Saving Lives With Pediatric Stem Cell Transplant Webcast April 6, 2010 Laurence Cooper, M.D. Introduction

Transcription

1 Saving Lives With Pediatric Stem Cell Transplant Webcast April 6, 2010 Laurence Cooper, M.D. Please remember the opinions expressed on Patient Power are not necessarily the views of MD Anderson Cancer Center, 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 Not all pediatric cancers are successfully treated with conventional chemotherapy, radiation or surgery. We wish it always could work, but sometimes it doesn't. Specialized treatments like transplant or cell therapy are giving pediatric patients a new advantage. Coming up a leading expert from MD Anderson, the largest transplant center in the world, will explain how stem cell therapy is being used to fight cancer in children. Hello and welcome to Patient Power sponsored by MD Anderson Cancer Center. I'm Andrew Schorr. Well, I am a cancer patient survivor as an adult, but, oh, my goodness, it just tears your heart out when you see a child diagnosed with cancer, and then there's some other fairly rare conditions too that are treated sometimes at cancer centers as well, and you may be aware that there's a Children's Hospital within MD Anderson to deal with these children who are affected that way, and people come from far and wide. Often in some cancers chemotherapy, radiation, surgery, can be quite effective, but not always. And then you get to other approaches like transplant. We always used to call it bone marrow transplant. Now we talk about stem cell transplant, other approaches to try to help have that child's immune system fight back. Well, with us now is a leading expert in that. That's Dr. Laurence Cooper. Dr. Cooper is section chief of cell therapy at the Children's Cancer Hospital at MD Anderson. Dr. Cooper, now we know that chemotherapy for example when it comes to ALL, leukemia in children, has been so effective, the combination of drugs. Where does transplant come in when we've made a lot of progress with the drug therapies? Why is it needed? Yeah, that's a great question. For the typical child, you're quite right, who has an acute leukemia, especially acute lymphoblastic leukemia or ALL, that little boy or that little girl doesn't necessarily need to go on and have what's called a bone marrow transplant or, as you so nicely opened up, a stem cell transplant because of the regimen of chemotherapies being so effective in the present modern age. However, that package of chemotherapy given for that young person unfortunately is not always effective, and a relapse can occur, and especially if that relapse occurs soon after the initial round of therapies has been delivered or under very

2 unusual circumstances where the chemotherapy itself doesn't work, then that family and that child needs more advanced treatment. So the world of bone marrow transplantation or stem cell transplantation really comes into focus for those families and for those children who have very aggressive underlying acute leukemias such as ALL that has relapsed after frontline therapies. What is Transplant? All right. Let's understand what transplant is. I mentioned that it's trying to give power to the child's own immune system to fight back against the cancer, and I talked about bone marrow transplant and stem cell. Help us understand these terms and basically how this cell therapy works. So the concept is that the chemotherapy and the radiation therapy for leukemias for instance has really reached a point of diminishing returns. In other words, just giving more chemotherapy is not necessarily going to wipe out the cancer but it's going to harm that child, so a whole different essentially armamentarium has to be put into play, and that's based on biologic therapy. So fortunately in our body we have when we're healthy a functioning immune system, and that immune system keeps us essentially free of disease as we go about our day-to-day lives. That immune system can be harnessed to go after a person's cancer. And the bone marrow transplant, or the stem cell transplant, those essentially are words that can be used interchangeably, are essentially trying to manipulate a person's immune system. So let me give you an example. Say for instance a young child comes to us who has a very aggressive leukemia and they no longer are enjoying a response to their front-line therapy. They will then come to a consult to our service, to our bone marrow transplant service, and we will provide them very high doses of essentially conditioning, what's called conditioning chemotherapy to wipe out their underlying blood progenitor cells, their blood producing cells that's in their marrow, and we will infuse in a replacement source of those blood progenitor cells or blood stem cells from another person. And in fact it can be from a family member or it can be from somebody completely unrelated to that family. And it can even be, and I'm sure we're going to talk about this in a minute, from a little baby. It can be from neonatal blood or umbilical cord blood. All three of those sources of blood progenitor cells when they're infused in that child that's undergone conditioning therapy can like seeds in a lawn settle down into the bone marrow of that recipient, and then out of that grows a new immune system. And there are some really important parts of that immune system that help put that patient then into remission. And those elements of the immune system that we focus on are called T-cells, T for thymus, and NK cells or natural killer cells. It's 2

