dr Jeremy Abramson, including the following topics: Choice of Bruton tyrosine kinase (BTK) inhibitor as first-line therapy for chronic lymphocytic leukemia (CLL) (0:00) Perspectives on the use of chemoimmunotherapy versus BTK inhibitors as front-line treatment for CLL (2:31) Chimeric antigen receptor (CAR) T-cell therapy-associated ICANS (immune effector cell-associated neurotoxicity syndrome) and infectious complications in patients with CLL (6:21) Available data with bispecific antibodies for CLL (9:38) Sequencing CAR T-cell therapy and pirtobrutinib for patients with previously treated CLL (11:09) Integrating bispecific antibodies into community-based practice; strategies for mitigating associated toxicities (14:25) CD20 versus CD19 as a therapeutic target in lymphomas (20:31) First-line treatment selection for patients with mantle cell lymphoma (23:07) Chemotherapy combined with nivolumab or with brentuximab vedotin as initial therapy for Hodgkin lymphoma (30:12) CME information and select publications  

Join Drs Amelia Langston and Jonathan L. Kaufman, MD, as they discuss current CAR–T cell for B-cell lymphomas as leading researchers and practitioners in the field. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/987069). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Cancer Immunotherapy With Chimeric Antigen Receptor (CAR) T Cells https://emedicine.medscape.com/article/2500108-overview Multiple Myeloma https://emedicine.medscape.com/article/204369-overview CD19 https://www.ncbi.nlm.nih.gov/gene/930 BCMA in Multiple Myeloma - A Promising Key to Therapy https://pubmed.ncbi.nlm.nih.gov/34575199/ Histology, Plasma Cells https://www.ncbi.nlm.nih.gov/books/NBK556082/ Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma https://pubmed.ncbi.nlm.nih.gov/33626253/ Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Patients With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1): A Phase 1b/2 Open-Label Study https://pubmed.ncbi.nlm.nih.gov/34175021/ Progression-Free Survival: What Does It Mean for Psychological Well-Being or Quality of Life? [Internet] https://www.ncbi.nlm.nih.gov/books/NBK137763/ Ide-Cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma https://pubmed.ncbi.nlm.nih.gov/36762851/ Clinical Management of Triple-Class Refractory Multiple Myeloma: A Review of Current Strategies and Emerging Therapies https://pubmed.ncbi.nlm.nih.gov/35877215/ Bispecific Targeting of CD20 and CD19 Increases Polyfunctionality of Chimeric Antigen Receptor T-Cell Products in B-Cell Malignancies https://pubmed.ncbi.nlm.nih.gov/35597752/ Bridging Chemotherapy: Multiple Myeloma https://www.ncbi.nlm.nih.gov/books/NBK584176/ Autologous Bone Marrow Transplant https://www.cancer.gov/publications/dictionaries/cancer-terms/def/autologous-bone-marrow-transplant Myelodysplastic Syndrome (MDS) https://emedicine.medscape.com/article/207347-overview GPRC5D-Targeted CAR T Cells for Myeloma https://pubmed.ncbi.nlm.nih.gov/36170501/ Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma https://pubmed.ncbi.nlm.nih.gov/36507686/ Elotuzumab: The First Approved Monoclonal Antibody for Multiple Myeloma Treatment https://pubmed.ncbi.nlm.nih.gov/27493709/ Natural Killer Cells in the Malignant Niche of Multiple Myeloma https://pubmed.ncbi.nlm.nih.gov/35087536/

In this week's episode, we'll discuss if some patients with relapsed or refractory primary mediastinal B-cell lymphoma can be cured by checkpoint blockade alone. Next, autologous CAR T cells are highly effective, yet not always feasible in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Lastly, we'll discuss ironing out beta-thalassemia during pregnancy.

Please visit answersincme.com/FSV860 to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, an expert in hematologic cancer discusses the use of chimeric antigen receptor (CAR) T cell therapies in B-cell lymphoma. Upon completion of this activity, participants should be better able to: Recognize the clinical rationale for using chimeric antigen receptor (CAR) T cell therapies for relapsed/refractory indolent follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); Describe the clinical profiles of approved and emerging CD19-directed CAR T cell therapies for relapsed/refractory indolent FL and CLL/SLL; and Outline clinical considerations for the use of CD19-directed CAR T cell therapies for relapsed/refractory indolent FL and CLL/SLL.

