It is my pleasure to welcome Tammy.

Transcription

1 AAMDSIF_ Page 1 of 19 This is a pre-recorded presentation, so the presenter will not be taking any questions. However, all questions asked during the live presentation, along with answers, are included at the end of this presentation. To learn more about our upcoming patient and family conferences in your area, please visit AAMDS.org/conferences. To view other recorded presentations or to register for other live online learning events, please visit AAMDS.org/learn. Welcome to our webinar titled Understanding and Managing Iron Overload in MDS. Thank you for joining us. My name is Angie Onofre, director of patient programs at AAMDSIF, and I'll be moderating the presentation today. As we get started, I would like to acknowledge Celgene Corporation for providing an educational grant to help support this webinar program. Today's presenter is nurse practitioner Tammy DeGelder. Tammy graduated from McMaster University with a bachelor's of science in nursing. She worked in the in-patient hematology and stem cell transplant ward for four years. At this time, she received her certification in oncology nursing. She then went onto clinical trials where she worked with both solid tumor and hematology phase one, two, and three trials. During this time, she graduated from the University of Toronto with a masters of nursing in the acute care nurse practitioner program. For the last six years, she's been working with outpatients, stem cellstransplant population. She is an advocate of patient education and support groups and has done many talks on CML, MDS, and myelofibrosis. It is my pleasure to welcome Tammy. Thank you very much. I must say, webinars aren't my forte because I usually love to look at my audience and see whether you're bored or not, but otherwise, now I'm just going to sit and talk at my computer and you can listen as wish and you won't have to worry about whether you are you don't have to worry about whether I'm looking at you or not. So, I'm Tammy DeGelder. I am from Hamilton, Ontario, and that is about 45 minutes on the other side of Toronto. So, that's where I'm located. And if you go to the next slide, I have I can't see the slides right at the moment. I am not connected to the website, so somebody is going to be viewing or proceeding on with the slides and moving them forward. My disclaimer is that I am Canadian, and I must say we have the most stylish prime minister alive, Justin Trudeau, Page 1 of 19

2 AAMDSIF_ Page 2 of 19 and he excellent at yoga. So, that is where I'm coming from. I'm coming from a Canadian root perspective, so I know there's an international population here today, so I won't be able to answer questions on drug access or what actually is happening. I'm talking from a Canadian perspective. So, if we go to the objectives of this presentation, we just want to understand it's about iron overload and we just want to understand what the normal iron is in the body and how do you become iron overloaded in MDS, how to treat iron overload, and, as always, appreciate that we don't have all the answers. Certainly, everything is a work in progress and there's a lot of research that still needs to be done in MDS to understand. So, if we go to the next slide I first want to just look at what is MDS. I'm sure a lot of you know, but just in case somebody doesn't know, I like to think of MDS as a garden the bone marrow where you make you white cells, platelets, and red cells. The bone marrow's like a garden, and in the garden, the seeds grow up into trees and make fruit. And so, you can think of your apples as your hemoglobin cells or your red cells, cherries as platelets which help with coagulation and peaches, which are your white cells, which help fight off infection and make up your immune system. Now, when you have MDS, what happens is your trees don't grow up properly because there's something wrong with the actual seeds, and that's why you could have low white cells, you could have low red cells, or you could have low platelets. And you actually have to truck in some fruit sometimes. You have to truck in some red cells or a bag of blood in order to boost up your red cells. And sometimes, you have to truck in platelets which help you coagulate. Now, unfortunately, we cannot truck in white cells, because they just don't last as long. But certainly, when you think of a transplant, you can truck in somebody else's immune system, somebody else's seeds, to help grow in your body. So, in MDS, either there's too many seeds on the ground so that the trees can't grow very much, or you just have not very many seeds at all that are making defective trees, and then the trees can't grow fruit. And either that's by either a genetic mutation that happened sometime in your life usually, you have not been born with it or something happened to your cells where there is it has a methyl group, so the seeds just don't grow up into what they're supposed to be if they're red cells, platelets, or white cells. And that's what Vidaza works because it takes off that methyl group and allows the seeds to grow. Page 2 of 19

