Dr. James Mason provides a brief history on coronaviruses, what makes the current COVID-19 virus different and its impact on cancer patients, while discussing current known treatment options.
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Good morning, everybody. Welcome today. Two of the scripts. MD Anderson Cancer Centers 2020 Cancer Care Symposium Thank you to everybody who joined us yesterday. And if your back today, welcome back. If you are unable to join us yesterday, well, welcome to today's session. I know some people have been chatting for those of you that we're sad that we weren't having this in person this year. You wanted to come to sunny San Diego. You probably would have been slightly disappointed. Maybe coming this year, we've had some rain overnight. It's it's mostly cloudy in a lot of areas here. It'll be a high in the low sixties today, with some more rain happening throughout the day. So not very sunny San Diego this morning. But we're for us. This is This is whether this is what weather looks like in San Diego to us. I know some of you have been chatting already this morning. It looks like we have some people here from Chicago, Laredo, Texas, San Diego, of course. Waco, Texas, Oakland, California Some people from Oceanside. We have some people from Minneapolis, Minnesota, Houston, Texas, and then Redwood City, California. So welcome, everybody and thank you for letting us know where you're all dialing and remotely for us today. So just some morning announcements to go over conference agenda and material, so the conference agenda and the materials can be found on the scripts. Health CMI Conference happened on the Livestream event page. The APP is available free of charge for all participants. Today's program is also being recorded and will be available to access approximately one month after the event. For life stream details. All participants will be muted during the lectures to avoid background noise. For best streaming results, be sure to close all other Web pages and APS on your computer that may slow down your Internet connection. Be sure to close any VPN or office connections that may slow down your Internet speed. 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I think I'm considering. I feel like it's gone pretty smoothly and hopefully you all have enjoyed it so far. I'm going to introduce our first speaker this morning. Dr James Mason. He's going to be going over Kobe, 19, and the oncology patient, and so you'll get some helpful information and things that are unique. The doctor Mason has worked on specifically with scripts, Health The doctor. Mason is a hematologist oncologist who's been in practice for over 26 years. Dr. Mason has a special interest and blood and bone marrow transplantation. He believes in taking a collaborative approach to medicine and is part of a large integrated system of physicians, nurses, pharmacists and specialists, all dedicated to providing excellent patient care In addition to his experience with therapy programs for breast cancer and certain solid tumors, Dr Mason performs blood and marrow stem cell transplantation for patients with Hodgkin's lymphoma, non Hodgkin's lymphoma, multiple myeloma, acute and chronic leukemia and other diseases of the blood and bone marrow. His research focuses on acute leukemias and computational biology. Dr. Mason, a San Diego native, is director of the scripts Blood and Bone Marrow Transplant Program and the Stem Cell Labatt Scripts Clinic, Torrey Pines. Under his leadership, the BMT program offers innovative care incorporating dose intensive chemotherapy and or immunotherapy, and has recognized as a leader in the B M T filled on the West Coast. It's a huge honor for me to be able to introduce him, and I look forward to his presentation. Dr. Mason, Good morning. Thank you for the opportunity to talk to you today about Kobe 19, and the oncology patient. Yeah, it's my disclosures. And so we're all living Covert. 19 has changed the lives of everybody on Earth at this point. So what I was going to do today is to review a little bit about what it actually is. What is the virus? How does it function? Why is it so difficult to control to treat to go away on and a little bit about what's going on with the treatments for it? Why many of these treatments appeared to be to be promising. And then we hear they don't work and a little bit about the future of how Kobe, 19, is going to affect oncology going forward of this next year. So what is SARS Good, too? So it stands for severe acute respiratory syndrome coronavirus, too, So that's actually the actual name of the virus. What it causes is a respiratory disease, a largely respiratory disease, because we'll talk about many manifestations, particularly Jermaine for the oncology patients. But it causes primary recipe disease that we call coronavirus disease coded 19. So the proper name for someone from the diseases coded the viruses. Severe acute respiratory syndrome virus coronavirus to wear saris. Kobe, too. Coronaviruses are a family of viruses. They were first identified in 1966 and our own enveloped, single stranded RNA virus. They have a kind of a spherical, uh, they're envelopes and, of course, shell around them, and that is a spherical course shell. And on that there are these glycoprotein projections would stick out. I think you've all seen pictures of this sort of the tennis ball with little projections on them, and because of those projections that gives him sort of a crown like appearance and that hence the name Krone. So that's why they called coronaviruses. They They're a fairly ubiquitous virus there, all through animal and human populations all over the world. They're not new is not like HIV, which emerged out of Africa perhaps in the 19 forties, and transition from an animal new to human beings. Croteau viruses air far, far from new They've been with us since antiquity. They infect both humans and other animals and their animal reservoirs for coronavirus, which are actually quite interesting and speak probably to what happened in the current pandemic. Um, so a number of animals can can develop coronavirus infections. Some of those coronavirus infections are unique to that animal species or class of animal. Others can be transmitted as zoonotic infections between animals and human beings and then actually back to animals again. That's appear to be particularly from carrying coronaviruses, some of which make them sick, some of which don't and we think that the current pandemic was caused from a bad transitioning into human beings so that we can never really be sure. We believe it is started in the Wuhan food markets in December, November, December of last year's about a year ago now and then rapidly from there, transitioned into human beings. Um, there are other animals. Can Caritas well, civet cats, dogs. Actually, there are. There are well documented cases of transmission for people to zoo animals on, then into personal pets, two cats and dogs not common and typically not very serious. Although I'm sure we've looked hard enough, we could