Pediatric Cord Blood Transplantation Webcast August 27, 2008 Colleen Delaney, M.D. M.Sc. Introduction

Pediatric Cord Blood Transplantation Webcast August 27, 2008 Colleen Delaney, M.D. M.Sc Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Introduction Hello and welcome to Patient Power. I'm Andrew Schorr, and once again we are connecting you with a leading expert from the Seattle Cancer Care Alliance. And today we are going to talk about an issue for children although it relates to adults as well. Now, imagine your child is diagnosed with an acute leukemia, and there are various types, and one of the main approaches of course for many years pioneered at the Fred Hutchinson Cancer Research Center, part of the Seattle Cancer Care Alliance, is of course bone marrow and then later peripheral blood stem cell transplant. It set a worldwide standard for that. But what if you don't have a match? What if there is not someone in your family? What if there is not an unrelated match donor in the registry? Maybe your ethnicity is such that it doesn't match up with mostly the people of Caucasian, Western European descent who are in that registry, and you just don't have a family match? What then? Well, maybe you have heard that one of the areas that's being perfected is using the stem cells that are in the umbilical cord when a baby is born. Cord blood transplantation. Well, we are going to learn about that today and not only understand what's been done for a little while now but also the leading edge of it in clinical trials. So I want to welcome an expert from the Seattle Cancer Care Alliance who knows tons about it and is really a renowned expert, and that's Dr. Colleen Delaney. Dr. Delaney is a pediatric oncologist, and she is director of the cord blood transplant program, and she is assistant professor of pediatrics at the University of Washington, and of course she is at the Seattle Cancer Care Alliance. Dr. Delaney, thank you so much for being with us, and we are going to talk in a minute about your clinical trial and hopefully making cord blood transplantation for children and adults more effective, but tell us about cord blood transplantation and what it has meant to people who have otherwise not had a match. What is Cord Blood Transplantation? Well, thank you for having me, first of all. It's a pleasure to actually be able to talk about my work. So cord blood transplantation in general and what it's done. This is actually a very important year in the cord blood transplant world because it sccapatientpower.org 1

marks the 20th anniversary actually of the first cord blood transplant performed. And this transplant was originally performed in Paris, France. The child was from the United States. This was a child who had bone marrow failure syndrome so the bone marrow stopped making cells. And he was brought over to Paris, France, and this was based on research that had been done looking at the cells in the cord blood. And researchers felt that there were truly stem cells that were present there. And so this transplant was performed successfully, and that child is still alive today and really was the first proof of the principle that you could take cord blood and perform an alternative type of bone marrow transplant. So since that time cord blood transplant has really evolved and taken off. The most beautiful thing about cord blood is that first of all it's medical waste, but it can be recycled to give life to other patients in need. So I always tell expectant mothers that they can give life twice. They can give life not only to their own child, but also potentially give life to those who need a transplant but can't find a donor. And so as you had stated cord blood can be used as an alternative form of blood stem cells for those patients who can't find donors, and reason we can use this is that those cells that are found in cord blood are very naive or uneducated. And so what that means is that we do not need to match that patient who is very difficult to find a conventional, living donor. We can match that patient to a cord blood unit and find them donors more than 99 percent of the time, and that's because we don't have to match so stringently, and those units can be given to the patient and give them the chance of a life-saving transplant. You know, one of the things that I have learned about that is very cool I think as you go into this new frontier is that obviously there are times when you want to have more of these stem cells from cord blood, maybe an additional unit I think as you call it, and that you found that you can have a unit from one umbilical cord, and then another one from another baby, and pool them to create what you need for that child who needs the transplant, and that it works. Yes. That's absolutely true. So in the beginning stages of cord blood transplant, so after that first one was performed, we quickly found that the number of cells that are available in that unit of cord blood, which is, you know, to put it in perspective only about 20 to 30 teaspoons of blood, and so we know that the number of cells there are very small, and the number of cells really do help predict how a patient will do. And so we think the more cells we can give the better off it will be for that patient. And now, this is adults and for kids. And so a lot of people think the kids don't have any issue with this, and that's not true. So as soon as you are about 40 pounds or so, it could be difficult to find one cord blood unit that matches you well enough and gives you enough cells. And so in the last decade many people have been working on ways to overcome these problems. And one of the ways, as you suggest, is to give two different donors, two different babies' cord blood cells that were collected at the time of birth and frozen to one single patient. And the other thing that can't be I think sccapatientpower.org 2