Get our free download! Implementing AMA Style – 8 Things to Get Right In this episode, we discuss the latest FDA approvals from June 19 –  June 23, 2023.  Here are the key highlights: ·       The FDA has given approval to Pfizer's Talzenna and Xtandi for treating metastatic castration-resistant prostate cancer in adults with certain genetic mutations. The approval came following successful Phase 3 TALAPRO-2 trial results. ·       Sarepta Therapeutics' Elevidys, a gene therapy for Duchenne muscular dystrophy, has received accelerated approval from the FDA. Elevidys, the first gene therapy of its kind, is approved for ambulatory pediatric patients aged 4-5 years with confirmed mutation in the DMD gene. ·       Jardiance and Synjardy, initially approved for adults in 2014 and 2015 respectively, have now been approved by the FDA for use in children aged 10 and older with type 2 diabetes. This approval came on the back of the DINAMO phase 3 trial results. ·       Pfizer's Litfulo, a once-daily oral treatment for severe alopecia areata for individuals aged 12 and older, has received FDA approval. This is the first treatment approved for adolescents with this condition.  ·       Amgen's Blincyto has received FDA approval for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (B-ALL) in first or second complete remission with minimal residual disease. This moves the drug from an accelerated approval to a full approval status. ·       Argenx's Vyvgart Hytrulo, a subcutaneous version of the original drug Vyvgart, has been approved by the FDA. It is indicated for generalized myasthenia gravis (gMG) in adult patients who test positive for anti-acetylcholine receptor antibodies. ·       Bayer's Ultravist (iopromide) injection, the first contrast agent for contrast-enhanced mammography, has been approved by the FDA. This new imaging tool enhances visibility of suspected or known breast lesions. ·       The FDA has refused to grant accelerated approval to Intercept Pharmaceuticals' drug obeticholic acid (OCA) for treating non-alcoholic steatohepatitis (NASH). This is the second time the FDA has declined to approve the drug for NASH due to potential risks. ·       Please check back every Monday morning for last week's approvals so that you can stay up to date.  See all the episodes here. ·       This podcast is brought to you by Nascent Medical. If you're a project manager at a CME or medical communications agency and need on-call medical writing assistance please visit Nascent Medical. We are a team of MD- and PhD-level medical writers and can create slide decks, white papers, ad board summaries, manuscripts, needs assessments, and much more. We also do medical editing using AMA style and factchecking. Visit nascentmc.com  ·       Intro and outro music ·       Garden Of Love by Pk jazz Collective

Join Drs Amelia Langston and Bijal Shah as they discuss CAR T-cell therapy for B-cell acute lymphoblastic leukemia, including clinical trials and real-world experience from their centers. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/987067). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Cancer Immunotherapy With Chimeric Antigen Receptor (CAR) T Cells https://emedicine.medscape.com/article/2500108-overview Acute Lymphoblastic Leukemia (ALL) Treatment & Management https://emedicine.medscape.com/article/207631-treatment#d15 Non-Hodgkin Lymphoma (NHL) https://emedicine.medscape.com/article/203399-overview CD19 https://www.ncbi.nlm.nih.gov/gene/930 Tisagenlecleucel https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tisagenlecleucel Tisagenlecleucel in Children and Young Adults With B-Cell Lymphoblastic Leukemia https://pubmed.ncbi.nlm.nih.gov/29385370/ Clinical Significance and Management of MRD in Adults With Acute Lymphoblastic Leukemia https://pubmed.ncbi.nlm.nih.gov/32903253/ Blinatumomab (Rx) https://reference.medscape.com/drug/blincyto-blinatumomab-999984#10 FDA Approves Inotuzumab for Adults With B-Cell Acute Lymphoblastic Leukemia https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-inotuzumab-leukemia Immune Effector Cell Associated Neurotoxicity Syndrome in Chimeric Antigen Receptor-T Cell Therapy https://pubmed.ncbi.nlm.nih.gov/36081506/ Cytokine Release Syndrome https://emedicine.medscape.com/article/2500111-overview Systemic Inflammatory Response Syndrome https://www.ncbi.nlm.nih.gov/books/NBK547669/ CD28 https://www.ncbi.nlm.nih.gov/gene/940 Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-Cell Acute Lymphoblastic Leukemia (B-ALL) (ROCKET) https://clinicaltrials.gov/ct2/show/NCT02535364 KTE-X19 for Relapsed or Refractory Adult B-Cell Acute Lymphoblastic Leukaemia: Phase 2 Results of the Single-Arm, Open-label, Multicentre ZUMA-3 Study https://pubmed.ncbi.nlm.nih.gov/34097852/ CAR T-Cell Therapy Approved for Some Children and Young Adults With Leukemia https://www.cancer.gov/news-events/cancer-currents-blog/2017/tisagenlecleucel-fda-childhood-leukemia Allogeneic Stem Cell Transplant https://www.cancer.gov/publications/dictionaries/cancer-terms/def/allogeneic-stem-cell-transplant clonoSEQ Assay https://ous.clonoseq.com/for-clinicians/how-clonoseq-works/ Management of Hypogammaglobulinaemia and B-Cell Aplasia https://www.ncbi.nlm.nih.gov/books/NBK584138/ Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse After Tisagenlecleucel in Children and Young Adults With Acute Lymphoblastic Leukemia https://pubmed.ncbi.nlm.nih.gov/35019853/ Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial https://pubmed.ncbi.nlm.nih.gov/36399695/ Therapeutic Targeting of Mutated p53 in Acute Lymphoblastic Leukemia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939537/ MLL-Rearranged Acute Lymphoblastic Leukemia https://pubmed.ncbi.nlm.nih.gov/32350732/ Liposomal Vincristine for Relapsed or Refractory Ph-Negative Acute Lymphoblastic Leukemia: A Review of Literature https://pubmed.ncbi.nlm.nih.gov/24490021/ Consolidation Therapy With Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients With B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results From the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial https://ashpublications.org/blood/article/140/Supplement%202/LBA-1/493429/Consolidation-Therapy-with-Blinatumomab-Improves