find some serious cases, but it can go back and forth, although we do not think the personal pets and anywhere risk to our patients ourselves in general, that's not really how this disease spreads. Uh, interestingly, I insist in the news This'll week, and I should digressed to say this has been a really interesting topic to review because it happened so fast. You know, this whole thing is, I said, occurred in the last year, um, and with identification of the virus and and so forth in really a very short period of time. And there, there. As of a couple of weeks ago, there were over 10,000 publications, Um, in revolving around Sarobi started Kobe, too. Andi was a couple weeks ago. I'm sure there's 11 or 12,000 by now. They're carrying an incredible rate of information dissemination, Um, and one of things which you may have heard about just this week last. Actually, 48 72 hours was in Denmark, where there is now a quarter of a million people locked down because the mix which they farm in that area have developed coronavirus. So it's the zoo developing essentially Kobe infections with a mutated virus, which we don't think it's gonna matter too much in terms of the infectivity or severity of infection from it. Few cases in human beings through a couple of dozen cases already in human beings from the make. Probably this is going to be a sea change in terms of the disease, but it might have some implications for vaccine development because of these things mutate. It makes harder Thio effective, really develop vaccines much the way it's hard. Thio develop influenza or cold vaccine. So so he goes back and forth and different animals, and it really has a lot of implications for future events as well. So as human beings experience this, there are really two types of coronavirus infections. There are seasonal coronavirus infections, and then there are the epidemic or endemic in this case infections, seasonal coronavirus, infections we're all familiar with. We've all had them. So there are four coronaviruses which are common in human beings and caused what we think of it is the common cold. There are other viruses also, many which cause the common cold there, rhinoviruses and others. But there are four types of coronaviruses which do this. These are not the same coronaviruses that we're experiencing with SARS or mirrors thes air, different viruses. But they're closely related now. One of the things that comes up is if you've had a regular seasonal coronavirus as part of a common cold syndrome, Does this provide any protection against SARS? And as far as we can tell, the answer is probably not much if any, although it's a little bit unclear. There has been some signal to say that perhaps infections are less intense under those circumstances. It could also be some reason to think it could be worth. In certain ways. We'll talk about that a little bit, but any event again, As I said, these are not new viruses, even part of humankind. Mankind forever. And they're part of a common cold. However, they can change mutate, and you can develop new virus that come out of animals. And these are the ones which caused the large scale epidemics or pandemics. There have been so far three of these that we talk about there were surely others. We just didn't identify them in the past. And again, these are not mutations from the season. The cold viruses thes are new coronavirus transmissions out of an animal vector. There was SARS Kobe in 2002, which we all knew about. Fortunately, it didn't get too far into human population. It did have some worldwide spread because of air travel. It had a big impact on China, and Hong Kong. Aan den kind of burned itself out. During that event, there was a lot of research. The viruses identified it, Waas typed it, waas and their attempts to treat it, which we then had at our disposal. When the current viral infection began in which we have used a decade later, there was murders. Will be numbers is the Middle East respiratory syndrome and that's coming from a camel, actually. So it became pretty clear early on, the camels were affected for this this limited. It's, uh, immediate area of transmission, obviously, due to what's coming out of on banned. The virus itself didn't spread very well again. There was some worldwide spread by air travel, but typically it was contained. It did not spread very effectively by Arizala on my phone light, and it burned itself out. Although it is still out there, um, it actually go away. It can still be found and then approximately another decade goes by seven years, and we have stars. Kobe too. So this, of course, um, reared its head about a year ago in China, probably coming out of an animal vector. Probably back. Onda rapidly started to spread in human beings. This was quite different now than than the first stars emerge. This one started spreading much faster. It seemed to be much more transmissible from human to human. Um, there is a lot of politics in their early days. China very quickly however, by middle of January is able to produce the R N a sequencing of the virus for the world to have. But by then, of course, it had already started spread out of China, first into Europe and the United States in ways in which we probably did not fully appreciate until it was well integrated into the population. So by the time we began to enact locked down measures in Europe and in the US and February March, the viruses who was already well out there spreading from person to person. So how does it do this? So the virus spreads much to wear cold virus does. It is very, very closely related to our common cold. Viruses cause the spreads a little bit the way influenza does that, being that there's both an aerosol transmission, you could inhale droplets of the virus on Do you can get infected that way, and there's a foe. My transmission, that is, you can touch surfaces, which there's living virus, and then inoculate yourself by touching your eyes, your nose and your mouth and develop infection in that matter. Both are true with this particular virus. It appears that infectivity is very high in families. We know from cold viruses, for instance, that if a family member has the common cold yeah, and you're living at home with them, it's about 30% chance that you're going to get the cold virus as well. It appears that with uh, with covert infections, it is a little bit higher on that. Maybe a 50% chance that it was a family member involved that you're going to get the virus as well. And again, this is mostly from media air between enclosed environment. That's why now we believe the virus is becoming more active in the winter because we're going back indoors. During the summer months, it went down quite a bit. People outdoors off the air blows the particles away. Less probability of infection. It all comes down to probability at the end of the day. Once you're inside those, those viral particles can hover in the air and be inhaled. They settle on surfaces and be picked up that way. There are surfaces around the door, knobs, tables, bathrooms of moist towels where the virus