3 AAMDSIF_ Page 3 of 19 So, if anybody who's on Vidaza Vidaza not only kills cells, but also, it's a demethylating agent which takes off that methyl group. So, if you flip over to what is MDS, this is just a pictorial of hematopoiesis or how your stem cells grow up into white cells, platelets, and red cells. So, in MDS, if you look at the bottom, there's immature precursor cells. So, those are your nothing cells those seeds that aren't growing up into what they're supposed to be. So, that can crowd out your marrow, and then you can't either produce white cells or you're just not producing the seeds. So, that's what MDS is. I thought that would be a good introduction, just in case anybody didn't quite know what myelodysplastic syndrome was. So, if you look to the next slide, we have Iron Man here. And even though Iron Man is a technologically advanced super hero that Marvel has made, we do not want to become iron men especially in iron men or women especially in myelodysplastic syndrome. So, what we want to understand today is what is iron overload, how you get it in MDS, and what can we do to make it better? So, if you flip over to the next slide iron in the body. We just have to understand how much iron is in our body. So, our total iron in our body is about 3.5 grams. And you can see on the right, that most of the iron is tied up in your red blood cells. So, any percent of your body's iron needs are used for the production of red cells each day. You can also see that iron is found in the bone marrow. You find some iron in the liver, muscles, microphages or fancy cells that eat up garbage in your body. And you can also see that we absorb about two or three milligrams of iron a day. So, that's really important to remember. We only absorb two or three milligrams of iron a day. We get rid of, through our GI tract and also women through menstruation. We lose about one to two milligrams of iron a day. So, it is a pretty tight system we have here. And one other thing is that in making new red blood cells I said 80 percent of the body's iron needs are using used for making red blood cells that only requires 20 to 25 milligrams of iron a day. So, you have to think about all this, knowing that it's a really tight system, and that we absorb one to two milligrams and that we get rid of about one to two milligrams of iron a day. Page 3 of 19

4 AAMDSIF_ Page 4 of 19 So, iron if we flip over to the next slide iron, by itself, can be dangerous, so iron always needs to be bound to a protein. So, as I said, most of our iron is bound in our hemoglobin cells and hem is a protein that binds the iron to form the hemoglobin cells, so it keeps it nice and stable. When you get iron into your body, transferritin which is the third term on your slide here is responsible for iron transportation. So, it's responsible for taking iron and transporting it from one cell to another or through your blood system into cells. Ferritin, which is your second term, is a protein that all binds to iron, so it creates this ferritin protein that functions as an iron storage molecule. So, this is where extra iron is stored, and it's bound to a protein to keep it nice and stable. And then ferroprotein is a protein that transport iron from inside to outside the cell. So, it's really, really, important to know that iron needs to be bound to a protein. Okay? So, we're flipping over to the next slide, and you can see, again, how much daily iron. We take in about 10 to 20 milligrams, but we absorb only 1 to 2 milligrams of iron a day. And then you can see that transferritin it transports iron. And then you can see that the hemoglobin takes up most of it. Some of it is stored in ferritin and then there's just some others that are in some iron that's in other processes. Biggest thing to know is that our bodies are not programmed to get rid of iron. We are programmed to keep iron. So, these are all basic principles that we need to know in order to move on to understanding iron overload in MDS. So, the question is on the next slide is how much iron is in a bag of blood? Because, as you know, hemoglobin cells contain iron. And when you're getting a bag of blood, that essentially is a bag of iron. So, if we flip to the next slide, we understand that one unit of blood so, one bag of blood will contain about 200 to 250 milligrams of iron. So, if you remember, we only absorb we only intake 1 to 2 milligrams a day. 200 to 250 milligrams of iron that's a lot of iron. So, therefore, after 20 units of blood, you have 4 grams of iron in your body. And if you remember, back in the other slides, we only have about three and a half to four grams of total iron in our body already. So, you are essentially doubling the amount of iron that's in your body with only 20 units of blood. So, that is quite a problem with MDS because in MDS, as you know, sometimes you don't make enough Page 4 of 19