3 these two cell populations in particular that when they grow from the graft then essentially are in another place. They used to be in somebody else's body and now they're put into this child's body. When they grow up in that child's body after transplant they are then energized to go after remaining cancer cells, just the same way that those T-cells and those NK cells before they were transplants they were protecting that person from infection, so now when they're moved over to a new person they are now capable of not only protecting from infection but importantly to go after and to selectively destroy residual malignant cells. Dr. Cooper, let me just kind of spit this back to you to make sure that I and our audience understand. So when a child has developed one of these illnesses their immune system in a sense has let them down. Either it had a gap in it that they were born with or it developed where it couldn't recognize these malignant cells. Yes. And by giving, infusing, if you will, a healthy immune system from another person, that can fill in those gaps or take over and kind of give them the healthy immune system that unfortunately they had gaps in before. Yeah, that's exactly right. In fact, one of the great mysteries really that we study in the world of immunology, and really since the dawn of immunology and cancer people have worked to understand why a cancer occurs in a patient with a healthy immune system. And in fact what it really speaks to is the fact that the cancers that evolve over time in a person to where they become lumpy, bumpy disease or a person actually feels the effects of having a leukemia or a lymphoma or some other malignancy, when that cancer has gotten to that state it has to have slipped out essentially from the immune surveillance mechanisms that we all have in our body and has evolved therefore over time to resist your own body's immune system. So it's really the ability to move immune systems from one person to another, to physically extract that immune system from your donor and move it into that recipient that really allows the immune system to reset itself. And the cancer can't keep up because then it's faced with a whole other new challenge, and that challenge is fortunately for the recipient an immune system that's coming in that's not seen that cancer before, and those immune evasion strategies that have essentially kept that cancer growing in that child now essentially are nullified in the face of this new repertoire, these new T-cells, these new NK cells that are growing up over time after the transplant process. 3

4 The Research Team Dr. Cooper, let's talk about your program. This area of medicine that you're discussing is very specialized, and while we've been doing transplant for a number of years now and somebody won a Nobel Prize for helping develop it in adults, in kids there's less experience. Now, at MD Anderson the adult transplanters and your department all work together to combine that wisdom, right? Yeah, I think that's an important point. I think one way to consider bone marrow transplantation or cell therapy or stem cell therapy is really that it is a type of medicine that's driven by experience, and it's driven by a knowledge that gained in the context of doing protocols and innovation. And when you are innovating and you are thinking of ways essentially to rescue that child, because after all when they come to see me they have very aggressive cancers as we talked about earlier, you need all your wits about you if you're going to deliver therapies that's going to be curative. To have a program where you are state of the art, where you are driving essentially the new technologies and making everything available, you want to have a wealth of experience, and one way to get that experience is to partner with our colleagues who take care of older patients, in other words, adult patients. Because, in a way, thank goodness, the number of children across the country who need to come to transplant for essentially to be cured of their disease it's much smaller than the number of adult patients who come to transplant who need to be cured of their particular disease. However, that adult and that child have very similar biology, very similar responses to the types of conditioning regimens and stem cell sources that we would infuse into them, and therefore we can use the knowledge base, we can use the experience of all the really thousands of patients who undergo transplant for adult cancers to help the hundreds of patients who are children who are undergoing transplant for their particular malignant diseases. Now, we've talked about drug therapies have helped so much in some cancers in children, not all, but certainly ALL is an example, we're learning how to combine them has raised the cure rate dramatically, but typically drug companies are not developing drugs for kids. It's a very limited population. So is also part of the experience learning where drugs come in too and trying to see are there adult drugs that can be used safely for children? 4