can live quite a bit longer. These are all areas of infectivity, and so what we're seeing is that individuals develop these infections, not outdoors, not in community settings such as going to the grocery store things like that. That really is a matter of bad luck to catch it that way, if you're if you're wearing a mask and wash your hands. But when people have family gatherings and social gatherings were master off, people are close to each other for sustained periods of time meeting hours. That's when the infectivity rate just shoots up. And that's when you start to develop these clustering of infection. Because now, when you have that kind of environment, infectivity rates probably about half. And so if you put 10 people in a room like that during it Thanksgiving gathering, for instance, it's not unreasonable to think that half, um, are going to be infected within the next several days. How does the virus do this? Well, the virus utilizes something called Ace to angiotensin converting enzyme to, uh, this is a protein that sits on the surface of ourselves. Naturally, it's a natural part of the human body, and it's particularly expressed in heart. G. I track lungs and nasal mucosa. His role is to neutralize angiotensin two and controls blood pressure and this other vascular things. But the SARS virus the coronavirus is have adapted themselves to use. This is their portal of entry into the self. So what happens is that once you inhale or otherwise, inoculate yourself with the virus into, say, the nasal mucosa, the virus that identifies the East two receptor latches on and inject itself into yourself. And whether this be amazingly poster or the lung, they become particularly affected. This is why we think that the virus hits those tissues so hard. And why also can hit other tissues such as cardiac, for instance, and G. I tract because this is where the receptors are in abundance. So this is relevant for many, many reasons. One. These receptors increase with age, and so the older we are, the more of these receptors there are. In addition, many of the medications that we have developed to control blood pressure, such as the inhibitors and the angiotensin two receptor blockers. Eso got arms up, regulate the H two receptors, and so, at least in principle, um could exacerbate the predilection to get these infections, but also potentially provide portal for treatment with the with the virus. The receptors are also increased in smokers, so this is something which has become very clear. The individuals who are older, who are smokers on many other lung diseases are enhanced risk for a bad outcomes, and it may be far more than simply that they're already have poor loves, quote unquote. But they actually have more receptors, and so they can develop more enhanced infection. Um, interestingly, there's sort of an asthma paradox in the asthma. Patients don't seem to be experiencing this quite as much. And that may be because although they have the receptors in their lungs, they may even be increased by the inflammation they many asthma patients use inhaled cortical steroids in cortical steroids, decrease the expression of the receptors and made factory kind what we call as the paradox. So as patients develop this infection, it can manifest in many, many different ways, and the biology of this is really just kind of beginning to be understood. And I said there's 10,000 publications, and probably most of these publications involved not as much the clinical manifestations of the disease but as the biological manifestations of the disease and trying to really understand what happens and why some people, many people, that most people develop very little clinical manifestation from the virus. Depending on your age, you may develop virtually not yet. Others develop a life threatening and fatal infection. A lot of this appears to resolve revolve around in part is we talked about the president, the number of receptors, but also what happens once those virus gets into those cells? The person's own immune response. So there are two basic types of immune responses. The innate immune response. And there's adaptive immune response. The innate immune responses basically that part of the system, which is primed and ready to go and response to chemical signals from whatever is occurring inside the body. The adaptive responds to mawr to the immune responses which happened subsequently. They it responds to an teaches that are present inside the body. And so you have these cells what you call it, NK cells, natural killer cells. These are part of the innate immune system, and they're the first line of defense against acute infections and cancers. Well, at the same time, they regulate the adaptive immune response. So there there they can respond Unlike other types of T cells, they can respond on their own immediately to, uh, infection or information. Yet they also then feed back into the adaptive immune response, and so they can trigger a much broader immune response than what they themselves do. And they appear to be functioning in a very big way. With Kobe disease. Three NK cells function by regulating their activity with both activating and inhibitory receptor. So imagine this immune cell that has activated receptors, which will turn it on, and inhibitory receptors, which will shut it down. And that's how it actually functions in the body. The Activating Receptors initiative process of Saida toxic Congratulations. So when it's activated, the cell has thes thes side. A toxic congratulations, which flood the body with CIDA kinds. Immune messengers to create inflammation in the body, killing the cells which are immediately around it, which are presumably they're to be killed because they're either infected or their cancerous, and that's the job of the cell. The problem is, then the cell is supposed to back down and become more quiescent again. That's usually done through a number of inhibitory receptors, one of which is the MHC type one receptor or like it. Problem here is that once this process begins, there are natural killer receptors on many of the tissues infected with coronavirus, and as a result, the system becomes kind of a cascade effect of side economy release and then exciting the T cells again creating side a toxic Olympus eyes and activated and K cells. In some individuals, this leads them to more and more information and tissue damage and the tissue damage being most importantly, of course, lung damage and, uh, pneumonia. So this is what we call side a kind of storm. And it's been a big part of the biology of those patients who become sickest with this disease. It is a part of even in those individuals who don't think I'm very young. We've all probably experienced this when we had that particularly difficult common cold where you really felt quite fatigue. But you also fell a little short of breath. It's hard to take a full inspiration. What was happening there was cited communities in the lung inflammation along inflammation makes the tissue mawr stiff, makes it less dispensable, and you perceive that is not being