5 AAMDSIF_ Page 5 of 19 red cells and you need them. You need red cells in order to function. You need red cells to bring oxygen to your body. If you don't have red cells, then you're not going to do too well. People who have hemoglobins of 60 they're feeling pretty tired and pretty short of breath. So, we need the iron, but with every bag of blood, we have to remember that we are giving a bag of iron. So, when you get to the next slide, what happens when you get extra iron you can see here, on the following slide the too much iron usually transferritin saturation is about 30 percent. So, when you get a bag of blood, transferritin is really trying hard to transport all that extra iron and bind it to a protein to make it safe. But what happens is the iron over-saturates the transferritin, and then you have iron molecules just floating around, not bound to a protein. And this is called non-transferritin bound iron. And then the uncontrolled iron that's not attached to a protein can go to your liver, heart, or thyroid gland which is shown on the right there. Okay? So, when you get lots of bags of blood and you have excess iron, your body can't put a protein on it. The iron becomes it's just by itself, not bound to a protein, and then it goes into other organs. And we'll see what happens when it goes into other organs in the next slide. So, the biggest take home message on the next slide is iron by itself is dangerous. So, I always like to have pictures. So, if you flip to the next slide this is my son, and he is nicely in his room. He's nicely resting there. But if you flip to the next slide, you see his pesky sister and his pesky sister is creating havoc in his room. And the pesky sister is like an iron that isn't bound to a protein. So, that's just a picture to keep in your mind there. So, what does free iron do? In our next slide because iron can donate and accept electrons, it can actually catalyze and convert hydrogen peroxide into free radicals, and if left in unbound within the cells, it can cause cell death in a particular organ and cause dysfunction. So, if you look to the next slide, you see free iron. And in the liver, it can cause cirrhosis and dysfunction. I don't know if anybody's having those issues yet, but iron likes to store in iron, and it causes liver dysfunction. In the heart, when iron collects in there, you can have arrhythmias, heart attacks, heart failure. It can cause that. In your endocrine organs, you can actually be more prone to diabetes, thyroid, and gonad issue. And also, even in your marrow Page 5 of 19

6 AAMDSIF_ Page 6 of 19 your bone marrow likes to collect iron. And sometimes, when you have too much iron, you can't produce good cells either, so you have MDS, you have seeds that aren't producing good fruit, and then you have this extra iron which is also not allowing those seeds to grow as well. So, we have found, in MDS, if we get rid of the iron just get rid of the iron in the bone marrow sometimes, people's counts actually improve because it's not the marrow isn't being crowded out by iron. So, in the next slide, just to review, when does iron become a problem? We know that there's about 3 to 4 grams of iron in our body, and tissue damage will occur when the iron is about 7 to 15 grams so, after about 30 to 50 units of red blood cells. So, probably there's some people who have had that many transfusions, and certainly, in our institution here today, I have a bunch of people who have had lots of blood transfusions. So, is this a problem? If we flip to the next slide thalassemia is a genetic disorder that people are born with where they can't make red blood cells and they have to constantly get transfusions. And we know, from thalassemia, from studies way back, that if you don't get rid of iron, by the age of five, after five years of transfusions, people get liver fibrosis and then they start running into arrhythmias or heart problems. They have hypogonadism. They don't grow properly. They start getting diabetes, hypothyroidism, hyperparathyroidism, and also, some cardiac issues. So, we know that the before iron chelators, in thalassemia patients who had to keep on getting transfused, a lot of those people lived until their early 20s. Now, with iron chelators, this population can live longer due to the iron chelators. So, we know that having lots of transfusions over a long period of time can cause early death. So, if we think go to the next slide our summary of iron is it's in a fine balance. We know that not much enters or leaves the body normally. And the body can't excrete iron. We know that. It's a closed system. We have no way of getting rid of it. And blood transfusions contain a lot of iron and we keep it. So, those are the main principles that we've just gone over in the last few slides. So, then, if you go to the next slide, the question is is this really a problem in MDS? So, there have been a few studies. The first study, they looked at about 2200 people diagnosed with MDS. The median age is 77. Generally I don't want to insult anybody but generally, it is a disease of older people, though, in my institution, I have 30-yearwww.verbalink.com Page 6 of 19