5 Advances in Pediatric Oncology You touched on a really important point, and I think it is something that our country quite frankly has not paid enough attention to. So pediatric oncology in general is at a tipping point in that there have been great strides made over the last decades, really from the 1950s, 1960s to the 1990s when in fact the signature disease, the most common disease in pediatric cancer being ALL, that disease has gone from a very low level of overall survival to where it's about 70 to 80 percent five-year survival for that particular child presenting today at my center. That's a huge accomplishment, but the warning is out there. The warning is that in the last 20 years, in other words, from 1990 to 2010, where we are now, the overall improvement in pediatric cancer survival has been less than two percent a year. In other words, we are completely plateaued. And why is that? Well, the problem is that we're still using drugs that were essentially designed for those early trials. We're still using drugs that were developed in the 1950s, if you can believe it. Essentially 50-year-old drugs are being infused into our children today. Not only are those drugs essentially not able to provide effective therapy for children, they damage children who are the survivors of pediatric cancer. So if you look long term at a 30-year survivor, so particularly looking at for instance a five-year-old who comes in today with ALL, and then you look at a 35-year-old survivor, so essentially 30 years from today, what does that person look like? Well, unfortunately, because of these elderly drugs that we're giving that 35-year-old has an uphill climb, has issues that are essentially severe medical problems associated with the very drugs we gave, in other words these poisons that we're giving to get rid of a lethal disease, ALL. So what's to be done about this? Well, up to this point there's been the general hope in the community that drug companies, for-profit drug companies, would be energized essentially to provide pediatric therapies and would do so on a voluntary basis, but the problem with that approach is that it's not really resulted in any meaningful advances to pediatric cancer. The reason is obvious, and that is that these companies are driven by a profit motive and it's incredibly expensive to develop new drugs. These are not evil companies, they're not out there to harm people, but they have to recover their costs. And when one considers that it's about something like 700 to 800 million dollars to develop a new drug for cancer they cannot get a return on their investment for developing drugs that are targeted for pediatric oncology. So consequently over the last really decades there's really been only one new drug for pediatric cancer, and that actually really got going here at MD Anderson, and that was called clofarabine. And you contrast this really with the many, many drugs associated with billions of dollars, that's billions with a B, that are being essentially developed for adult malignancies, there's a huge essentially gulf here that has to be bridged. Fortunately, there are centers for instance such as MD 5

6 Anderson that are energized around this issue, and we have really made a conscious effort to try and find approaches where adult, quote/unquote, adult-type drugs can be infused into children. And one way to do that is directly partnering with our adult colleagues who for instance are here at MD Anderson. A great example of that is a drug called busulfan. Busulfan has come in many different formulations, and one of the new innovations from MD Anderson and from our transplant team has been making busulfan as an intravenous drug and not only using that intravenous formulation in adults but to then do the necessary legwork and take on the expense and really the moral imperative to get that drug into children so that we can study its effects. Wow. Well, thank you for that answer. I think that will be fascinating to people around the world and really talked about a very important issue in pediatrics and pediatric cancer. We're going to take a quick break. When we come back we want to begin to understand if somebody is a candidate for a transplant where do these cells come from, and you talked about different options. And also particularly about cord blood, because many people are not familiar with that, how can that help as well and how are cord blood cells accessible to them at MD Anderson. Much more in our discussion with Dr. Laurence Cooper from MD Anderson right after this. Conditions Treated through Transplant Welcome back to Patient Power. We're visiting with Dr. Laurence Cooper who is section chief for cell therapy at the Children's Cancer Hospital at MD Anderson. Just to make it clear, Dr. Cooper, we've used this example of ALL several times and talked about aggressive leukemias, but when we talk about transplant and cell therapy there are other conditions that come into play, too. Why don't you help list some of those so as we talk about it those parents know that it could apply to them as well and their child. Yeah, I think that's an important point. There are really essentially a spectrum of diseases, both malignant, in other words cancerous, as well as noncancerous for which a child or a young person can come to the attention of a transplant doctor such as myself. We mentioned already the acute leukemias, especially acute lymphoblastic leukemia, but there are other acute leukemias, for instance acute myeloid leukemia, AML, so both of those are important essentially malignancies for which pediatric transplant has a curative role. In addition, there are other malignancies in the blood, for instance, lymphomas, that can also be cured with bone marrow transplantation or stem cell transplantation. That decision about when to take a person with lymphoma to 6