Go online to PeerView.com/ENP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Did you miss the PeerView DLBCL Seminar & Tumor Board at the Annual Hematology Meeting in New Orleans or want to revisit this important educational event? Access this program to watch a panel of experts debate the emergence of potent, antibody-based treatment platforms for patients with DLBCL, including novel CD19-directed antibodies, antibody-drug conjugates, and CD3xCD20 bispecific agents. These discussions are paired with case scenarios offering guidance on how to integrate these platforms into personalized management for DLBCL patients. The panel also explores the identification of candidates for treatment with novel antibodies; therapeutic sequencing and bridging strategies; and appropriate safety management and monitoring. Don't miss this informative video to receive CME/MOC credit! Upon completion of this activity, participants should be better able to: Summarize updated evidence and guideline recommendations surrounding the incorporation of CD19, CD79, and CD3/CD20 targeting antibodies in the management of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL); Integrate novel antibody-based treatment platforms into treatment plans for patients with DLBCL, including as sequential therapy over multiple lines of treatment, for patients unable to receive transplant, or in conjunction with cytotoxic regimens; and Develop team-based plans to manage practical safety and dosing considerations related to antibody therapy, including for patients with R/R DLBCL receiving active treatment.

Go online to PeerView.com/ENP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Did you miss the PeerView DLBCL Seminar & Tumor Board at the Annual Hematology Meeting in New Orleans or want to revisit this important educational event? Access this program to watch a panel of experts debate the emergence of potent, antibody-based treatment platforms for patients with DLBCL, including novel CD19-directed antibodies, antibody-drug conjugates, and CD3xCD20 bispecific agents. These discussions are paired with case scenarios offering guidance on how to integrate these platforms into personalized management for DLBCL patients. The panel also explores the identification of candidates for treatment with novel antibodies; therapeutic sequencing and bridging strategies; and appropriate safety management and monitoring. Don't miss this informative video to receive CME/MOC credit! Upon completion of this activity, participants should be better able to: Summarize updated evidence and guideline recommendations surrounding the incorporation of CD19, CD79, and CD3/CD20 targeting antibodies in the management of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL); Integrate novel antibody-based treatment platforms into treatment plans for patients with DLBCL, including as sequential therapy over multiple lines of treatment, for patients unable to receive transplant, or in conjunction with cytotoxic regimens; and Develop team-based plans to manage practical safety and dosing considerations related to antibody therapy, including for patients with R/R DLBCL receiving active treatment.

Diffuse Large B-Cell Lymphoma or DLBCL is the most common type of lymphoma. Much progress has been made in treatment of the disease lately, particularly with emergence of CAR T-cell therapy, but not all patients are benefiting from it. This episode of Cancer Topics features Drs. Loretta Nastoupil and Chijioke Nze exploring treatment approaches for two cases of refractory DLBCL: a 60-year-old man with no comorbidities (1:30) and a 39-year-old woman with HIV (18:35). The guests also discuss improving patient access to CAR T-cell therapy and managing its toxicities (10:35), as well as emerging therapies for DLBCL (14:30). To learn more about management of refractory DLBCL, check out the ASCO course linked bellow. Guest Disclosures:Loretta Nastoupil, MD: Honoraria – Gilead Sciences, Novartis, Bayer, Janssen Oncology, TG Therapeutics, Bristol-Myers Squibb, ADC Therapeuitcs, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche; Research Funding – Janssen Biotech, Celgene, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Chijioke Nze, MD, MPH: No Relationships to Disclose Resources: ASCO Course: Second-line Therapy for Relapsed/Refractory Diffuse Large B-cell Lymphoma (Free to Full and Allied ASCO Members) ASCO Podcast: Cancer Topics - New Therapies for Lymphoma (Part 1) ASCO Guideline: Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor (CAR) T-Cell Therapy ASCO Article: Navigating the Evolving Treatment Landscape of Diffuse Large B-Cell Lymphoma If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.  TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Loretta Nastoupil: So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing a refractory disease, and potentially succumbing to the lymphoma. Hello, my name is Dr. Loretta Nastoupil, I'm an Associate Professor and Deputy Chair of the Department of Lymphoma and Myeloma, at the University of Texas MD Anderson Cancer Center. Welcome to this ASCO Education podcast episode. It's my pleasure to welcome Dr. Chijioke Nze. Dr. Chijioke Nze: Hello, everyone. I'm Dr. Chijioke Nze, a Hematology/Oncology fellow at MD Anderson, I'll be co-hosting this episode with Dr. Nastoupil. Dr. Loretta Nastoupil: We've seen notable advances in diffuse large B-cell lymphoma research lately, with novel treatments including CAR T-cell therapy, offering the prospect of long-term remission for some patients, yet many patients are not even receiving second-line or later therapy, and even fewer are treated beyond the second line. How do you approach a patient with refractory diffuse large B-cell lymphoma? In today's episode, we'll explore strategies for management of refractory diffuse large B-cell lymphoma through two patient cases. So, Dr. Nze, walk us through our first case. Dr. Chijioke Nze: Our first case is Frank. Frank is 60 years old and has no comorbidities. He presented with severe back pain in September 2021, and was evaluated locally. He had a CT scan that showed retroperitoneal mass, prompting further evaluation. He had a biopsy of the left retroperitoneal mass in November 2021, which was consistent with diffuse large B-cell, germinal center B-cell of phenotype Ki-67 of 90%. He had a subsequent PET-CT scan, which showed a large conglomerate, and invasive left retroperitoneal hypermetabolic mass