7 AAMDSIF_ Page 7 of 19 olds with MDS who we transplant, okay? They looked at this 2200 people, and they looked at the transfusion dependent patients and they saw a higher incidence of shortness of breath, liver disease, and infection, in the transfusion dependent MDS patients. They also saw in these transfusion dependent patients that 82 percent experienced some sort of cardiac event within 3 years of follow-up. And then, they also saw an increase of death in transfused dependent patients when compared to MDS patients who do not need transfusions. So, it seems that people who need transfusions and getting iron on a regular basis seem to have more side effects associated with this. If you flip to the next slide, there was another retrospective study 762 people with MDS and it found that people with ferritins less than 1,000 lived longer than people with ferritins greater than 1,000. So, I don't know if I have to convince anybody who MDS and is getting a lot of transfusions that, "Oh, my goodness. What am I going to do? I should be on something to get rid of all this iron." Well, if you flip to the next slide, there are opposing arguments, and the opposing arguments are that if we flip to the next slide the data used that we have for MDS and iron overload is controversial because it's retrospective. We actually look back and see what people did. Good studies look prospectively. You get a bunch of people and then follow them in prospectively, and not looking back. So, whenever any study is retrospective, you always have biases associated with it. So, some people say, "Yeah, that's nice you have that information, but I don't agree with it because there's no prospective studies." Another argument is that people who need transfusions generally have worse disease. So, if you have a worse disease, of course you're not going to do as well as people who don't need have a good prognostic MDS, okay? Opposing arguments is that treatments are expensive and it has many side effects. And another issue is that MDS population is generally older and susceptible to diseases anyway. So, if you look at the next slide if you look at people who are hospitalized for cardiovascular disease, of course the after 65, there are more people in the general population who are going to have cardiovascular disease. So, a person's argument would be like, "Yes, an MDS person had a cardiovascular event, but they were going to have it anyway, even if they didn't have MDS." So, those are pretty legitimate arguments. In Canada, we're trying to strengthen our guidelines as to why we iron chelate. We're trying Page 7 of 19

8 AAMDSIF_ Page 8 of 19 to do one study where we're comparing Exjade and placebo in low risk MDS and transfusion related iron overload, but it's a very hard study to accrue to because either if you believe you should be iron chelated and you have iron overload, you wouldn't want to be on a placebo trial. So, this particular study is very slow accruing and probably will be finished in about 2018 or so. We also are, in Canada, have an MDS registry where every person who gets MDS, who is diagnosed with MDS, is put on a registry so we can follow them prospectively. So, we can see what treatments they need, how many transfusions they need, and if they were given iron chelators or not. So, that's what we're doing in Canada. So, if we flip to the next slide, how do we test for iron overload? Well, the first thing is the most common it's just to do a ferritin test, which is a blood test. It's a non-invasive blood test. So, you just give a tube of blood and we can test how much ferritin is in your blood. Now, the only issue with ferritin is that sometimes, it can be elevated when you have an infection or when you have cancer or even when you're stressed your ferritin can be higher because your cells it's just a response pathway that happens when you have either cancer infection or are stressed. So, it's not a direct way of measuring, but it kind of gives you a good idea what is the general iron in your body. The next one is gold standard liver biopsy. And I can tell you that in our MDS population, the liver biopsy MRI and the cardiac iron loading by MRI those tests we do not use at all. Once very rarely will we do a liver biopsy, but most of the time, we just use a ferritin and we actually count how many transfusions a patient has. If a patient has had 30 transfusions, we know that they are iron overloaded, unless they have been bleeding. Of course, if you have a GI bleed, you're getting rid of the iron. Anytime you bleed, you're getting rid of iron. Okay, so as long as somebody hasn't had a massive bleed event and we know they've been getting lots of transfusions, we just generally use the ferritin test. I know in the U.S., they may use those other ones as well. Liver biopsies sometimes, if your white cells are low and your platelets are low, you don't want to be going poking around either because you could make a risk for bleeds. So, we've identified that iron is a problem when you get lots of transfusions. So, how do we fix iron overload? And the best way if we flip to the next slide we see a person giving blood. Basically, that is the Page 8 of 19

9 AAMDSIF_ Page 9 of 19 best way to fix iron overload. Unfortunately, you can't take away blood if you need blood all the time, but with Vidaza, sometimes we see an MDS that a person's hemoglobin cell number will be normal. We will normalize. The Vidaza actually worked and the hemoglobins will be normal and we could actually phlebotomize people. Also, I do a lot of stem cell transplants, and we in MDS population where they had lots of transfusions, we give them a transplant and bring somebody else's stem cells in. They grow, they produce a normal hemoglobin, and we are able to get rid of iron through phlebotomies. So, this is the best way to fix it. Not very many side effects or anything, but not really a good way to fix it for MDS and somebody who needs transfusions all the time. So, if you flip to the next slide what is chelation therapy? And basically, a chelator which is a pill or sometimes an infusion that you take is a molecule that will actually attach to that toxic iron molecule. And then you can see, it attaches together. It makes it non-toxic, first of all, which is a good bonus, and second of all, it your body recognizes that it needs to get rid of it and it will actually dispose of it through your urine or feces. So, it gets actually rid of two problems. First of all, it gets rid of the toxic components of the iron, and second of all, it allows you to get rid of the iron. Because remember you can't get rid of iron on your own. You need some help. And a chelating agent is an actual helper. So, why chelate? The relationship between iron overload and survival has been well established in genetic anemia. So, what I said before about thalassemia those people people with thalassemia used to die in their early 20s and now they're living longer because we are giving them iron chelators to get rid of the excess iron. So, that has been well established. And some of the retrospective analysts indicate that iron overload is associated with morbidity and mortality in MDS meaning that with higher iron levels, you tend to die sooner. And unfortunately, though, there's no data available whether iron chelators in MDS reduces death. We don't have any of that information, but it seems logically to make sense. So, if we look in the next slide in Canada, we had a bunch of smart people I work with a couple of those people who actually developed a Canadian Consensus Guideline for iron overload in MDS. So, they established that once you have a serum ferritin level of over 1,000, you have to be transfusion dependent Page 9 of 19