7 transplant can actually be quite complicated and quite nuanced. So without going into all of the specifics I'll just mention it in broad brush stokes to say that for some children with aggressive diseases transplant for lymphoma can be lifesaving. In addition to those diseases that are malignant, in other words cancerous, there are also noncancerous conditions for which replacing the bone marrow, essentially the process of the bone marrow transplantation, can be curative. For instance there are diseases that come under the broad category of bone marrow failure syndromes. And what that really is speaking to is that some elements in the bone marrow, for instance the immune system, the red blood cell system, the platelets, in other words those little tiny pieces of cells that help you clot, some element has essentially given up. Either the child was not born with the correct factory cells in their bone marrow or those cells essentially have been damaged over time. That bone marrow function can be restored by bone marrow transplantation or stem cell transplantation. And those children do not have a malignancy. They are essentially getting a restorative, if you would, type therapy. And then there are other types of decisions around nonmalignant transplant which have nothing to do with the bone marrow per se but have everything to do with the fact that that little girl or that little boy is missing a critical enzyme or a critical protein in their body, and one source of that enzyme or that protein is in bone marrow and those cells that are produced from bone marrow. So again you can see in your mind's eye how that young person can be saved by moving bone marrow from one person to another or stem cells from one person to another, not to cure an underlying malignancy but essentially to provide a source of fresh and healthy cells essentially to get them out of trouble, to produce that protein, to produce that particular enzyme. Where Stem Cells Come From Let's talk about the sources. So first of all we should mention that there are some cases when the source could be the child, him- or herself, right, an autologous transplant. Where would that come into play when you could sort of reboot their immune system with their own cells? So for some children, and perhaps we'll just refer back to children for instance with lymphoma or children with a solid tumor called a neuroblastoma or even some children with brain tumors, for these children, their underlying malignancy, their underlying cancer is still responsive to chemotherapy. In that situation we can provide whopping doses, and I'm talking very high levels of doses of these chemotherapies such that we completely wipe out the bone marrow as a side effect of really providing a very intensive chemotherapy package to that underlying tumor. So really it's a consequence of trying to wipe out the tumor with these very high levels of chemotherapy that the bone marrow gets destroyed. 7

8 And then of course to save the patient, in other words to restore the bone marrow function, we infuse back in bone marrow progenitor cells or bone marrow stem cells that have been collected from that young person before we gave the whopping doses of chemotherapy. So it's really done, this concept of autotransplant or autografting, it's really done so that we can essentially dial up the intensity of the chemotherapy. You mention cord blood. So people now I know around Houston, New York, some other areas, new moms are offered the opportunity to have the very immature blood cells in the umbilical cord or from the placenta stored and made available to people who need it, and of course there are some parents where someone, some child is affected in their family with cancer where sometimes if they have another child that cord blood is stored or even sometimes in the hope for an adult. Tell us about cord blood and what that could mean as a source. So this is really a big growth part of our clinical practice. In fact you are correct that the United States has really a lead role to play, but it's actually worldwide now, this concept of banking umbilical cord blood. So I think to answer your question let's just think back for a second to the delivery room where mom has just delivered that baby, and the baby is essentially handed to mom. The umbilical cord blood is clamped and tucked, and then the placenta is delivered. And the placenta with that piece of umbilical cord still attached has what up until that moment that child was being delivered has baby blood moving through it, and that's the way the baby grows inside the mom's uterus. So in the placenta, in the little piece of cord still left attached is for all intents and purposes baby blood, and that's what we're calling umbilical cord blood. And that really has been an extraordinary opportunity for physicians such as myself who take care of children undergoing transplant because that baby blood is very special. It contains in it stem cells, and I will just draw your audience's attention to the word stem cells here. These are not the types of stem cells associated with what's called embryonic stem cells. For instance, President Bush had outlawed essentially or forbidden research into embryonic stem cells. That policy has just been rescinded by our present president, Mr. Obama. These are stem cells that I'm speaking about that are stem cells that can restore the function of blood. They are progenitor cells for what's called hematopoesis. So in baby blood as part of our physiology, as part of being human, those stem cells are circulating in that baby. So once the baby is delivered and the placenta is then extracted or delivered, there's an opportunity really for free to get ahold of some baby blood. Otherwise that placenta and that cord will be discarded. So it's a very simple procedure where the staff in the delivery room can essentially milk out the blood from that placenta and that little bit of cord and bottle it, physically 8

