Doc Discussions with Dr. Jason Edwards
THIS is the podcast you have been looking for! "Doc Discussions" are just what the title says they are: physicians from a wide range of specialties, talking about relevant, up-to-date medical topics, not to mention tips on habits to help you live your best life. Your host, Jason Edwards, MD, is a board-certified radiation oncologist with a PhD in cellular and integrative physiology at St. Luke's Hospital in St. Louis, Missouri. Dr. Edwards explores not only diseases but also suggests techniques to optimize mental and physical health for a long and good life. Real people. Real advice. Real good. This is Doc Discussions, with Dr. Jason Edwards!
Doc Discussions with Dr. Jason Edwards
Revolutionary Advancements in Blood Cancer Treatment with Dr. Mark Fesler
Discover the revolutionary advancements in blood cancer treatment with Dr. Mark Fesler, a leading hematologist and oncologist at St. Luke's. We promise you'll gain a comprehensive understanding of the intricate phases of clinical trials, from safety assessments to efficacy evaluations. Dr. Fesler sheds light on the transformative shift from traditional cytotoxic drugs to cutting-edge immunotherapies, including checkpoint inhibitors, chimeric antigen T cells, and the promising bispecific antibodies that are changing the landscape of cancer care.
Navigate the complexities of clinical trials through the lens of Nassim Nicholas Taleb's "Black Swan" concept, appreciating the delicate balance of risk and benefit in drug development. We'll uncover the significant breakthroughs in bispecific antibodies for blood cancers and discuss the ethical considerations of fast-tracking treatments for patients facing limited life expectancy. Additionally, we tackle the reproducibility crisis in clinical trials, highlighting the importance of reliable and robust findings in ensuring patient safety and treatment efficacy.
Look to the future as we explore the expanding potential of bispecific therapies beyond blood cancers to solid tumors like breast, prostate, and lung cancer. Dr. Fesler shares insights on ongoing clinical trials at St. Luke's and emphasizes the move towards outpatient treatments and earlier lines of therapy. Learn about the specific immune-related cancers that show promising responses to these therapies and find out how patients can get involved in these groundbreaking studies. Join us in celebrating the relentless efforts of healthcare professionals and researchers driving innovation and improving patient outcomes in hematology and oncology.
Hi, my name is Jason Edwards and this is Doc Discussions. I'm here with my good friend, mark Fessler, who's a hematologist, oncologist specialist, and that means he specializes in blood cancers, leukemias and lymphomas. Mark, how are you doing today?
Speaker 2:Jason, thanks for having me on your program. I really appreciate it. You bet, you bet.
Speaker 1:And so one of the things we wanted to talk about what some of the exciting things that we're doing here in St Luke's as far as clinical trials.
Speaker 1:But I want to give a brief overview of clinical trials.
Speaker 1:The purpose of clinical trials is to see if drugs are safe and effective and if they can improve the outcomes that we have when we treat patients, whether it's with cancer or heart disease or anything else and so the first thing they do when they're designing clinical trials is they want to see if the drug is safe, and so they have a phase one clinical trial, and that's just to give the drug to people and see how they respond and make sure that it doesn't hurt them to any significant degree.
Speaker 1:Then they have a phase two clinical trial, which is also very limited in numbers, and this is when they try to see what dose is probably the best to give the patient, and so we know it's safe. Now what dose is the best to give? And then, once you have that information, you go into a much larger clinical trial where you take patients and half the patients you give one medication have to get another medication which may be the current standard of care, and then you follow them for a long time and you follow their side effects and you follow how effective the medication is at treating whatever you're trying to treat Now, mark, what kind of clinical trials are you working with right now?
Speaker 2:Yeah, so Jason, we're primarily working with phase two and phase three clinical trials here at St Luke's. Phase one trials where you're just starting out with a compound. You don't know whether it's really safe or effective. Oftentimes our studies that are a bit more labor intensive, they are probably larger commitments on the part of the patient just because they really know nothing about how this drug reacts in humans. There may have been some precedent, nothing about how this drug reacts in humans. There may have been some precedent, you know, in animal-related studies and so most often those types of studies are restricted to, you know, really large university-type centers. You know with phase one programs. So we've been focusing on more treatment, you know, trials at St Luke's to really try to see potentially if we can help push the bar on cancer-related therapies in terms of effectiveness, both from a quality of life and quantity of life perspective.