10 AAMDSIF_ Page 10 of 19 because you have to be getting iron in order to get rid of iron, right? That makes sense. You want somebody with a good prognosis life expectancy greater than a year or a transplant candidate. We also know there are some studies out there showing that if you get rid of excess iron before a stem cell transplant, people can actually do a bit better. And then you can see the target serum levels is decreased iron chelation therapy when your ferritin is less than 2,000, and discontinued chelation therapy when it's less than 1,000. And, like I said, we don't use a lot of those fancy tests. All we just basically use is the serum ferritin the blood test to see how much iron is in people's blood. So, if you look to the next slide, this is just showing that deferoxamine or Desferal intravenous iron chelator actually gets rid of iron in your body. And so you can see at 0 there, the iron is way high almost at 8,000 and then, if you have about 2 years or 3 years' worth of treatment, it goes down to about 2,000 or less. So, we know that these iron chelators actually do their job and get rid of the excess iron in your body. So, there's a bunch of iron chelators. If you go to the next slide, you can see all the different types of chelators we have. The last one on the right I have no experience with whatsoever. Ferriprox, I don't even think is available in the U.S., and is used for thalassemia patients who are not responding at all to the other agents. So, we won't really talk about Ferriprox at all. The first one is Desferal. This is the older agent, and it is a subcutaneous or inyour-skin infusion. So, it's an infusion that has to be given over a long period of time every day. And the reason why it has to be given for such a long time because you don't absorb it I'm sorry. The half-life of that is only 10 to 15 minutes. So, the drug comes in, it's active for about 10 or 15 minutes, and then it goes away, right? So, you need a drug that is active for long periods of time, and that's why you need to just keep on giving the Desferal. So, that is why it's an infusion and you have to some people are on the infusions at night between 10 and 15 hours a day. So, this is quite cumbersome, as you can imagine, because you have to be you have to inject yourself with this or hook yourself up to this and it has to be running for long periods of time. And some people get site reactions to it as well. And they could never use Desferal as a pill form, because it's just not absorbed well by Page 10 of 19

11 AAMDSIF_ Page 11 of 19 your GI system at all. So, that's why it had to be in IV form. And then, about 10 years ago I guess now 'cause I it was said that I worked on clinical trials, and I actually worked on the Exjade trials in Canada when it was first coming out. So, this was when Exjade came out, it was excellent. It's an oral tablet and I don't know if anybody is on Exjade, but it's like, dissolvable pills that you put in a glass of juice or water and they dissolve up. There's some great YouTube videos on how to mix your Exjade, and I think even Novartis has a little mixer. It looks like a margarita mixer that helps you mix up your Exjade. And because it's absorbed well so you can use it as pill form and you only have to use it once a day because it has an excellent halflife of 8 to 16 hours. So, it works once it's in your body, it keeps working for long periods of time. Now, if you move over to the next column there Jadenu this was just put out by Novartis is 2015, and it's exactly it is Deferasirox like Exjade is, but it's a different combination. So, it doesn't have any lactose in it, so anybody who is lactose intolerant that sometimes got a lot of GI symptoms with Exjade, can be switched over to Jadenu which doesn't have as much lactose in it. Exjade, you have to take on an empty stomach; Jadenu you can take on either an empty stomach or low-fat, light meal, which is about 250 calories and less than 7 percent fat. So, that's a little bit different. And there's a higher bio-availability to Jadenu, which means you just have to take less of it than the Exjade. So, basically, your Exjade dose is cut down to 70 percent because Jadenu has a higher bio-availability. And it also has an excellent half-life, so you only have to take it once a day. So, this is all great fun. Some people would say, "Okay. Let me sign up for these agents. I have lots of transfusions. I have lots of iron in my body. I should be on an iron chelator." Well, if you go to the next slide, they do come with lots of side effects or some side effects and some people are really intolerant to these things. First of all, Desferal it's an intravenous. So, you can get injection site reactions just around the site where you're giving yourself the Desferal. Also, with any of these drugs, it's a class effect. You can have hearing and eye difficulties when you're on iron chelators, and it's really important to have hearing tests and eye tests done once a year. You have it just before you start iron chelators, and Page 11 of 19