able to take a full breath. But this is magnified many, many times with the current Kuroda box infection. It also provides potential port of authority, and one could shut that down biologically than one that could potentially prevent those types of end stage tissue damage. This could be done by either attacking the very end stage Siddiqui's release, or perhaps a little more approximately affecting the process. Which leads to. We'll talk about that because we talked about therapies in a moment. Lastly is part of this this immune response. What happens is become sort of a two edged sword. Not only is there tremendous inflammation generated as part of it, but the cells themselves a side of toxic emphasize the natural killer cells become exhausted after a period of time, so you sort of get the worst of two worlds. You have a great deal of inflammation, which is that destroying the patient's lungs and potentially other tissues, and the same time the immune system is becoming exhausted, unable to respond effectively to an ongoing infection. And this has been the problem, particularly in our older patients with this disease and in those individuals of any age who developed severe coronavirus infection, so that's deserted the short version of a biology. As I said, it's changing fast, and there's a lot of information, which comes out literally every week on the topic. The information on the NK receptors was just updated just a sort of a week or two ago on bail. Be much more to come on This, and this is, uh, this is a big area for the development of pharmaceuticals, which might potentially be able to treat the disease. So what are the clinical manifestations of coronavirus, too? Well, it is an upper respiratory infection in his essence, as we've talked about so fever, cough, shortness of breath, fatigue and particularly in younger individuals, diarrhea with nausea and vomiting can occur. All of that can occur in any population. Many individuals are asymptomatic. Young Children have minor infections or are asymptomatic most of the time. Are there serious cases? Of course there are. But from a probability standpoint, they're really very few and far between. As we get older each increasing decade, the chance the infection being more serious rises such that by the time you're over 80 the chance of this severe coronavirus infection is in a range of about 15% so it's very, very high. The chance of mortality is very high, so it's very age dependent. It's also dependent upon coal mobility's. We know that individuals who have a lot of vulnerabilities, particularly obesity, diabetes, some extent cardiac disease, right? A much higher chance for for your outcome. Obviously, individuals who would have a lot of lung disease office are as well. Cardiac disease definitely occurs, and it's something which is being actively studied now. It was underappreciated in the early days of the coronavirus infection, But now, as we see more survivors of infection, as we study individuals more with active infection, it becomes clear that the virus can cause mild card itis and other cardiac manifestations, including sudden death. This again is not surprising, given the fact that these two receptors air on the mile cardio. It was to be predicted. Many individuals are describing what we would call brain fog. They just can't concentrate while after the infections. Exactly ideology. This is not understood, but it seems to be quite riel. Neurologic manifestations in general occurred. It's very common, particularly early days of the infection to have headaches, and biologists and I think it's an underrepresented symptom complex. And then lastly, there are all the all the signs which symptoms we talked about. What are the signs of? This is well and whatever. Some of the symptoms, well, one is quite gil apathy. We know that these individuals, and particularly intersecting with our field hematology oncology, are very susceptible to enhance Kregel ocrates beyond what would otherwise be occurring to the extent that we actually now have algorithms or antiqua aggravating patients with significant coronavirus infections. Additionally, as I indicated, there is immune exhaustion which occurs and so one of the earlier signs signs of diseases, in fact length leukemia on the CBC And then, of course, the signs and symptoms and multi organ system failure in general. So what are the treatments for SARS? Cov, too. They are evolving. And as you all know, there's been enormous controversy and and the debate about the efficacy of these various of these various treatments. Um, and I think as we look at this in the last extraordinary year, it has to do with the rush to develop therapies, which is really unprecedented. I mean, it's never really been anything quite like this is the worst pandemic and 100 years. We have technologies now in terms of information dissemination and drug development which we've never had before. And when you merge all that together there's been this rushed to publication is rushed to develop treatments, which is completely valid. But the result of that is we don't have the advanced studies and the understanding of what we're doing, the way we have had with other illnesses. Very often they're analogies made to HIV AIDS. Yet that was a disease which emerged slowly and in retrospect, took 20 plus years to get a handle on this. We're trying to get a handle on in a few weeks, basically in months, and as a result of that, there's been tremendous confusion, two hugely exacerbated by the political environment which we found ourselves in the last year. And as a result of that, there have been things brought to the clinic much faster than normal and with an unsure amount of science behind them. One of my favorite Richard Richard Feynman quotes is the first principle is that you must not fool yourself and you are the easiest person to fool, and I think that's been particularly true with health care practitioners in this in that we've been so happy, so happy to have things to do for these patients, that we fool ourselves thinking that they're working well when in fact, they're clearly not so anti viral therapies. We can break this down by looking at certain core ways of looking at the therapies and viral therapies in, you know, ma janitorial therapies. Uh, other immunosuppressive therapies and I won't go into vaccine therapy. Vaccine therapy, obviously, is the Holy Grail here until we have herd immunity from the vaccine, not natural herd immunity. We don't want that that's going to result in tremendous number of deaths. But what we want is herd immunity from the vaccine, as we have with other diseases that will actually stop this. And obviously there are many, many approaches to developing vaccines, which are ongoing now, and we will have vaccines have in the next year or so. But until hundreds of millions of people are vaccinated, the disease won't stop. So what do we have in the meantime, to help to control it? Well, antivirals were obvious short term solution here. If you think about it, though, it's probably not surprising we haven't