Speaker 1:You bet, and I've heard patients say in clinic like why haven't they come up with a cure for cancer? I've heard patients say in clinic like why haven't they come up with a cure for cancer? And my retort is often we don't have a cure for the common cold. If what you define as a cure is like, you will never see it again. But we do cure a lot of cancers and the cure rate has gone up significantly, especially over the past 50 years. Pediatric malignancies is probably where you've seen the biggest benefit, and that's in large part because parents are much more likely to enroll their children on clinical trials than they are to enroll themselves on clinical trials, and so you've seen this huge improvement in the cancer cure rate in children. But we're also seeing some gains in adults as well, and that's where you're working at right, mark.
Speaker 2:That's right. Yeah, we're continuing to push the bar in terms of effectiveness in really most diseases that I take care of the blood cancer. So the cure rate for Hodgkin's and many forms of non-Hodgkin's lymphomas improved in the last five years. We've seen significant gains in multiple myeloma. We're seeing advances in treatment of leukemia. Formerly, you know, only younger people could get treated for the acute leukemias and now I've got patients in you know, their 80s and 90s who are living with reasonable quality of life getting treated for acute leukemia at a community cancer center. So I have seen significant improvements in the way that we take care of all the blood cancers since I've come into practice.
Speaker 1:And on the chemotherapy side, which is the medical, oncologist side of the treatment spectrum, the newer drugs were the immune therapies. First we had the chemotherapies through the 80s and 90s and then the immunotherapies came out, which amplify your own immune system and help your own immune system fight the cancers, and now there's even a newer class of drugs that you're working with. Can you tell us about that?
Speaker 2:Yeah, so you know, 60s, 70s was cytotoxic, kind of DNA damaging type drugs.
Speaker 2:These things were, you know, often harmful to, you know, a lot of normal tissues. And you know, increasingly in the last 10 years we've gotten more kind of small molecule inhibitors, targeted medicines, medicines that act on various pathways within the blood, cancer cells, whether it be myeloma, lymphoma or leukemia. So we've made pretty nice gains in that respect. There's been general immune therapies, where you kind of activate the immune system to check the can to attack the cancer. Those you know are kind of some common names that we all are familiar with, but that's a class of medicines called checkpoint inhibitors. And then more recently we've developed more targeted immune therapies, both in the form of chimeric antigen T cells, which is a cell therapy that basically transforms somebody's immune system to attack the cancer, and then, even more recently and excitingly because it's kind of simpler type therapy off the shelf lower rates of toxicities. That's this thing called bispecific antibodies, which essentially grab the cancer cell and somebody's own immune cell, bring the two in close proximity and allow the immune cell to attack and essentially kill the cancer cell.
Speaker 1:And the side effect profile of this therapy is a little bit different. Patients typically tolerate it well, but you can have some reactions when the immune system gets overstimulated.
Speaker 2:Yeah, yeah. So with sort of the older chemotherapies we thought about, you know basically hair loss, you know low blood counts, something called cytopenias, you know risk for infections, low blood counts, need for transfusion support, often GI toxicity in the form of mucositis, sometimes nausea, diarrhea, those were kind of the classic chemotherapy-related side effects. And now the immune medicines are sort of moving away from all that, so there's less kind of damage to normal tissues and what we're seeing is kind of two major forms of early side effects with bispecific antibodies. One is called cytokine release, where essentially you can think of it as just an immune system activation characterized primarily by fever. But then also these chemical messengers can cause the lungs to get a little leaky, hypoxia, and then the blood vessels get a little leaky and that causes something called hypotension. That cytokine release syndrome is usually treated and dampened by steroids, also by other immune-mediated modifiers, a medicine called tocilizumab, that kind of inhibits one of the cytokines called IL-6. The other kind of early toxicity or side effects that concur with bispecific antibodies and really other forms of immune therapy as well, is called neurotoxicity, and this is usually reversible for most patients and it can span a spectrum of severity. But with bispecific it's mostly you know, kind of mild and it might just be some mild confusion. It might be difficulty, you know, remembering a word or the ability to, even, you know, write a sentence, and this can be alarming for you know, patients and their caregivers. So this type of you know side effect needs to be taken seriously. Oftentimes just supportive care and doing nothing, this will resolve on its own, but oftentimes we'll intervene with steroids when we identify this and we monitor patients real carefully for this.