with satellite nodularity and contiguous bulky retroperitoneal adenopathy. He had bulky, FDG-avid metastatic retrocrural and intrathoracic adenopathy as well. He was treated with R-CHOP for six cycles, and at the end, achieved complete remission. He had a PET-CT a year later that showed new and worsening intensely FDG-avid abdominal adenopathy. This was new from a PET scan he'd had in January 2022 of the same year. He had a biopsy of this retroperitoneal adenopathy, which was consistent with relapsed diffuse large B-cell germinal center phenotype, also Ki-67 of 90%. Locally, he was treated with ICE, times five cycles, and had a follow-up CT scan at the end, which showed persistent bulky nodal disease with periaortic regional nodes with double 5, consistent with persistent disease. He also was found to have new and more conspicuous nodes in other areas as well. He presented for his first visit at MD Anderson in September 2022. Dr. Nastoupil, when you see a patient like this coming into your clinic, what's your typical approach? Dr. Loretta Nastoupil: For a diffuse large B-cell lymphoma, we are always hoping for cure with frontline rituximab, containing anthracycline-based chemotherapy. And so, it's always a gross disappointment when patients experience relapse. The timing of that relapse right now informs our current approach. And the reason I mention that, is because there have been three large randomized studies conducted and reported out just in the last year demonstrating that CAR T-cell therapy is the preferred option for patients who experience either primary refractory disease, or relapse within 12 months. And that is because they resulted in better outcomes than standard salvage-based chemotherapy and high-dose therapy autotransplant in the setting of chemosensitive disease. I have to acknowledge, of the three studies that were done, two were positive trials, so that's why currently, we have axi-cel or Axicabtagene ciloleucel, or Lisocabtagene maraleucel, and not tisa-cel or Tisagenlecleucel, as CAR T-cell therapy options. And again, that's because two of the three studies were positive trials. Now, the challenge is why would we have two positive studies in one negative trial? There are a lot of caveats to how those studies were conducted, but I think one of the biggest important lessons to be gained is that if you're going to consider CAR T for these high-risk patients, you want to do it as soon as possible, because that delay from identifying CAR T as a preferred option to actually infusing cells in a disease-- in a case particularly like this, where patients may have bulky, aggressively-behaving disease - that prolonged time may actually have an impact on outcomes. Dr. Chijioke Nze: Excellent. Thank you. So, you've mentioned he had an early relapse. How would you define early relapse in this patient population? Dr. Loretta Nastoupil: Thinking back to how we've been approaching diffuse large B-cell lymphoma over the last two decades, the PARMA study, which was done prior to Rituximab, suggested that for patients who had chemosensitive disease to a platinum-based salvage chemotherapy, which generally, was at least a partial response on CT, if they went on to high-dose therapy autologous stem cell transplant, 50-60% of those patients could anticipate cure. Whereas for the folks who continued on salvage chemotherapy, 10-20% of those patients had favorable outcome. So, we generally do try salvage-based chemotherapy, and for patients with chemosensitive disease, go on to high-dose therapy autotransplant. However, in the modern era where we've approached patients who've had rituximab as part of their frontline therapy, at least two studies - the ORCHARD study, and the CORAL study suggested that only 20% of patients who relapse in the post-rituximab era, particularly within 12 months, were successfully salvaged with platinum-based chemotherapy and high-dose therapy autologous stem cell transplant. Now, fortunately for patients who fail salvage, we have had CAR T-cell therapy as an option based off of three pivotal phase II studies, demonstrating about 40% of patients could anticipate a cure with CAR T-cell therapy. So, it only made sense to try and move that therapy up into second line, and the preferred population was those that had progressed within 12 months of frontline rituximab and anthracycline-based chemo. Now, to qualify for those studies, patients had to be considered fit for the control arm, which was salvage and auto transplant. Nonetheless, I do think for a patient like this, who's 60, without any other significant comorbidities, whose biggest challenge to longevity of life is his aggressive lymphoma, CAR T-cell therapy should be considered as soon as possible for this patient. Dr. Chijioke Nze: Is there still a role for high-dose therapy and autologous transplant in the new era, given the efficacy shown with CAR T-cell therapy? Dr. Loretta Nastoupil: I think there is. And the reason why I say that is, the trials that were done really did focus on the highest-risk patients, which were those with primary refractory disease or those who progress within 12 months of frontline. Now, there are patients that will have later relapse. And so, I do think for those patients, particularly those who are young and otherwise fit, should be approached first with a platinum-based salvage chemotherapy, in the setting of chemosensitive disease, proceed onto high-dose therapy and autologous stem cell transplant. Now, what do we do for those patients who have a late relapse but are otherwise older, or who have comorbidities that would make them suboptimal candidates for the high-dose therapy preceding stem cell transplant? I have a couple other options for those patients - so, there was a trial done with liso-cel for patients who were otherwise older, or not fit for intensive therapy. It's a single-arm phase II without a randomized comparison, but also demonstrated that liso-cel in second-line, later relapsed patients who are not fit for intensive therapy, resulted in comparable outcomes to what we would anticipate on that third-line or later setting. We also have other non-CAR T-cell therapy options, such as tafasitamab, which is a naked CD19 antibody, which has been combined with lenalidomide in the L-MIND study, again, for patients without primary refractory