made a lot of success here. Antiviral therapies in general are almost never curative. Unlike antibacterial therapies, where we think curing people since penicillin and really a little bit before. And a viral therapies are suppressive but not curative. They're not viral cycle there. Viral viral static. That's true of herpes virus infections. That's true of HIV AIDS, although we're doing really well there. And that is, unfortunately true. Here is well because this is not the first SARS infection. We had a number of viruses which had already been tested in the first stars and emerged, and it's not surprising we adapted those here. We also tried the antivirals that were used in AIDS, one of the most successful and most I guess discussed. Uh, viral therapies has been rammed. Disappear from the severe is a inhibitor of viral RNA dependent RNA preliminaries. So the specific RNA antiviral a study was done early on called the Act One study. It was a multinational study, and they looked at about a little bit over 1000 patients. They were randomized to receive, uh, disappear 541 patients versus a placebo in 521 and the data suggested that they were recovering faster. These were very sick patients needing at least option therapy, if not Mawr, either innovation or ECMO. And it suggested that it's shortened the period from by about five days, 10 days versus 15 days to recovery. Of those patients who are going to recover the medications given intravenously, a 200 mg load and then 100 mg a day for days two through 10, and doing that there, there was a signal that patients were getting better and indeed getting. Of course, it is worth something to get out of the hospital or become, well, a little bit sooner and value. But the bottom line and anything like this, that really the gold standard is are you going to live longer? And that, unfortunately, has not been shown to be the case And again, Part of the problem is lots and lots of small studies which are not definitive. We do have a couple of large studies of which are becoming very helpful to us in understanding these things. One is the Solidarity Trial, the Solidarity trials organized by the World Health Organization, W. H O involves over 11,000 patients in over 30 countries, so it has the strength of a very large number of patients. So better statistics. It also has the strength of being in multiple countries so that the outcomes are first of all applicable to other countries and understandable too. So there's less distressed about, but also because it may be some biological and genomic differences in populations that affect this particular virus. This will help you to less of that as well. And unfortunately, with him disappear, it showed no survival advantage. Um, in fact, the outcomes are very similar in the two groups that the mortality rates in a well stated group of patients was about 11% in each group. I should digress to say this is very similar for bait and if you're on, which also had a mortality rate of about 10 or 11% in each group. And this was all. This study also was very helpful in showing no survival advantage for the much hyped hydroxy clerk win. And this room is it so put the bad the fact that these air going to be life saving medications, the survival doesn't seem to be different between individuals to receive them and individuals who don't, um, company promoting this particular antiviral is quick to say it hasn't been as effectively studied yet, and it may be some truth to that. And it may be still be some suburbs of patients to do benefit, and it may make auction dependency. And those individuals were going to get better anyway, um, a little, a little less prolonged. But for those individuals who are are, of course, to a poor outcome, it does not appear to make a difference. Immuno modulators. So the first of these, of course, is hydroxy Clark Win, which was used very, very early on in the disease. It became politically hyped very quickly, as we all know, and this is very unfortunate because it appears to have really no role at all. It does not appear to improve outcomes in the disease when used to visit, surmises frankly, dangerous on. So we do not recognize that as a viable therapy from this very should say is that we use the Bible therapy because it may make a small difference. Other immuno modulators air still being studied. Um, they're excited. Multiple trials, including the UK recovery study. Another large studies thousands of patients and there are a couple of different approaches here which are uncertain benefit now, but of some promise and other approaches like this will be developed. So what is toast Elizabeth? So total is a mob is an I l six interleukin six inhibitor, which we use in rheumatology conditions. We use it in our fields and hematology oncology for individuals having, uh, excited time release in car t therapy. And that's where I'm most familiar with it in my world. But it is a big part. Interleukin six is a big part of the end stage side a guy and release inside the kind storm and patients were very sick with coronavirus as well. So Tosi is being used in that in that area and again with uncertain benefits so far. But there is a signal to site it might be helpful and should be continued to be studied. If you think about the immune response to the coronavirus as a tree with the branches of the tree being those effective side of kinds like I'll six TNF Alfa, etcetera. The trunk could be represented by other types of of, uh, enzymes such as Bruton kindness and routing kindness. So B T K inhibitors, which we're very familiar in cancer, right? This is a brutal native. This is calif route, etcetera. That burden of these are agents which affect the whole side of kind process much earlier on. So perhaps a way of dealing with this is not to try to pick off individual cyber kinds like interleukin six once they're already out there, but to try to block the process from ever occurring to begin with. And so their ongoing trials. Bruton Chinese inhibitors to see if in individuals who are being developed more advanced coronavirus infection, we can shut down that that side of kind storm before it ever occurs again. This is not something you want to prescribe for your patients outside of a clinical trial. Um, this doesn't necessarily mean that your patients who happen to have, for instance, mental cell lymphoma or CLL who are already on a routine Chinese inevitably going to be protected from from the severity of coronavirus infection, therefore, could be more cavalier. But there is some reason to think for this may be a productive area of research and their ongoing clinical trial. Yeah, Now the glucocorticoids. Well, this is, of course, a very, very old family of medications decades and decades old. Um, that we've understood since the early part of the 19th century that's a methadone is one of those that has been used with some effect in coronavirus infections. But there are some caveats along with this to this is probably actually one of our most effective medications. But the caveats are both the degree of efficacy and what can