understated or underestimated about the potential power of cord blood is that these units are readily available. So they are not going to move away. They are already frozen. You know, they are on the shelf and ready to go when a patient needs them. All right. Let's take this further. So the first issue is have enough cells for the need of the recipient. And then the second is have enough cells that are ready to go to help build a healthy immune system to overcome the cancer or other condition they may be facing. So that's been a lot of your work. Tell us about that, what you are doing in clinical trials now and what's happened along way for children and for adults to try to have enough cells and have them ready to go so that, I guess you call it engraftment or building a new immune system happens quickly where otherwise the patient is at risk for potentially fatal infection. Major Advantages of Cord Blood Okay. So again the advantage of the cord blood is that they are collected and stored and ready to go at the time of birth. So that has always been considered one of the major advantages. The other advantage is as we talked about the need for typing is far less. So the matching requirements are far less. The other thing, the other advantage is that there are less viral infections that can be transmitted with a cord blood unit. So in the beginning when we know these advantages are there, the biggest problem is really overcoming the cell numbers as you talked about. So what are we doing now to help overcome that and to make possible cord blood transplants where patients are not having these prolonged periods where they are waiting for engraftment or waiting for their blood system to return? So that still is one of the major barriers and thought to be one of the major risk factors for getting a cord blood transplant. And what makes most patients most wary of doing this is that the amount of time it takes for a blood system to return is so long. So I started doing research, 1999, 2000 is when I started looking into all of this. And we quickly realized, I work in Dr. Bernstein's lab as a fellow over here at the Fred Hutch, and we were working on ways to make stem cells multiply. So we have developed a system here, in all of these years of thinking about this, we have now developed a system where we think we are fooling these cord blood stem cells that we isolate, fooling them into thinking that they are still in an environment like a bone marrow. And so we can get these stem cells to multiply in number and maintain their function as a stem cell. So again to put it in perspective, this is work that has been going on for many years, not just by me, but other people as well. And really being able to multiply the number of stem cells is the holy grail of stem cell biology. And so the issue is that most people have not been successful at this because when you take a stem cell and you put it into the laboratory into a petri dish or, you know, a bag or whatever, that stem cell we believe does not get the signals that are required that sccapatientpower.org 3

it normally has inside the bone marrow. And so that's the tack that we have taken is to say, well, how can we recapitulate the bone marrow environment? And so we have developed and manufactured a special protein that we know is found in the marrow, and we grow the cells in the presence of this. Now, the goal of this research is really to make cord blood transplantation safe for anyone who needs it regardless of how small their units may be, so that if we can take one unit and expand it, grow it in number in the lab, the hope is that we can give enough of these cells to a patient that their white cells will start to return much more quickly. So in the order of one to two weeks versus the order of three to four weeks that we normally see now, and these patients will not have life threatening infections in the early period post transplant. Now, let's back up a minute because bone marrow transplant, peripheral blood stem cell transplant has been the standard now for many years. So what data do we have on how a cord blood transplant let's say in children compares related to success? That's a great question. And some of this is still evolving. So there are though a number of centers in this country who firmly believe that cord blood is as good if not better than some of the more conventional forms of transplant, so bone marrow or peripheral blood. In fact in some centers, for example in Minnesota, if you were in Minnesota and you needed a transplant they would look first to your family, and if no one was there, they go straight to cord blood transplantation. Now, the belief is that when you get a cord blood transplant, one of the major causes of patients having transplant-related complications is something called graft versus host disease. And this is when those new donor cells go into the patient, recognize the patient as someplace where they shouldn't be, as a foreign host, and attack the patient. Because cord blood is naive, the chance of a patient getting chronic graft versus host disease, so a problem that can be life threatening and long term, is less. And so as we think about the use of cord blood and as we are able to collect more of these units and store more of these units, and as patients are getting better matched units, the thought is that this will lead to even more improved outcomes for patients who are getting cord blood as compared to bone marrow peripheral blood. So current literature would suggest that cord blood transplants, mismatched cord blood transplants are equivalent to matched unrelated donor transplants. And there is some data that has come out especially in pediatrics for kids who are getting fully matched cord bloods, that their outcomes are superior to those getting matched, unrelated donors. So this is still a work in progress, but I think we are all going to witness a significant increase in the number of cord blood transplants that are performed as we overcome some of these other issues like cell dose numbers. sccapatientpower.org 4