9 bottle it, and ship it to programs such as occurring at MD Anderson as well as really cord blood centers throughout the world where those cells then can be frozen into large banks. And that's what's called a cord blood bank. And when the mom or the dad give consent, in other words they agree to the collection of their child's baby blood from the placenta and from the cord to go to a bank such as MD Anderson, they really have given a tremendous gift. Because that blood then essentially is put into a large computer base where children essentially who are unknown to them, in fact that mom or dad and that baby when they grow up will never know if that cord blood has ever been used, but for those children who are out there who have a particular problem where they need to come to see me in the pediatric cell therapy program or the pediatric transplant program and they need an infusion of these hematopoetic cells, these progenitor cells as part of undergoing the bone marrow transplant, I'm using these words kind of generally, in other words stem cell transplant, we can thaw that baby blood and infuse it back into that new person and restore their bone marrow function. So it's really an amazing gift, and it's a gift that you don't get any credit for. That mom or dad is not going to get any credit for this, but they will have the satisfaction of knowing that if the right situation occurs their baby's blood that otherwise would have been discarded essentially along with the placenta has now been thawed and used to save somebody's life. Right. It is so cool. Now, one point we should make, if I get this right, Dr. Cooper, is those immature stem cells, progenitor cells, are more adaptable often than from an adult donor. That's right. And that's been very helpful especially for our minority patients. Because very often when a patient comes in from a certain ethnic group and they're looking for a donor to give them bone marrow or to give them stem cells they unfortunately can't find one. Because for a whole bunch of complicated genetic reasons it turns out that for instance people of color or people of very unusual ancestry such as Samoans have a difficult time finding other people who are like them in the registries of unrelated donors. However, the cord blood as a source of progenitor cells for those patients as well as patients who would have identified an unrelated donor from more conventional registries, the cord blood essentially can slip into their body in a way that's a lot easier and we don't have to go through all of the matching process that's associated with infusing stem cells that's derived from an unrelated adult donor. So these umbilical cord blood cells are essentially much more pliable, much more plastic, and much more able to essentially engraft in a way that they can reconstitute a person's bone marrow function and not get rejected. 9

10 A Curative Therapy? All right. I've got maybe what's a controversial question in medicine to ask you, and that is you describe what we're seeing in children who are treated successfully with chemotherapies as they grow up and lead hopefully a long life, but maybe they're 35 or 40 or 45, and we're talking about the curative approach of a transplant essentially. And certainly it's no walk in the park. It's difficult therapy. But should transplant in your mind be used earlier where it's potentially curative, and maybe the harmful side effects of some of the older chemotherapy drugs can be avoided altogether? Yeah, that's a great question. I think the way to think about that is that medicine in 2010, in the modern age, especially for patients for instance at MD Anderson who come to us often with very difficult-to-treat diseases are looking for our combined expertise, and there's no one size fits all for every patient. Each patient really has to have a personalized approach where their plan is developed according to their particular needs and their particular cancer. So for some patients the risk of continued chemotherapy, the risk of radiation, the risk of surgery essentially can be trumped by moving directly to transplant. But the opposite can also occur, and the opposite can occur where transplant is seen as too onerous, and that particular patient should go on and have other types of therapies with an eye to getting into remission with a less toxic therapy, albeit potentially not having as much of a curative intent. So there really is this balance between toxicities and your chances of overall survival. And for that family, for that child, it really has to be laid out in a way where everybody is on the same page. And as a matter of fact I think that really the job of a pediatric transplant physician is one of an educator because sometimes it's not black and white. Sometimes there really are shades of gray where we are struggling, both the clinical team as well as the parents, to plot a course that answers that family's needs, emotional needs, as well as physical needs, to provide them essentially with a realistic chance of survival that doesn't essentially rob that particular child of performance when he or she grows up. Dr. Cooper, notwithstanding what you just said about really personalized care which is so important, still parents generally when they listen to this program use how you're feeling about things as sort of a barometer generally. So being our barometer and working in really a changing field and really the leading edge of medicine how hopeful are you that some of the natty problems of children you just couldn't help or help well before, that with these technologies and your skill and the wisdom of your combined group and other peers around the world that you can really move things forward? 10