disease and who would not be appropriate candidates for intensive therapy. So, I do think we have alternative options, it's just when we look at the totality of the data right now, my conclusion is that CAR T-cell therapy, particularly for high-risk patients, is the most likely chance to result in cure. Dr. Chijioke Nze: Excellent. In a patient who we are considering CAR T-cell therapy, what are some of the short-term and long-term consequences, or toxicities that we should worry about? Dr. Loretta Nastoupil: One of the challenges right now with CAR T, and why it's still only available in specialized centers, is the acute toxicity, which is really a derivative of its mechanism of action. We take patients' own T-cells, we use a viral vector to introduce extracellular receptor, but also a co-stimulatory molecule. So, once these cells engage their antigen, sort of prime to react to that, and that can lead to pretty rapid T-cell expansion, release of cytokines, recruitment of other inflammatory cells to that tumor bed, and as a result, a large portion of patients can anticipate to experience cytokine release syndrome, which again, is the result of the activation of these T-cells, the expansion and the recruitment of other inflammatory cells. Fortunately, for most patients, this results in fever alone that can be managed with supportive measures. Occasionally, they'll have concomitant hypoxia or hypotension, and unfortunately, few patients will have significant or severe toxicity. The other toxicity that's less easily manageable or less predictable is the neurotoxicity that can vary according to patient-specific characteristics, such as age, and the amount of tumor burden, their performance status going into CAR, but even more importantly, the construct that's utilized, with highest rates of neurotoxicity associated with axi-cel. Again, likely speaking to its construct and the CD28 costimulatory domain that is unique to axi-cel. As a result of these acute toxicities, patients are required to stay within two hours of their treating center for the first four weeks, and they're also discouraged from operating heavy machinery, such as driving, for the first eight weeks following CAR T. So, I do you think this creates some barriers to access to this therapy, particularly the patients that are treated in community settings that may reside long distances from these certified CAR centers. Dr. Chijioke Nze: So, you mentioned that obviously, given the specialized care needed for the CAR T therapy, that they're kind of localized in certain sites. What are some of these issues with access that you're noticing both in the logistics of giving CAR T, and also in patient access? Dr. Loretta Nastoupil: I'm hoping we're going to address one of those issues right now, which is, education and awareness, because we've had these three randomized studies, and two being positive readouts just in the last year. It's important to get the message out that CAR T-cell therapy for high-risk early relapsed refractory large cell lymphoma patients can result in a significant improvement in event-free survival and progression-free survival over the standard of care. And so, being aware that this therapy can result in more favorable outcomes is step one. Step two is, we have to ensure that there are minimal barriers to getting those patients into these treating centers as quickly as possible. So, recognizing who delivers the care - is it your traditional stem cell transplant physician? Is it a lymphoma doctor? What centers are certified? Some of these issues can be addressed with quick internet searches. So, for instance, in our center, we have a 1-800 number for anyone who's interested in CAR T-cell therapy that connects them directly to a CAR T coordinator who can help them understand do they meet the FDA-approved indication? Would they be interested in seeking consult? And we try and prioritize getting those patients in the door as soon as possible since time likely does have an impact on outcomes. And then, partnering with our community oncologist - you're going to be the primary oncologist for these patients leading up to CAR, and then after that four-week window, when we're keeping the patients in close proximity to our centers, we often send them back. And so, making sure that they're comfortable knowing what potential late toxicities to be on the lookout for, which include B-cell aplasia and risk for infection, or prolonged cytopenias, beyond just lymphopenia. And so again, there's a need for education and partnering with our community sites to make sure that there is successful handoff of these patients back after they've completed the monitoring for the acute toxicity. And then, really trying to explore opportunities to utilize some of the better tolerated CAR T, such as liso-cel, in your non-traditional academic centers. Those that are equipped to handle phase I studies or stem cell transplant, for instance, may not be affiliated with the university. So, I think those are all types of strategies that could be employed to try and improve access for patients. Dr. Chijioke Nze: And then, you mentioned the liso-cel, but in some of the toxicities, are there ways of predicting which patients will do better or worse? Are there ways to reduce toxicities? And is there any hope for things such as outpatient administration of CAR T? Dr. Loretta Nastoupil: So, my answer today may improve over time as we get larger numbers and more experience, but what we currently understand is that the patient performance status, their degree of tumor, how quickly that tumor is increasing, LDH and some inflammatory markers such as CRP or ferritin pretreatment can provide some insight into a higher risk of toxicity. And then obviously, the construct that's utilized. Again, axi-cel has higher rates of neurotoxicity. All will have some form of cytokine release syndrome, generally speaking, but rates of grade three or higher are quite infrequent, particularly with liso-cel and tisa-cel. So, it's multifactorial. That then raises the question, can we do anything to alter those modifiable risk factors? Can we reduce the disease burden? Can we improve the performance status? Can we do anything to reduce the inflammatory markers pre-treatment? And so, those are strategies that are being discussed, and I think in