All right. There may well be parents listening today who have an urgent need to try to figure this out. Where do they go? What's the approach that's likely for them? So, Dr. Delaney, you explained the point of view of the University of Minnesota related to going to cord blood transplants if you don't have a family match. What's your view in children anyway as far as how you proceed in your thinking of looking for matches? Do you look through the registry for unrelated donors, or where does cord blood fit in? So I think that really is almost an - it's institutional. There's institutional biases, but there is also an individual approach for each patient that we see. And here our approach is that we still look first to a family member, and if there is a perfectly matched family member, we would do that transplant above any kind of unrelated bone marrow transplant, cord blood transplant. And the reason for that is that we still believe because of this graft versus host disease that your risk is less if you have a matched related family member. So from there, if there is a child who comes to us and has a disease that is not rapidly progressing or they are running the risk of relapsing within a month, we can, we do first look at who is available out there in the conventional sense of the word. So in the 10 million I think it is up to now living, volunteer, unrelated donors we will do a quick search, and if someone has a possibility of finding a perfectly matched unrelated donor that won't be difficult to find, then we often will pursue that first. So we can do a concurrent. So we can look also at the cord blood donors that are available. And so some of this depends on what we find. If we see perfectly matched cord blood units and the patient is someone who needs to know about their transplant relatively urgently, so they are a young patient who has relapsed leukemia, and the idea is to get their transplant scheduled as soon as possible, we would then go with our first available donor. And that often may be a cord blood. Sounds like, though, we are in a changing landscape as you and the other centers take a look at what your experience is, where we are with trials. Now let's mention about your very early, your phase I trial. I think you are doing your eighth patient tomorrow. That's correct. And there have been, about a third of the eight have been children. And so you are gaining experience in kids as well as adults with these sort of expanded cells that you are doing in the lab. So tell us whether that trial is available to anyone. So if someone comes to the Seattle Cancer Care Alliance, a child or an adult, are they offered the trial or where does that fit in and what the recommendations are. sccapatientpower.org 5

Right. So we have a number of protocols that are available to any patient who comes here specifically for a cord blood transplant, or even if they don't come here for a cord blood, and that's found to be their best donor we do have a number of options. The expansion trial is one of our priority protocols. Now, any patient who comes here does need to be in remission at this time point in time in order to be eligible for our cord blood transplant protocol. So if it's someone who is in relapse, that patient would need to first attain a remission in order to proceed to transplantation. So if they have hit that mark, then there is a number of other disease eligibilities, but essentially if you have a blood cancer, an acute leukemia, a chronic leukemia and you are someone who needs a transplant, we would first look at you for eligibility for the expansion trial. Now, we will really believe with our early results and the encouraging early results that if we can help patients to engraft more quickly that they will have less time in the hospital, they will less infections in their first month after the transplant, that this benefit really is something that we would like to offer to most patients. It should be stated, though, that this is, as you said, a phase I trial. And as a phase I trial, it is essentially a safety trial meaning we are looking at the safety of infusing cells that have been expanded. We don't believe there will be any infusional toxicities, and one of our major goals also is to look at what the outcomes have been. And we can compare this to an exactly, another protocol that is essentially exactly the same except the patients get unmanipulated, so two cord blood units that have not been manipulated in the lab. And when we look at these two different protocols even though these results are very early, they have been quite encouraging, and we have cut the engraftment time in half. Cord Blood and Family History Well, that's great news. I have a bunch of questions. Now, as our listeners know, I am a chronic lymphocytic leukemia survivor, and I was in a clinical trial and am a big believer in that. I did not have a transplant. I had drug therapy. I should mention that after I was diagnosed the oncologist gave us the confidence to have a third child, and this was 1996 or '97. We had heard a little bit about cord blood then, and so we made an effort very early then to have the cord blood from our now 11-year-old kid, Aton, harvested or I don't know what the right word is, and it wasn't successful. They didn't get enough. The team at this particular hospital really wasn't experienced with it. But for people now as we are listening they wonder well, first of all, should they routinely if they have a child have the cord blood kept either for the benefit of that child or a family member or someone else? So how does that work now in the idea of having cord blood kept? And let's say if there is a cancer survivor in the family who is worried about a relapse, could the cord blood from that infant help? sccapatientpower.org 6