12 AAMDSIF_ Page 12 of 19 then follow-up once a year afterwards to make sure you're not having effects of iron chelators. So, that's one thing you have to think about when you're going on these medications. Also, it really affects your kidneys and liver. So, your kidneys and liver do not like iron chelators at all. So, you can say that if you already have liver dysfunction or kidney problems, you may not be able to take iron chelators because it's going to make your kidneys and liver not work as well. Again so, there's some people who can't take iron chelators just because they have other things going on in their life as well, and you're often more prone to some infections with the Desferal. If you look over to Exjade, the there's probably lots of people on Exjade. You know about the GI side effects. The diarrhea is a major one, right? So, when you're starting Exjade, you really want to go slow and work your way up, because some of these GI side effects can become quite bothersome. If you do get those diarrheas and you've ruled out that it isn't CDIF or some other infection, you can use anti-diarrheals. Sometimes, people stay away from dairy products. And, if you experience the nausea and vomiting, you just want to keep hydrated. Also, with Exjade I don't know how many people who've got the skin rash, but that can certainly happen. It can be anywhere from mild to moderate. Sometimes you can keep on with the drug; sometimes you have to stop and then restart the drug, and the skin rash doesn't come back. Changes in kidneys and livers. So, again, it's a class effect, so you have to really monitor how your kidney and liver's functioning, and if those enzymes go up, that you stop the medication. So, it's really important once you're on an iron chelator to follow-up with your doctor as much as possible. And then the next slide is Ferriprox. And, as I said, I don't have really any experience with this at all, but I just thought I'd put some of the side effects associated with that as well. So, just as a disclaimer, you may say, "Okay, I'm a person with MDS. I'm getting lots of transfusions. Why am I not getting iron chelated?" Well, there may be a lot of reasons why. You may have a lot of other things going on like diabetes, kidney dysfunction all sorts of other things that may be going on in your life cardiac issues that doesn't make you eligible for iron chelators. So, it's best if you are an MDS patient who's getting lots of transfusions and not on an iron chelator that you just ask your physician why. Page 12 of 19

13 AAMDSIF_ Page 13 of 19 "Should I be on an iron chelator?" Sometimes, as clinicians, I know sometimes, people the amount of transfusions kind of creep up on us. We don't realize, "Oh my goodness. This person has had 30 transfusions." So, some of the when we get to the take home message, I'll give you some ideas as to how you can keep track of your transfusions and ask your physician about iron chelators. If you flip over to the next slide, a take home message is, "Drugs don't work in patients who don't take them." So, I always like, in a presentation, to say something about drug compliance. More and more, drugs are becoming oral, in a pill form, which is great because you don't have to go to your cancer center and get an infusion, which is awesome. But as nurses and doctors, we have lost control. We can't tell whether you're taking the drug or not. And as a nurse practitioner, I assume that when people I give them a prescription, that they will be 100 percent compliant and do take the drug exactly how I have prescribed it. But I am wrong in that assumption. Most people don't take their medications as prescribed, and a lot of people don't even take their medication consistently. For iron chelators to work, if you are on them, you have to take them consistently, on a regular basis. Like Doctor Coop said "Drugs don't work in patients who don't take them." So, that's my little soap box message there. And then, another couple of take home messages number one keep track of how many transfusions you had. That's an easy your physician should be looking after that as well, but you, as a patient, a person with MDS, should just keep track of how many transfusions. And if you're not on an iron chelator and you've had more than 20 transfusions and getting them on a regular basis, you should just ask your physician, "Should I be on an iron chelator?" And then they can say why or why not. Other more take home messages avoid multi-vitamins with added iron. You already have lots of iron. So, adding more iron to your diet won't help you make red blood cells. You already have lots and lots of iron, as we all know, right? The problem is is with the seed. If we go back to our garden the problem is with the seed. The seed is not growing the tree to make the nice red blood cells. So, don't have extra iron in your diet. Though, I will say that, you can still eat a steak. It's okay. Page 13 of 19