happen when used inappropriately. So the recovery try again looked at a randomized group of patients. About 2000 patients there, randomized in a 1 to 2 fashions. About 2000 got. That's a method zone. About 4000 had usual care, not this evil but usual care. Overall, the mortality rate in these very sick patients and these were so too dependent patients, patients innovation. These patients on ECMO was about 23% in the depths of methadone group and about 26% in the usual care group. Not a big difference, but it was a statistically P value 0.1 It's statistically valid difference and therefore meaningful to us in clinical care of these patients. But this was not the home run that we obviously all wanted. Nevertheless, because the state appears to be riel, um, this has become a standard of care now for patients who are very sick with Corona virus, too. It should not be used in the big copy of those. It should not be used as a as a prophylactic. So our patients are getting decks and methods own again with our myeloma. Patients taking their weekly 20 mg of decks are not by any means being protected against coronavirus infection and the god goes back, Thio seems, with our other patients receiving these various medications, they're in no way immune. Moreover, the opposite may be true. So when we look at patients in these studies who received Dexter Methadone, who did not have severe disease, did not yet need go to supplementation. The curves flipped and the outcomes were worse. So it may be, as we all suspected, that is actually immune suppressant and making it condition and the susceptibility of the patient worse and so therefore it should be used in the U setting. It should be used in decompensating patients, setting as a standard of care but shouldn't be used in those patients who have mild disease, so a direction to convalescent plasma. So this was how I became involved in this we in the stem cell program here in scripts of a very large collection program for stem cells. And we're actually one of the largest collection programs anywhere for the National Maradona program, collecting hundreds and hundreds of donors per year. When coronavirus hit in March, the program was effectively shut down because we're going to get donors into the program. I'll talk about that in a couple of minutes, and as a result of this are freezes. Nurses and our machines were literally sitting around. Convalescent plasma has been used for decades for the treatment of viral infections, that concept being that if someone has had a viral infection, they'll have made neutralizing antibodies to it, hence their protection from further infection. And if one collects those antibodies from the plasma, they could be given to others with therapeutic effect. This has been done for decades with various diseases, and more recently it's been done with the first saris infection. It was done with murders and has been done with Ebola in the last several years with probable efficacy. As a result, a male clinic generated, government funded program was rapidly set up to disseminate plasma to those individuals who were ill from coronavirus infection collected from individuals who have already had documented coronavirus infection. We participated in the early phase of that I've studied. Our program is very quick to set up the program. We have the capacity to do that in the 1st 30 or so Patients treated here in San Diego came out of that. The script experience Waas, that it was a very easy thing to do. The donors were very willing to donate, and we're in good physical health, even though some of them were still testing technically positive for coronavirus by PCR, we believe these fragments of our name, not actual effective molecules. Nevertheless, there viral titles were already up by a couple of weeks afterwards, and this can be can be collected. The process is simply a process of fairy sis, so for those not familiar with it, basically what happens is that the on ideas placed in one vein another. In another vain, usually an anti cubicles, the blood is put into a free test machine, which centrifugal E separates the blood into its components. You can take off whatever component you like my field. Normally, we take off a modern nuclear cell that's of the size that contains stem cells. You can also take off platelets events, what you want, and you can take off plasma. Within that plasma fraction are the neutralizing antibodies. Typically, to do this, you would take off approximately 4 to 800 m els of plasma. And within that, that's one or two units of dosed, uh, plasma. And that should be enough neutralizing antibodies to treat a patient. The risks are that the idea risk so the individual donor has to be beyond their period of infectivity, which means they have to be at least a couple weeks out. They have to go through the normal screening process that we would with any other donor, looking for every other type of infection hepatitis, HIV, etcetera, etcetera. There's quite a long list of a nationally bond. Then once you've done that, the products still could have some negative consequences. There's no free lunch here. There is a volume to this. So they said, a unit is is between two and 400 MLS Uh, rather for 800 MLS. And so the volume of the infusion itself can cause a transfusion related cardiac problem. It's called Taco. In addition, the antibodies president can cause transfusion related lung injury. It's important if you're doing this, that individual female individuals donating have be screened for H. L. A. Antibodies if if they're not in the Liberace. And then lastly, there's a very radical risk that if someone has had coronavirus infection, um, that the antibodies could actually exacerbate the clinical outcomes much the way a second dengue infection will be worse than the first. And so this is not a entirely risk free type of therapy. How well does it work? We truly don't know. As many of you know, there's a lot of politics around this. Earlier in the year, when it was touted, is decreasing the severity of disease and bad outcome by 30%. That's simply not true. The study has not shown that so far, but there is a signal that it could be useful therapy and in some individuals may help them to turn the corner, as we alluded to earlier Since ace to is the receptor for SARS. Cov to therapy is looking to block. That may have seen efficacy, and there's a lot of ongoing research into that as well. ECMO extracorporeal membrane Auction nation For those individuals who are very second of end stage disease can be life sustaining. It causes lymph opinion, however, and so it may have a negative outcome itself. And then I want to talk a little bit about anticoagulants and curricula. Apathy. We know that individuals with this disease, particularly those individuals who have severe disease but even some who have just really moderate or even less than modern disease even enhance risk for curricula, apathy and coagulation events. Individuals who are already have a DVT, or P E, or Heidi Donora greater than 2500 should be antiquity with pepper noise, if possible. But