So these are all excellent questions, and I think whenever I go out and speak about my work, a bulk of the questions are really around this. What does a woman do when she is about to give birth? What are her options in cord blood donation? What I always tell expectant mothers is that, you know, you have an opportunity here to potentially save the life of another individual. The only time that I truly strongly advocate for storing your own cord blood is when you already have someone in the family who either, you have another child who has ALL, acute leukemia, and even if that child is in remission and even though we cure most of the kids nowadays with acute leukemias without transplant, that is an indication for potential future need of that cord blood unit. And those families can actually get their cord blood units stored free of charge for their own use, which is something that a lot of people don't know. So they don't have to go through a private bank and pay the $2,000 up front. If there is a medical necessity within a family that cord blood can be stored free of charge through a program in Oakland, California. So that's the first thing, and I always advocate that those families do store their own cord blood. Now, the other question is, so, first-time parents having a baby, should I pay the $2,000 and store my cord blood or should I see if I can donate it to a local public bank, or should I let it get thrown away, or should I give it to research? Now, this really depends on where you live unfortunately, and I think this is something that is again a work in progress, but in the Seattle area, the Puget Sound Blood Center does have a cord blood bank. And they are one of the first banks to receive national funding from HRSA in the first round of funds to help these public cord blood banks stay afloat. So this is something that's done free of charge, and it's for the benefit of current cancer patients or patients, actually not even just cancer patients, kids who have non malignant diseases too, inherited disorders where a transplant is beneficial and can't find a donor. So any of these units that go to the public bank can be searched for and used by these patients right now. And I advocate for that the strongest, especially if the child to be born is of mixed race or is a minority because those are the units that really need to be put into the banks now because those are the patients who need those transplants now. A lot of families say well, you know, what if we need it? What if something happens? What if my child who is unborn gets leukemia? And my answer to that is it's very rare to have a child who gets leukemia. And secondly we wouldn't use that cord blood for that transplant because otherwise we could, that's called an autologous transplant meaning it's your own cells given back, and one of the reasons a transplant works the way it does is because the donor cells we give are foreign, and they are like a little army there to mop up any of the leukemia. If we were to give that child their own cord blood back, they would not do that. And so I always tell parents that it is unlikely that you will need it in the future. And if you are, so then the next thing is well, maybe my grandfather has Alzheimer's and there is research being done for that, or maybe someone has a heart attack and sccapatientpower.org 7

there is cord blood cells being used for that. Now, it is just as likely that you could use public cord blood for that, and you don't need your own either. Yes. It's a fascinating area. Now, let me ask you about this. So people can come from far and wide, and they do to Seattle to either participate in your trial or have a cord blood here or be evaluated for transplant in general to see where this fits in. If someone comes, brings an infant for a cord blood transplant, how long are they here for? Well, that's another good one. So in general patients arrive here, and when they arrive usually a plan has already been put in place. So they can be wherever in the country, contact us, come for a consult, initiate all of this work to be done prior to them actually arriving in Seattle. So that means we usually already know who the donor is going to be whether it's a cord blood donor or whether it's an unrelated donor. So we already know all of that. We generally know what protocol we think, so what clinical trial we think the patient should be transplanted on, and that's based on disease and other factors. So all of that is generally set. And the patient arrives, and generally there is about a two-week work-up period. After that the patient starts their transplant regimen. And then we expect that the patients stay in Seattle for about 100 days after their transplants. So not after they get out of the hospital but after their actual cells are infused. So it's over a few months. Yes. You know, I think expectations are always, you know, very important, and to expect that you will be out of here in three months would be overshooting it, so I usually tell people it's about five months, and maybe sometimes it's a little bit less, and maybe sometimes it's a little longer, depending on whether there's complications. Now, then there is the other obvious question, Dr. Delaney, is I know in bone marrow transplants sometimes people need it again. What about with cord blood transplant, can it be performed a second time if needed? Yes, it can be. Now, I think in general rejection or someone needing a second transplant for whatever reason, we don't see thankfully all that often anymore even in cord blood. But it can be performed again. And generally we can find a second set of donors in the cord blood world if needed. sccapatientpower.org 8