general, as we get more effective therapies that enter into the treatment landscape, it's probably some of the best ways to try and reduce some of those risk factors. Dr. Chijioke Nze: Rounding that up, are there any exciting developments or things to look out for, for exciting therapies in the relapse setting? Dr. Loretta Nastoupil: A couple of things beyond CAR T that I think we should all be aware of and anticipate to be in our toolkit relatively soon; probably, one of the most exciting, is the development of the bispecific antibodies. So, another challenge with CAR T is the requirement to collect these patients' own T-cells and send them off to a central manufacturing site, and the turnaround time can be anywhere from 3-4 weeks. And again, in a situation where you have an aggressive disease, that can be a long time to wait. And so, is there any treatments that are more readily available, that again, will be effective at reducing disease burden? And so, by specifics kind of fit those unmet needs to some extent - you have essentially two heads; one head is going to bind the endogenous T-cells that eliminates the need to leukapherese these patients and manufacture, and then the other head is going to generally engage CD20, which we know is an effective targeted antigen, particularly in B-cell lymphomas. And there are a number that are under development. We saw preliminary phase II data with glofitamab, epcoritamab, as well as combination strategies with mosunetuzumab. So, I do have optimism that the bispecific antibodies will potentially enter into the treatment landscape. I anticipate they'll probably be used first post-CAR T, but will likely move their way into earlier lines of therapy. I've already mentioned tafasitamab in combination with lenalidomide, which is an effective non-chemotherapy option. We have antibody-drug conjugates, such as Loncastuximab, which is a CD19 antibody-drug conjugate. It's essentially targeted delivery of chemotherapy, and it looks to have a pretty promising activity as a single agent in that third-line or later space, and then polatuzumab, which is a CD79b antibody drug conjugate, in the relapse setting has been combined with bendamustine and rituximab, but also demonstrated significant improvement in the frontline setting in the POLARIS study where vincristine was replaced with polatuzumab. So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing refractory disease, and potentially succumbing to the lymphoma. Dr. Chijioke Nze: And then, one additional question: How do you approach a patient who is not quite as fit, in thinking about what their options are for later-line therapies? You already mentioned some of these, but which of those would you prioritize in this setting? Dr. Loretta Nastoupil: Again, as we get more experience, we develop skills that help us sort of navigate all these different options. In my practice, if I'm even considering CAR T, I'm going to delay bendamustine until after I've collected those cells. I think that's one caveat that-- we do get nervous about the quality of those autologous CAR Ts if they're generated in someone who's had recent exposure to bendamustine. So, that may help me sequence that later on. We have questions right now about what's the optimal sequencing of CD19-directed therapy because we have several options beyond just CAR T-- As I mentioned, we have Lonca, we've got tafasitamab and lenalidomide. Currently, we don't have prospective data that really informs that question, and there's a number of research studies underway to try and help us understand if there is a preferred sequence, or even if it matters how we handle CD19 targeting. For my older, frailer patients where I'm really worried, they're not going to be able to tolerate something like liso-cel, or they're not going to be able to have that caregiver, and they're uncomfortable relocating to an area where CAR T might be available, my general approach right now is to consider tafasitamab and lenalidomide first in that relapse setting, followed by either Lonca or Pola-BR. Selinexor is another option. It's an oral agent, though again, in my opinion, if we look at the totality of the data, may be less effective than the other options. So, I might reserve that as a last option for someone, again, with relapsed/refractory large cell. Dr. Chijioke Nze: Excellent. Thank you. This has been very helpful. Dr. Loretta Nastoupil: All right. So, Dr. Nze, now I'm going to turn the table and ask you some questions. I'm going to change this up a little bit - she's now a 39-year-old female. She has significant comorbidities. She has HIV, and again, large cell lymphoma. So, let me walk you through her case, and then we'll discuss some of the challenges, again, in a very different scenario, albeit a similar disease. So, our female is, I mentioned 39, pre-existing HIV, she's treated frontline with six cycles of R-CHOP and intrathecal methotrexate for CNS prophylaxis. Because of her comorbidities, again, not well controlled HIV, she also has a poor functional status at the time of relapse. This was a couple years ago, and CAR T was not an option in second line, though she is someone who had a relapse that was beyond 12 months. So, for her second-line approach, because of her comorbidities, she actually receives rituximab in combination with high-dose cytarabine, dexamethasone, and oxaliplatin for three cycles, and actually achieves a chemosensitive disease and is referred to our stem cell transplant colleagues. Unfortunately, at that time, due to comorbidities, she was deemed not to be an appropriate candidate for high-dose therapy, and she's been monitored for signs of relapse. Despite being in the minority, she actually does not have a recurrence of her lymphoma but has a number of other, again, challenges in regards to her comorbidity, including multiple infections, resulting in recurrent hospitalizations. And so, it's always been a challenge for me in being intimately involved in her case, deciding when she's presenting, how alarmed to be about recurrent lymphoma versus infection, and how I might approach her in the setting of relapsed large cell lymphoma. So, what role does prior type and response to therapy play in treatment selection at your next line of treatment? Dr. Chijioke Nze: I think in this patient, it sounds like she got one