Speaker 2:Usually both of those cytokine release and neurotoxicity occur within the first month or so of treatment. It's pretty rare to get them after the first month. What we get concerned about with later on in immune therapy is there is sometimes a general depletion of the immune system. You can imagine that if you're depleting somebody's plasma cells or B cells, sort of the cells that form the immune system, sort of make antibodies, there's generally an increased rate of infections that we see over time with these types of therapies. We'd see the same thing, generally speaking, with kind of the older chemotherapies as well. As you continue to treat a disease, generally the immune system becomes more fragile. That's just the nature of treating blood cancer. But so we have to in later months on bispecific antibodies. Be attentive to preventing infections. Having people on antibacterials antivirals, to you know prevent those types of infections.
Speaker 1:So would it be fair to say that? You know, like of course there's a big general term, everything exists on a spectrum and you know our bodies have our immune system at about the right rate. But if we can, if we have a cancer or something we're dealing with, we need to kind of amplify that. And most of the time it's tolerated pretty well because they have the dose of the drug down to amplify the immune system to the right amount. But sometimes it can be overdone and you can have some side effects with it, whether it be low blood pressure or other things. Is that accurate?
Speaker 2:Yeah, I would say that's right, jason. It's kind of like you know, probably there's an immune dysfunction that goes along with the cancer itself, and then essentially what do you mean by that?
Speaker 2:Yeah, what I mean by that is, you know, probably the actual blood cancer itself creates some immune deficit. For example, somebody with myeloma probably just at baseline once they're diagnosed often has depletion of normal antibodies so they might be more susceptible to getting sinus infections or pneumonias or that type of thing. And then, unfortunately, sometimes even with successful treatment of a blood cancer, oftentimes there's still immune deficits that persist and require, you know, patients to be careful in terms of exposures, to be on certain medicines that you know help, you know, prevent, you know, various infections from occurring.
Speaker 1:You know, this is really positive and it's an exciting time and it's always good to hear that we're pushing the needle forward as far as trying new things. Good to hear that we're pushing the needle forward as far as trying new things. There's an investor named Nassim Nicholas Taleb who wrote a book called Black Swan, and it talks about rare events that happen in the stock market. But I think it actually can apply to clinical trials as well, because you're there's some side effects that you know, okay, and then there are some things that you don't know, but you're at least aware that you don't know them. So there are known unknowns and that can be on the side effect profile, and then there are what he calls the black swan, which is the unknown unknowns, and that's the purpose of these clinical trials is to figure out and monitor the patients closely and see what are their cure rates, what are the positive things that we expect, but also follow them so closely that we find things that we didn't even anticipate.
Speaker 1:And one of the beauties of these large trials is you have multiple people following these patients over time and these patients, the people following them, oftentimes are nurses, research nurses. And these patients, the people following them oftentimes are nurses, research nurses and their only interest is to. They don't. They're not a part owner in the stock of the drug company. Their only interest is to find the objective truth about what happens with these patients as they go forward, so we can have the most accurate view of the knowns and unknowns and the side effects and the benefits. And that's science in general is to kind of first acknowledge that we don't know things and then come up with a hypothesis and test it and then analyze the data as strictly as possible.