the question then becomes what to do later on for individuals who are being discharged from the hospital in many programs, including ours, have established programs where they receive a picks, a ban river rocks, even for a month post transplant to help prevent those secondary coagulation events, which can be so difficult and potentially life threatening, receive this, particularly in our ICU patients with life threatening or limb threatening events. But this can also occur in the outpatient setting, where patients can have heart attack, stroke or other events. And so there is some rationale for a low level of of antique regulation for a few weeks. Posting media infection. Is there a role for a traditional Chinese medicine? This originated in China. They had the initial uh, experience. About 700 patients were given. This particular um product, which is a is a concoction, actually deke option of about 25 different herbal products 20 to 25 depending on how it's made well in China. About 700 patients were tested, about 450 of those patients had a very rapid recovery from their coronavirus infection. But if we talked about, we know that will occur with many people, and so does that really mean anything we don't know? We do know that the number of the herbs in this particular product, which is continues to be used, particularly in China, have a number of anti inflammatory and anti viral effects, but again there, 25 of them in the product. So it's very hard to sort it out, but there's ongoing research to do that and then a little bit about cancer character independent. How is this change? What we do and how this has changed, what we want to do in the ongoing pandemic, because it's not going to go away as we just talked about our current science behind. This is still very input. We're trying to develop better antivirals and I inflammatory agents immune modulators vaccine. But none of it has happened yet. It's not gonna happen for the next several months or longer. The virus won't shut itself down since it's established now across the world, we know that it is is going up in Europe. It's going up in the United States as we go into the winter months and again, herd immunity will require that we have about 50% of the world population. Hundreds of millions of people in the United States alone. We need about 150 million people. They have immunity that will require vaccination and not natural current community, because that would result in an incredible number of deaths that we try to develop naturally. So this is gonna be with us for a while. How do we manage that? Well, we manage this, I think, by doing telehealth, we know that currently, telehealth is comprising about 20% of what we do, and that's probably not gonna go away. That's probably going to be a sea change and how we practice cancer care, particularly for those patients with things like Monaco Commodities who really don't need to be physically seen every three months. So this will help provide some reassurance to our patients and some safety measures for our patients that we're going to treat them at the same time. We must provide treatment because we know that in addition to the coronavirus effect, there's a much larger ripple effect of secondary delaying care. Patients are not getting their mammograms. They're not getting their vaccinations after transplant. They're not getting any type of regular medical care the way they used in the way we believe they should. This will result in secondary problems with more advanced colon cancers, more advanced breast cancers, etcetera, being found and with a negative outcome for our patient population. So we have to fight to get the patients into the clinic, make it safe for them and get them on going for regular care. Despite the fact that we have an ongoing coronavirus infection, we know that certain patients are more susceptible within our cancer population to in the bad outcome if they get and basically what we've already been saying. And what is common sense? Those individuals who have a performance status greater than peacock to those individuals who are have ongoing chemotherapy, those individuals who are already linked, the Penick, etcetera. They have a worse outcome and may need to have some delays in care. But delays and parents have to be balanced against the outcome if the land care occurs in terms of their disease. Lastly, I'll end by just talking a little bit about my field and where that's going during the coronavirus pandemic. This has probably been the most impacted of all of them, of all our fields, because a medical extensive transplantation has become over the last 20 years, highly dependent upon donor registries for the ability to find stem cells to do transplant. And what happened is Aziz. The coronavirus infection started, the world registry collapsed and it had to because the cells are collected. All of the world in a shipped around in a way in which sells from Belgium because come to San Diego from San Diego to Japan as they needed for transplants all over the world. We've been a leader in the collection of those cells, and there are about 100 programs worldwide, which collect the cells and move them around, utilizing about almost now 20 million potential donors. But when coronavirus happened, a number of things occurred. Number one, the donors became fearful of going in to have their Selves collected. And they're doing the necessary work out. The airline industry, which is so Tremain to the movement of these cells, collapsed in many ways in which we couldn't simply get products on the airplanes in a reliable way. And then we had to deal with the fact that both the donor and the recipient might become infected during the process. So we responded to this in a couple ways. One. We differed transplants, which were not critical, so patients receiving multiple myeloma transplants were delayed by three or four months is going to be some impact of that. But that was felt to be the safest thing to do. Individuals with acute leukemia, of course, could not be delayed. And so we did the best we could to get cells shipped to US theme National Marrow Donor Program and other similar registries reacted to this by by gearing up by requiring the cryo preservation of the products this allows time. So normally, stem surprise to ship fresh from a recipient in one location, the ship overnight to the receiving location, and then they're given to the recipient they're given to the patient who has at that time usually received a lethal conditioning rich. That obviously couldn't happen. For all the reasons we discussed, what if the donor came down with Kobe before their nation? We've had that happened here in this program. What if the airline didn't have a flight? What if the recipient developed code? What if a caregiver did so? The products would be now cryo, preserved and then held for several weeks before they could be used. And this is this tided us through and got us through that difficult hump in the spring. And now that the summer and things began to thaw out began to move a little bit more