adequate therapy on and the initial presentation with R-CHOP, and then with IT chemotherapy as well. She looked like she had a good response. I think the fact that she achieved a complete response and the duration of her response, lets me know that she likely has chemosensitive disease. This, in turn, helps me to pick what to do next. As you mentioned previously, we know how efficacious the CAR T therapy is, but in someone like her who had a long duration, trying salvage therapy and proceeding to autologous transplant might make sense. I'd be interested in your thoughts. Dr. Loretta Nastoupil: Yeah, I agree. And I think part of the challenge, particularly when we're facing patients with HIV, they're often excluded from prospective studies. And so, we're often in a scenario where we may not have the wealth of data to inform our treatment decision. But I do think in general, comorbidities play a major role-- we're navigating treatment options. Because again, traditionally, we've used intensive chemotherapy as our mainstay of treatment, and there are clear criteria that patients generally should meet that help us predict how likely they are to have significant or severe toxicity from high-dose therapy. And this is a prime example of even though she was young, her comorbidity made her a poor candidate for intensive therapy. I think the other sort of non-clinical factors that we sometimes take into consideration, because CAR T was approved off of single-arm phase II studies, again, none of which would've included someone like her, because of her HIV status, how do we extrapolate-- for instance, if she had relapsed in that third-line space, and suggesting that she did not have significant infection or other significant comorbidities, do we have experience to proceed with an autologous CAR in that setting? So, again, there've been a few cases where we have case reports where people have reported on their standard of care outcomes, particularly with CAR T in patients with active HIV disease, but one of the concerns I have in these scenarios is very selected. If you have active infection, that can make the acute toxicity with CAR significantly worse. And so again, we're trying to navigate a sort of limited data zone to try and help her and choose the right therapy. Again, you've met this patient with me, you helped care for her for some time, and you have a unique experience of also practicing in a county hospital where comorbidities, particularly, like HIV, can be much more common. What is your perception regarding barriers to accessing CAR T as it pertains to social factors, clinical factors, and again, this is a case that highlights some of those issues. Dr. Chijioke Nze: You mentioned at first that she had uncontrolled HIV. So, I think which, one, speaks to her treatment reference of her non-malignancy-related diseases, and trying to get that under control would be one of the first things I could think about. Thinking about how her care is managed and what kind of support she has are very important for us to think about as well. The other thing that's very important is, a lot of patients who we're seeing in the community may not have access to such specialized centers such as MD Anderson, where patients do have access to clinical trials and CAR T therapy. So, patients who are unlike her, who might qualify, may not actually be able to get these therapies as well. Part of the reason is, it can be insurance status, which is what we see in a lot of our patients. So, a barrier to get into the door. And then too barriers, lack of social support can be a big issue as well. And then there's also a big push in the community to improve the trust and awareness of these novel therapies, as you've mentioned. So, in a lot of the community practice, some of the community practitioners may not be comfortable with these, and a lot of the patients may not have heard of these new technologies, and also want to defer trying new therapies before having other people try new therapies before they consider them themselves. I think all these things present specific significant barriers to patients in the community. One, their ability to adhere to care, two, their insurance and their ability to get care and the financial toxicities associated with that. And then third, really understanding the options that are available. Dr. Loretta Nastoupil: And again, just to try and illustrate a couple other points. You know, we use a case here, which is a real case, with significant comorbidities such as HIV, which again, is something that is not frequently encountered, and will have a large impact on treatment selection. What if I just told you this patient has comorbidities, but she has moderate type-2 diabetes, and as a result, she has mild renal insufficiency, ejection fraction is actually adequate, would you have done anything different in this case? Dr. Chijioke Nze: No. I think in this particular case, I do think the fact that she did have a good response for a long duration of time, and did seem to have chemosensitive disease, I would probably still have tried a salvage therapy and autologous transplant in this patient. In the event that she was refractory, or had early relapse, and in that case, I would consider her to not be chemosensitive and would definitely have sought some more active therapies such as CAR T cell therapy through available products. Dr. Loretta Nastoupil: And then one last question for you: What if we just changed her age and we made her 79, but no other significant comorbidities, how would that have impacted your approach? Dr. Chijioke Nze: I'm going to turn that one over to you, I'm not exactly sure how I would treat with older patient with the same disease. Dr. Loretta Nastoupil: That's fair. So, if you have an older patient who has a late relapse, but not necessarily someone you would consider appropriate for salvage chemotherapy and high-dose therapy, then I think tafasitamab and lenalidomide would be probably my first choice in that setting, just based off of the L-MIND study. Dr. Chijioke Nze: Thank you, Dr. Nastoupil, for a great discussion of the management of diffuse large B-cell lymphoma. And thank you to all our listeners. We appreciate you tuning in to this episode of the ASCO Educational podcast.   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.