11 I think we're at a golden age really in what really is immunotherapy or immune-based therapy. We started the conversation really talking about the immune system, about T-cells and NK cells being gifted from one person to another. We now understand many of the rules of being able to essentially manipulate the recipient, manipulate the patient so that they can be engrafted, in other words they can receive these gifts of stem cells, whether it be from cord blood or from peripheral blood from an adult donor. By understanding those rules and essentially being able to now have all of the supportive care in place where those patients can essentially survive the transplant process has opened our eyes essentially to the idea now that it's the immune system, it's those T-cells and those NK cells for instance that can be essentially a source of therapy independent of the transplant process, independent of infusing stem cells. And this really is what I speak about in terms of this golden age because really for I think the future generations now of patients who come to see us, it's no longer about just infusing stem cells but it's now about infusing stem cells in addition to these designer T-cells or designer NK cells, natural killer cells, and that of course will lead to the natural question of when stem cell transplant might even go away for some particular diseases and all the patient will get is specific T-cells, specific NK cells that have been prepared to tackle and go after their tumor. The Importance of Clinical Trials Wow. Well, of course all this then brings up clinical trials. I was in an MD Anderson clinical trial for my leukemia, and not only did it work for me, I'm happy to say, but now it's an approved approach worldwide. So I urge parents and kids if you're listening to this too to consider if Dr. Cooper and the team offer you wherever you may be the opportunity to be in a trial for you to consider that. Not only might it well give you access to leading edge approach but could help many others too. Did I get it right, Dr. Cooper? Yeah, I think that's important to say. And I would say that sometimes the word trial gets mislabeled in people's minds as experimental medicine, and that's never the case. What we're really after is a way to improve upon our current strategy. So every patient who enters into a clinical trial gets two choices basically. Gets to receive standard of care or gets to receive something that may be better than the standard of care. Now, obviously if we knew it was better we'd just offer it, but we have to do a study. We have to do a comparison where we essentially are asking the question will this improve your particular ability or your child's particular ability to get over this particular disease compared with the standard. I think that's important to keep in mind. And again the transplant physicians really are experts in delivering that type of educational message to families. And again if families are unclear and they're worried they should ask questions because it's 11

12 really the doctor's responsibility, the nurse's responsibility, the pharmacist's responsibility to make sure that these ideas of clinical trials are well explained so importantly the families, and even the children, they also are involved in this, can make informed decisions about what type of therapy they want to be involved with. Dr. Laurence Cooper, section chief, cell therapy at the Children's Cancer Hospital at MD Anderson, I give you an A for being our educator today. Thank you so much for being with us and helping explain really where things are headed when we talk about pediatric stem cell transplant and maybe even these more specialized infusions going forward. Thanks for being with us. My pleasure. This is what we do on Patient Power is connect you with leading experts like Dr. Laurence Cooper and hopefully give you and your family important information so that you can ask questions, get answers and for your child, get better health. I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. Thanks for joining us. Please remember the opinions expressed on Patient Power are not necessarily the views of MD Anderson Cancer Center, 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. 12