fluidly. What we're learning, though, is that these prior preserved products are not the same as a fresh product that way. No this and we've been crying, preserving Ecologist products for 40 years. But this is providing an opportunity to see what happens with allergenic products. Which acquired, Preserved, we're finding is and there's a publication is a few days ago that there's about a 30% loss of efficacy inside that product. And there are various things which are related to that has to do with the number of white cells in the product and the length of time that has been shipped and thought and so forth. But there is a big detriment in efficacy, and so this has some implications. And so, for most of the patients is we'll have very little impact because, like so many cells, that 30% rock really won't mean too much. But for those products which would have been considered marginal, which would have normally been considered marginal, but okay, this changes that 30% decrease their means. You can't move forward and so there are many, many implications. But again, this is if something will have to adapt to as thes necessary and life saving treatments have to go forward despite our So that concludes the bulk of my talk, and I'll be happy to open up for any question. Thank you so much, Dr Mason. Um, that was very informative and easy to follow and understand. So thank you for that. Um, for the attendees. Don't forget you still have time to ask a question. Using the ask. Ask a question button on your screen there, under the presentation. I do have one question that's popped up so far. Dr. Mason for you. Um, why do we not use singular toe help with CIDA kind storm? This sounds similar to reactions to Dar selects. Have we looked at what receptors? The virus is hitting Medicaid, like we pre Medicaid for Dar selects steroids. Understands this is not really recommended, but a motivating Benadryl. Singular. So all those things have been tried through. The problem is that when the virus first hits your asymptomatic and there is a period of infectivity which occurs over over four or five days, median time to develop symptoms is about five days median time to develop severe symptoms. That that's that occurs about 12 days. So this is long period like getting a dark selects infusion, which occurs basically comparatively instantaneously, this kind of slow burn and so the self. So you would have to identify somebody who's becoming sick. And of course, they don't know they're becoming sick for five days and then take medications like that. Um, and again, in some ways, we're already doing that experience being done in those individuals who have asthma or pathologic conditions. Will they statistically have a lower rate of severe infection? We try to teach that data out, but that's how it could be stated. Epidemiologic fashion. Okay, Excuse me. Another question that came in for patients with the mythological malignancies or thrown both side of Pena from treatment who are hospitalized with co vid. What is your platelet threshold for holding anticoagulants be about the same as it normally is. About 50,000. I think when when played account drops below 50,000, you have to be very cautious about giving and regulation outside of a of an ongoing active robotic American. Okay, another question came through. Do you think patients should be tested for covert before each chemotherapy treatment Really controversial? Nobody really knows. In the ideal world Well, if we look at the most effective areas places for covert control, it's been those places where you can test lots of people, lock them down, and then traits. We have been able to do that very effectively. When they do that, all the United States, um there are programs now considering testing whole cities in Europe right now, this is an effective way to do this unclear. The microcosm of that would be to test all of our cancer patients all of the time to see whether they're they're active. The problem with this is you have to be testing people all of the time because since the virus is so ubiquitous now, if somebody test negative today, that has nothing to do what's gonna happen tomorrow? And so if you do this, you would have to test everybody as they come in that morning for real time test in most places, simply can't do that logistically. Thank you. We have a comment and question here. The attendee said, Your talk with excellent. Thank you so much. The question they have is have you seen an increased incidence in shingles and immuno compromised patients following infection with Coleman? It's a great question. Not that I know off. Um, it would be reasonable to think it could happen, though, Um, but I'm not aware of any data to say that there's an increased risk of there's a disaster post Kobe, but it wouldn't surprise me if that's true. Another attendee requested, if you could review the ace two receptor effect again, so so. The the H two receptor is the port of entry for the virus. So when the virus when you encounter the virus and it gets into the nose, the nasal tissue or lung, it enters the cell through the through the eastern receptor and then once into into the cell and can replicate and do what it does. So if there are two important aspects that one individuals who have more receptors older people, individuals of co morbidity is etcetera. We have a greater risk simply because more virus can get in or dose effect. The second is is an area of research because if you could block that, it's possible that it could be some ways to help to prevent severe infection. The individual that very high risk could take a blocking medication, for instance, which would lower their probability of a preemptive therapy much the way we do with high risk HIV patients for HIV prone patients. Something like that. Thank you. So far, no further questions have popped up again for the attendees. We have a few more minutes before our next speakers. If you would like to ask a question, please click on the button that says, Ask a question. We just had one pop up. Have have any useful conclusions been drawn from the lower rate of cove in 19 infections in Africa, where most health care systems are not as strong as in Western countries? Was it justice? Was it just a simple? Is people following precaution instruction better in those African countries? I know it's really interesting because the heavily heavily impacted countries of most developed countries obviously Europe, has been so heavily hit industrial China, United States and the fear waas early on in the disease that this is going to be devastating to Africa. But it hasn't been the case, and we're not sure why. It's not the case. Does it have to do well, Someone could be reporting to be frank, Um, but it's probably more than that. I think we would know if there was devastation occurring there. So what does it have to do with Does it have to do with patient population? Doesn't have to do with preexisting or concurrent infections, which could in some way be protective. We just simply don't know. But it is that you find it. Thank you so much.