In this week's episode, research shows that in patients with myelodysplastic syndromes, or MDS, the frequency of pathogenic or likely pathogenic germline variants is relatively high across all age groups, not just younger patients. Based on these results, it may be time to expand genetic testing to all patients.  Next, we'll review primary results of a prospective, multicenter study of children with acute leukemias or MDS who underwent T-cell receptor αβ+ and CD19+ cell-depleted haploidentical HCT with reduced-toxicity conditioning. Finally, an emerging unmet need related to CAR T cell therapy: patients who progress after receiving CAR T cells have poor outcomes and no agreed upon standard of care. We'll review findings from a large registry study demonstrating infrequent responses to post-CAR T cell treatment and short survival times, highlighting a need for novel strategies. 

In this week's episode, we'll discuss patient-reported outcomes in the phase 3 ZUMA-7 trial of CAR T-cell therapy in second-line relapsed/refractory large B-cell lymphoma, learn more about the association between the loss of α4A- and β1-tubulin and severe platelet spherocytosis, and discuss the interaction between prebiotic galactooligosaccharides and mouse gut microbiota in graft-versus-host disease.

In this episode, we discussed the three CD19-directed chimeric antigen receptor (CAR T-cell) therapies that have been approved for relapsed/refractory aggressive large B cell lymphomas (LBCL) after two lines of therapy:  Axicabtagene ciloleucel (axi-cel) https://www.nejm.org/doi/full/10.1056/nejmoa1707447 Tisagenlecleucel (tisa-cel) https://www.nejm.org/doi/full/10.1056/nejmoa1804980 Lisocabtagene maraleucel (lisocel)https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31366-0/fulltext 2.  Next, we delved into the three prospective phase 3 randomized clinical trials that were conducted to define the optimal second-line treatment by comparing each of the CAR T-cell products to the current standard of care ZUMA-7 for axicabtagene ciloleucel https://www.nejm.org/doi/full/10.1056/NEJMoa2116133 BELINDA for tisagenlecleucel https://www.nejm.org/doi/full/10.1056/NEJMoa2116596 TRANSFORM for lisocabtagene maraleucel https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00662-6/fulltext 3. Then, we briefly discussed the preliminary studies of CAR-T cell therapy in front-line therapy for large B cell lymphomaAxicabtagene ciloleucel (axi-cel) https://www.nature.com/articles/s41591-022-01731-4

Dr. Jack Cush reviews the news, journal reports, ACR and FDA announcements from the past week on RheumNow.com

Advances in genetic analysis, bone marrow transplants and cellular therapies have helped the leukemia specialist at the OSUCCC – James attain better outcomes for patients with blood cancers. “When a patient comes in, we get a sample from their bone marrow to know the genetics of their leukemia,” said Dr. Sumithira Vasu. “We want to know what is causing the leukemia to grow, and cause so much damage, and these genetics help us decide is this leukemia likely to be cured with chemo alone or does it need a bone marrow transplant … or cellular therapy.” In this episode Vasu explains the history and advances that have been made in bone marrow transplants, including the drugs that greatly reduce the effects of Graft-versus-host disease that plagued early transplants. New, cellular therapies, such as chimeric antigen receptor T cell (CAR T-Cell therapy) have shown great promise and the OSUCCC – James is a national leader in this game-changing treatment. “We take stem cells out of the body of a patient or a donor, send them to the lab and super charge them [through genetic modification] and then put them back in the patient's body,” Vasu explained. These new super-charged T cells found in the body's immune system can now better detect, target and kill the cancer cells in the blood. These super-charged T cells hunt for CD19, a protein that binds itself to the outside of cancer cells and has tricked the immune system into leaving them alone. “Now, because of the gene modification, they recognize the CD19,” Vasu said. The OSUCCC – James was one of a small group of comprehensive cancer centers that conducted the first clinical trials using CAR T-Cell therapy. And now, Vasu and her colleagues are among the leaders in the next step in the promising process. In the past, the bone marrow taken from patients was sent to a lab across the country for the genetic kick start. “Now, we are one of only a handful of labs in the United States that have the capability of manufacturing these cells in our own lab,” Vasu said, adding OSUCCC – James researchers have also identified two other targets in leukemia cells to attack: CD20 and CD22.