Speaker 2:Absolutely. So you know, one of the really important things is a lot of blood cancer patients when they get to later lines of therapy. Okay, so let's say one or two treatments, or even let's say three or four treatments have not worked all that well. Patients were having unmet medical needs. In other words, the treatments just didn't work well enough when we got to those later lines of therapies. And one of the nice things about the bispecific antibodies is that these things are working in spite of multiple other treatments not working. So these were FDA approved, actually on the basis of phase two studies. These were not even approved on the basis of kind of the gold standard phase three randomized clinical studies, because they moved the bar so much in terms of treatment effectiveness, both in terms of creating remission rates that were much higher than was seen with older treatments, as well as prolonging quality of life, remission duration and even in some cases, you know, overall survival than was anticipated. You know, back before these were available, okay.
Speaker 1:So the first thing I think of when you say that is that's like very exciting. But you know, any good scientist should also be skeptical. And that also makes me think, well, hey, hold on, they didn't do a large phase three study. Now I do have some view of history, and I know that's something they do in pediatric tumors from time to time is that when the results are so good in the phase two that it becomes a new standard of care and there's risk in doing that. But there's also benefit.
Speaker 1:When you're talking about patients who've been through multiple lines of therapies, sometimes they go through multiple lines of therapies. Sometimes they go through multiple lines of therapy very quickly and the tumor just from go did not respond to any of the therapies. But then you also have patients who go through those lines of therapy over a long period of time, and so it's like the best example that I can come up with is that you take bacteria and you put it in a culture dish and you put an a drop of antibiotic in there and all of the bacteria die except for one. It's that one is resistant to it and then that one grows and covers up the whole plate and that same antibiotic won't work anymore and then you give another antibiotic and it kills all of them except for one or one percent, and then that one takes over the culture dish and the antibiotic you previously used didn't work.
Speaker 1:And chemotherapy kind of works the same way with clones of cancer cells and so you can over time pre-select out just one or two cells that kind of become the dominant clone If somebody's had gone through multiple lines of therapy over a long period of time. So they have this very either way. They have this very resistant cancer cell. And the clinical trials, initially, I would assume, start off with those patients where the alternative is that the cancer just takes over you and so your life will be very limited. So, trying something that's new and experimental, there's some risk with that, but it's probably less risk than dying within a month.
Speaker 2:That's right. These, you know the really all the blood cancers. These are potentially fatal illnesses. So when people have tried a number of treatments for them and they've been unsuccessful, their life expectancy might be measured in the order of, you know, let's say, weeks to months. And so, as you rightfully point out, Jason, you know, kind of the risks of the cancer are so high that taking a new form of treatment that might have its own set of risk becomes, you know, kind of a really tolerable thing for them. And then if you get a treatment that works pretty well and also is fairly well tolerated compared to other types of treatment in that space, you know, that's where that gets FDA's attention. And the FDA, you know, sometimes is even apt to approve this stuff on the basis of, you know, a non-comparative study and just comparing to historical kind of cohorts of patients, let's say.
Speaker 1:Yeah, that's fascinating. And you know these clinical trials, they're very important, they're very well scrutinized, especially phase three trials, but all along the way there's a lot of scrutiny, phase three trials, but all along the way there's a lot of scrutiny. There's a kind of a phenomenon that's not talked about that often, but it's called the reproducibility crisis and you actually see it most in the social sciences, where they do clinical trials and they then try to repeat them at a later time or a different institution and find that the likelihood that they will repeat them and find the same significance is very low. Now, you don't see this in medicine very often, thankfully, but People are different in different places and things are different in different times, especially as far as, like personality and stuff like that. So I do think that it is important in any scientific study to have a high degree of skepticism and to really scrutinize these trials to a high degree and so that way, when they are FDA approved for prime time, you know, we can have some really confidence in that.
Speaker 2:Definitely.
Speaker 2:And what you know, what's happening now is that at St Luke we formed a bispecific immune therapy program.