Okay. Now, I do have a few questions that people received, and I think we have really been talking about it. But here's one that came from Tangie who is from Seattle. Tangie is a 21-year-old woman who had ALL in the past and AML, so two acute leukemias, and she had a cord blood transplant in 1996, and she says she has experienced some severe allergies including sneezing, runny nose, occasionally sinus headaches, and she has had a rash on her hands interestingly when she has been exposed to pumpkins. And so what about after the transplant, are there some unusual effects afterwards that are either short lived or might continue for a long time? Yes. I think that is something that is not specific to cord blood transplants, and it depends a little bit on what kind of conditioning. And what I mean by is what kind of chemotherapy and maybe radiation do patients get before their transplant. So not all patients get the same level of therapy prior to their transplant. So the more you get the more potential there is for long-term side effects. And again this is another area which is really blossoming in the transplant world because we are becoming, just as she has seen, much more successful in doing these kinds of transplants and patients survive them and are living longer term. So we are actively pursuing that here in the Hutch. We have investigators here who are looking at all the long-term effects. And the allergies, I'm not sure those are exactly related to the transplant or something else, but clearly some patients do see differences and do see side effects long term and can be more at risk for developing certain kinds of medical complications long term. Well, you are definitely on the leading edge of this, and we should point out to our listeners who may be anywhere around the world when we talk about the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center as of course one of the partners in the Seattle Cancer Care Alliance, this is really where bone marrow transplants started, and they led the way. So looking forward, Dr. Delaney, lots of questions to be answered about your research and your expansion of cells. What's your hope? Oh, my hope is that, well, I guess someday we may not even need transplants, but I think that's not in the immediate future. My hope is that we can safely perform these transplants and understand more about the complications of these transplants so that patients can go through this knowing when they start that they are not going to have graft versus host disease, that we are going to be able to figure that out, and that we are going to be able to manipulate our knowledge and manipulate these cells that we deal with so that we can make relapse a thing of the past. sccapatientpower.org 9

And I think these are all things that are very attainable. We are learning every day about how to decrease risk of graft versus host disease, what cells are responsible, what other cells can we give to prevent these problems. And I think this is still the early stages even though we are in the 50th anniversary of transplantation here. We are learning more and more. But in my lifetime I hope to see transplants performed and performed so that patients could do it all as an outpatient and relapse is a thing the past. Wow. Well, that's a wonderful vision. I wish you well with that. I have to ask you one other question since we have been talking about cord blood transplantation, and a lot of evaluation is going on compared to the other approaches for transplant, and you want people to be well no matter what I understand. One would ask, well, my cord blood transplantation, if more people are donating cord blood of all ethnicities, might that become the way transplant is done more routinely than the ways that have been around starting 50 years ago? Yes. I do believe that. I believe as our country becomes more involved in the storing of cord blood units at the time of birth, and as we see the ability to increase our donor pool that way, and as we perfect cord blood transplant, it definitely may be the preferred donor source. There is no risk involved to the donor because it's collected at the time of birth. There is no risk to the mother. There is no risk to the newborn child. And this is blood that's sitting there and ready to go. Now, the risk for donating marrow and peripheral blood, I don't want there to be any misconception about that. That risk is very, very low, but clearly isolating and finding these donors and making sure that they haven't moved and that they are healthy, all of these things are complicating factors. And if we can perfect cord blood and increase the number of units that are stored, it very well may be the preferred donor source. Well, we have to talk again, Dr. Colleen Delaney, who is head of the cord blood transplantation program at University of Washington and the Seattle Cancer Care Alliance. Thank you so much for being with us on Patient Power. Oh, thank you so much for having me. This is what we do on Patient Power. And of course we like to say knowledge can be the best medicine of all. We do this every two weeks, so two weeks from now we will be discussing with Dr. Edward Lin who is a renowned expert in colon cancer the topic of targeting colon cancer stem cells. So for many people who are affected by colon cancer or their families, this would be a great program. Thank you for joining us. I am Andrew Schorr. sccapatientpower.org 10

Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. sccapatientpower.org 11