14 AAMDSIF_ Page 14 of 19 Remember we only absorb one to two milligrams of iron in our bodies, and we get rid of that, so it's still okay to have a steak. Another one is two avoid raw shellfish such as oysters because they can carry a bacteria that thrive in iron rich environments. So, if your iron overload and this bug you eat an oyster and it has that bidtohealer bacteria, it will have a little hay-day because your body's full of iron and you can get sick. So, we tell people to avoid raw shellfish. And so wow that's the end of my presentation. I have no idea if anybody's still there or if you're interested or if you enjoyed it, but and I can't even see the questions, because I still don't have any sort of computer access, so I will turn it over to the sponsor and facilitate the questions. Thank you very much, and if anybody's still there, thanks for your attention. Thank you, Tammy, for your very wonderful presentation. We do have a few questions that have come through. Our first questions is from Ann Marie, and she was asking, "Is there any connection between iron level and platelet count?" Oh. That's an excellent question. And no, there's not. Sometimes, in MDS, people just don't produce platelets and it's just the way the seeds are growing and stuff. Maybe iron is crowding out your bone marrow and maybe you can't make a platelet because there's too much iron, but generally, there's no association between your platelet count and your iron level. Okay. Thank you. Our next question comes from John. He is asking, "Does the iron impact of a pure red cell transfusion decrease back to normal over time or is it strictly accumulative no matter how much time passes? If the iron naturally decreases, how much time does it take for the effect of one transfusion unit to go away?" Oh, right. Okay. So, if you remember, we have no way of getting rid of a bag of blood like, iron in our blood. We have no way of getting rid of iron in our body, right? So, if you get a bag of blood, unless you have bled GI bleed or whatever that bag of blood, that bag of iron, will stay in your body. The red blood cell will die from the transfusion. A regular red blood cell lasts between 120 about 120 days or so. The red blood cell will die, but that iron that was attached to it will just stay in your body. We have no physiological way of getting rid of iron unless we either bleed it out or have an iron chelator. Page 14 of 19

15 AAMDSIF_ Page 15 of 19 Okay. Thank you. Our next question comes from Stacy. She's asking, "How many units of blood is in a typical blood transfusion?" Okay. One unit of blood is one bag of blood. So, usually, in our institution, if you need a transfusion, we usually give two bags of blood. Usually the hemoglobin is eight using the American or 80 in Canadian terms. So, if it's under 80, we will usually give 2 units of blood. And each unit of blood will raise your hemoglobin up about 10 points or 1 point. So, it'll go from 80 to 90 or 8 to 9 in American terms. Okay. Does that answer the question? I think so. Yes. I believe so. Okay. Our next question comes from John. He is asking well, it's actually a dual question from Rosemary and John. They're asking, "Have there been any ways or anything on the horizon in regards to research that remove iron from red blood cells before they're used in a transfusion? Would this be a good thing to do?" Oh. That is an excellent question. If you removed the iron from a red blood cell transfusion, then you wouldn't have a hemoglobin cell, because a hemoglobin cell is hem plus iron, and you need the iron to make up a hemoglobin cell to make it functional to transport oxygen through your body. So, there will be never any way of getting rid of iron in a blood transfusion because you need that iron to make that cell to make it function to do its job to bring oxygen to your body. So, that's a good question. Some people have asked me that before. "Well, just take the iron out." Well, if you take the iron out, then you have a bunch of dead red cells. Right. All right. Thank you. Good question. Page 15 of 19

16 AAMDSIF_ Page 16 of 19 Our next question comes from Hugh. He is diagnosed with MDS specifically refractory anemia with excess blast minus two and he is treated with Vidaza, and he currently does not receive any transfusions. His most recent RBC score is 4.0 and his hemoglobin is 13.2, which is both below the normal range. He's asking, "Should I take a daily iron supplement?" And can you recommend or suggest the amount of iron that he should take as in milligrams? So, he is he's an MDS patient and his ferritin was normal or was his hemoglobin his hemoglobin was normal. Yeah. His RBC score is 4.0, and his hemoglobin is Yeah. So, no. Again, MDS is a production problem. Sometimes, people can have anemia or like, low red blood cells because you just don't have iron, right? And if you give them iron, they have a good building block and they can make a red cell, as long as they have enough iron. So, people who don't have enough iron, they can't make a red blood cell 'cause the iron isn't there. In MDS, you generally have enough iron. That's not your problem. Your problem is that you have production problem, a seed problem, in actually starting to make a red blood cell. But it sounds like in his case, that he has been having an excellent response. He doesn't need transfusions, if that's correct, right? [Crosstalk] He's not. Yeah, he's not on transfusions. So, taking extra iron isn't really going to help the situation. It doesn't mean you have to stay away from iron or anything, but taking extra iron won't help. It's the Vidaza that's going to help because it's gonna help those cells grow up into red blood cells or platelets or white blood cells what they were meant to grow into. So, in that particular instance, if somebody didn't have enough iron, I would say, "Yeah, you need more iron." But in this case, this is not an iron problem. It's more of a seed problem making red blood cells. I hope that answers that question. Page 16 of 19