Speaker 2:Okay, so we can give both commercial bispecifics, but we also have access to some clinical trials. So not only are we, you know, let's say, treating large B-cell lymphoma or follicular lymphoma in third line and beyond with commercial therapy, or let's say, multiple myeloma in fifth line therapy, but the clinical trials are trying to move these things to patients whose immune systems may not be quite as beat up and fragile, to patients whose immune systems may not be quite as beat up and fragile. And maybe these things, these immune therapies, will work even better if we move these things to earlier lines of treatment with that immune system is more strong and intact. And so that's kind of the focus of the current generation of clinical trials. And so, you know, we have some offerings that are phase two and then some offerings that are even moving the treatment even forward against some more standard treatments that are phase three and kind of comparative studies. So it's a really exciting time to kind of enhance our existing therapies with these bispecifics.
Speaker 1:And so you have a team of nurses and other health care professionals who follow these patients and follow their side effects.
Speaker 1:And when you talk to them about the clinical trial, you talk about informed consent and what the risks and the benefits are.
Speaker 1:And patients actually inherently not always but a lot of the time understand this stuff very well and can do a good value analysis, like especially if a patient has, you know, six weeks to live, it's, it's, it doesn't take them that long to figure out like, hey, this is, it's worth taking a shot, you know, with this new, new medication. And one of the exciting things about kind of all the immune therapies is you do see these Lazarus, like umlike effects where patients are very sick, they look like they don't have a very limited lifespan, and you give them these medications. And we had never seen this with standard chemotherapy really to the degree we do with the immune therapies. In my opinion, where patients have these miraculous recoveries it doesn't happen with everybody, but you do see it. Where their PET scans go from, you know there will be spots everywhere on their scan, cancer everywhere on their body, and then their next scan you will see almost nothing. And that is very exciting, I think from the medical oncology side.
Speaker 2:Definitely. Sometimes the cancer burdens in, you know, patients who are not responding to first, second line treatments, you know, become a high degree of burden, you know, and that can cause, you know, a high degree, these creating complete responses in, you know, let's say, third, fourth, fifth, sixth line therapy historically has been, you know, maybe a five, 10 percenter. Well, having that be more like a 40, 50, 60 percenter and seeing that tumor burden kind of melt away over a rather short period of time, I mean that can really have a huge impact on a patient from a symptom burden perspective and, you know, a quality and functional perspective as well. I mean it really hits all domains, sometimes in a very positive way.
Speaker 1:Yeah, you know, talking about unknown unknowns. 15 years ago I don't I can speak for myself I would have never anticipated that we would have these kind of responses. You may have. I'm an optimist by nature too, but I just never thought that we would see some of these responses, and so it's a really exciting time, Absolutely so. These bispecific therapies have proven themselves useful so far in the leukemia and lymphomas and myelomas. Is there any data to support their use in solid tumors yet, like breast cancer and prostate cancer and lung?
Speaker 2:cancer right now that actually we're administering here at St Luke for uveal melanoma would be kind of considered a rare sort of orphan disease that you know sometimes doesn't respond to standard therapy so well. So we are offering that for select patients, you know, with solid tumors. I would say that the whole field is likely to be transformed in the coming years by continuing to identify better and better targets for solid tumors and kind of enhancing the immune system attack on solid tumors. I think in blood cancers there's probably a little bit better targets right now there's also probably a phenomenon where the immune system doesn't get quite the level of what we call T cell exhaustion when exposed to blood cancer as opposed to the solid tumors. Sure, I think we're going to see this rolled out to a wider variety of cancers and probably be, my guess, more standard type treatment for solid tumors as we move forward. You know breast, colon, prostate, some of the you know common cancers that you hear most about.
Speaker 1:Yeah, that's interesting that you say uveal melanomas Dr Bradley Smith and myself and he does the lion's share of the work. We're a high-volume uveal melanoma hospital here. We treat them with plaque brachytherapy, where they have radiation seeds implanted on the eyeball for six days and then come out of the hospital, and so you know so. Anyway, shout out to Brad Smith, he's a great guy and he's the surgeon who does the procedure. But you're talking about when the cancer spreads to other organs, which it can commonly with this. Then that medication is used, and melanomas, renal cell carcinomas and medulloblastomas are three solid tumors that I know have a strong immune component to it, and so those are probably going to be the first tumors that they're going to see or they're going to try to use these medications with.
Speaker 2:I think that's right, jason. So all of those kind of share a common characteristic that you know one of the earliest forms of immune therapy given interleukin-2. This was a therapy that stimulated T cells to attack the cancer. It was those cancers that were kind of the most sensitive to that phenomenon. So I do think you're right, probably those are going to be where we see the largest early gains. But I think we'll eventually get smart enough to attack some of these other more kind of immune system resistant cancers, pancreas, those types of cancers, mark what do we specifically have to offer patients as far as clinical trials right now?
Speaker 2:So, jason, bispecific-wise, we've got two studies that are currently available and actively recruiting. One is for patients with third-line diffuse large B-cell lymphoma or follicular lymphoma, giving a drug called epcritimab, and really the purpose of the study is to see whether this can be administered all as outpatient type treatment. You know, formerly with immune therapies we often hospitalized patients due to the risk of cytokine release and neurotoxicity. Well, this study is kind of designed to see whether we can kind of push the envelope and treat patients all outpatient, which I think is going to be the wave of the future. The second study that we have to offer is actually in multiple myeloma. So the lymphoma study I just mentioned is phase two. The myeloma study is a phase three study.
Speaker 2:So commercially available myeloma treatments bypecific-wise are fifth-line plus treatment. So you can imagine that patients in their second, third, fourth line of therapies are sometimes needing more effective-type treatments. Well, that's where this trial comes in. It's called the MAGESTIC-9 trial and basically it's a randomized trial of a bispecific called teclistamab and patients are randomized between that or a standard of care type treatment arm. Pomalidomide, bortezomib and dexamethasone happen to be the drugs. Okay, and it's a one-to-one randomization. It's just to see what is better treatment in a second, third or fourth line setting in multiple myeloma. So it offers myeloma patients the potential to receive this bispecific as kind of a fairly early line of therapy to see whether we can push the bar and make this kind of treatment, this effective treatment, available for a wider portion of myeloma patients.
Speaker 1:Yeah, that's exciting. If it's a third-line treatment, the patient's performance status, I think, would be better, like the patient would be stronger and have more strength and stamina going into the trial than if they had failed five different therapies.
Speaker 2:I think that's a great point, Jason. And sometimes, you know, unfortunately, we lose patients due to either their cancer or other forms of, you know, heart disease or lung disease, before we're even able to give them, you know, fifth-line therapy. So if we can move these more effective therapies into earlier lines of treatment, you know it stands to reason that more patients are going to benefit from them.
Speaker 1:Yeah, that's an attractive option for patients. So, mark, if patients are interested in these trials, how would they get a hold of somebody to figure out how they could potentially be a subject in the trial?
Speaker 2:Yeah. So we're actively enrolling on both of those studies and patients can just call the cancer center number 314-205-6737. Any patient with those diseases we can certainly, you know, consider as possibility or potential option for those trials. We are excited to have been offered several other trials that we'll be opening in the coming months. One is a second-line trial in diffuse large B-cell lymphoma, comparing bispecific versus sort of standard chemoimmunotherapy. We've been offered a trial in mantle cell lymphoma, second line of bispecific versus chemoimmunotherapy, and then follicular lymphoma. Same thing, sort of immune strategy versus immune strategy plus bispecific. So kind of three second line trials trying to move bispecifics up In mantle cell. We don't even have an approval. So it offers an option for patients to receive a quite effective bispecific medicine for their disease when they don't have a commercial option.
Speaker 1:Well, there's a lot going on in the world today, and this is a reason to move forward with some optimism. I also want to thank all the laboratory techs, the PhDs, the scientists, the biologists who've done all the hard work to get us to this point, and it's so good to see some of these things coming to fruition and really making a difference in patients' lives. Well, mark, thanks so much for visiting with us. It's always a pleasure to talk to you. Mark Fessler is a true expert in the field of hematology, oncology, and he's pushing the bar forward every day.
Speaker 2:Jason, thank you so much. Thank you for giving me the opportunity to share this knowledge base with you today, and thank you for being a great friend and colleague. Yeah, thanks so much.