17 AAMDSIF_ Page 17 of 19 Yes. Thank you. Our next question comes from Raymond. He has a ferritin level of 486, which exceeds the high normal 464. He has been running high for some time, but has had no transfusions. He would like to know if this is something he should be concerned about. 486 is not. Remember you have to have transfusions, and your ferritin level should be over 1,000 before you need to consider iron chelation. 486 probably it's high because he has MDS, and sometimes MDS will make your ferritin level high. But certainly, he's not having transfusions, and this is totally acceptable. He does not need to be concerned or need to iron chelation at this time. Okay. Thank you. Our next question comes from Stacy. She is asking, "Are there any therapies that can keep us from getting blood transfusions in the first place?" Yes. So, sometimes, people have used Eprex Epotein to help you those are injections to help you make red blood cells. That's another like, you have the seed and then you need you need a whole bunch of things to make a red blood cell. You need iron, you need Epotein, and you need all sorts of things. However, Eprex only works in a very small amount of MDS patients. So, like I said, it's a production problem. It's a seed problem. That you're just not where you're starting from is not there's something wrong with that, and you're not making a red blood cell. The way we can fix that is doing a stem cell transplant, you know? You can get rid of your seeds and put somebody else's in so that they can grow. But obviously, not everybody is eligible for a stem cell transplant. I work with transplants and there are a lot of side effects associated with that as well. So, at this time, yeah, there's nothing else we're adding right now. Basically, you want to try to fix the seed. So, Vidaza is a great way of trying to fix the seed. Either it kills off the bad seeds or it takes off that methyl group so that that seed can grow. I hope that answers that question. Yeah. Absolutely. Our next question comes from this is actually our last question it's from Pauline. She was asking, "Can one get too much iron from iron rich foods?" Page 17 of 19

18 AAMDSIF_ Page 18 of 19 Oh, excellent question. Well, remember, we only absorb about one to two grams of iron a day and we get rid of it. So, generally, adding iron to our diet isn't really doesn't contribute all that much. Remember that a bag of blood contains 200 milligrams of iron, right? So, that's a whole lot more iron. But some things you can do is take calcium. If you're having a steak, have a glass of milk with it or a dairy product because calcium actually reduces your absorption of iron. So, you don't want to take a steak with a glass of orange juice because Vitamin C can increase your intake of iron. So, if you're having a steak, go for dairy products, right? Alcohol can actually increase your absorption of iron, so if you're having your steak with your lovely glass of wine, you will increase the absorption of iron as well. But if you take some tannins in tea with a meal can decrease your absorption of irons. So, you can have a tea with your steak. Whole grains and bran as well can decrease your absorption of iron. So, those are a few things that you can do to either decrease your absorption of iron, but really, the main culprit here is getting a bag of blood. That's where you're gonna get most of your iron from. So, still have a steak. Okay. All right. Thank you so much, Tammy, for your very informative presentation. For anyone that joined the webinar late or would like to watch the webinar again, this webinar will be posted on our online academy within four to seven business days and you will also receive an confirmation in a few days giving you the link and everything that you need to to know about this archived webinar. Once again, Tammy, thank you for your presentation. And, on the behalf of the Aplastic Anemia and MDS International Foundation, I would like to thank each and every one of you for joining us today and making us your resource of choice for information on bone marrow failure diseases. If we were not able to answer your question today, please send it to us via at help that's so that our patient educator can respond. Or, visit our online academy at AAMDS.org/learn for interviews with experts and other programs that may address your question. As a reminder, as soon as I am done speaking, a post-itup survey will appear requesting your feedback. We appreciate your time to complete this survey. Again, thank you for joining us and remember learning is hope. This concludes today's program. Page 18 of 19

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