“Pediatric Bone Marrow Transplantation”

Stella Davies has an impressive educational background, receiving her degrees in medicine and surgery from the University of Newcastle-Upon-Tyne in England; she came to Minnesota in 1989 on a clinical and research fellow at the University of Minnesota.

I have been practicing in pediatric bone marrow transplantation, and I want to cover a number of different areas with you today that are specific to pediatric bone marrow transplantation, but particularly emphasize how we decide which children should receive a transplant, because I think that is one of the hardest issues in pediatric transplantation. 

While we discuss that, I want to particularly focus on some of the more unusual pediatric diagnoses that are receiving bone marrow transplantation, because I think you are going to be seeing these diagnoses coming across your desks more frequently. There are unusual diseases, rare diseases, and diseases, in which the decision to transplant or not is a very difficult one. 

It is not clear-cut. I am then going to finish by just talking about an exciting new area of development in pediatric bone marrow transplantation, which is the use of umbilical cord blood for transplantation and talk about where it is appropriate to use that -- where it is appropriate to store cord blood, just in case, and where that field is going.

So, I am going to start by talking about malignancies, and I am going to talk about them fairly briefly, because it’s not intuitively hard to understand why a bone marrow transplant is good for leukemia. But I want to, again, just briefly touch on the indications for transplant -- how we decide which children with leukemia get transplanted -- and highlight the issues of transplantation for solid tumors and the differences between adult chronic leukemias and childhood chronic leukemias.

Let’s talk first about acute lymphoblastic leukemia. Acute Lymphoblastic Leukemia is the commonest sort of leukemia that occurs in children, and it represents one of the great success stories of pediatric oncology. Thirty years ago, less than ten percent of children would survive. That was the start of combination chemotherapy, when we were just starting to understand drugs. 

Over the last 30 years, generally because of well-organized clinical trials of participation of virtually every child in this country with leukemia, we have developed chemotherapy strategies which will cure approximately 75 percent of children with ALL. 

So, most children with ALL do not need a bone marrow transplant. So that is the good news and the real positive news and an area where we have learned a great deal about treating cancer that is actually transcribed into other areas of cancer care.

However, it is important to realize that childhood leukemia is not yet fixed. If you look at death rates in children, cancer is the commonest disease-based cause of death and, still, the most-frequent cancer that causes death in this country is leukemia, and that is because, despite the fact that we can cure most of these children, the incidence is much higher than the other kinds of cancer. So it is still a very important cause of death.

Now, as we improve our ability to treat children with chemotherapy, the indications for using a bone marrow transplant, which might have more toxicity, more immediate risk of death, more late side effects change, and that is the important message I want to leave nickeling in the back of your mind -- that which child with acute lymphoblastic leukemia should get a transplant is a moving target. 

It changes, depending on what the outcome of chemotherapy currently is. So, included in your packet -- and don’t worry about it now because it is a moving target -- but included in the packet, is definitions of what are currently considered the indications for who should get transplanted in ALL.

But, as we change our therapies and as we get better at using molecular biology to identify those children who are going to fail with chemotherapy, the list of what is indicated changes. So just bear that in mind. It is a moving field.

Acute Myeloid Leukemia is less common than ALL. About 20 percent of childhood leukemia is AML. Eighty percent is ALL, and we have been less successful with chemotherapy -- about 40 percent survival with chemotherapy alone -- quite a lot lower than with ALL. In this arena, it is a clear indication for a bone marrow transplant if there is an available sibling.

We expect about an 80 percent survival for a child with AML in first remission, transplanted with a sibling, and all the current available randomized studies show superior outcomes with transplantation if you have a matched brother or sister.

If you do not have a matched brother or sister, the optimal treatment is to continue with chemotherapy. If a relapse takes place, then that child is almost certainly not going to be cured without transplant and, then, it is an indication for seeking an unrelated donor or umbilical cord blood, and we’ll talk more about that later.

What about solid tumors in pediatric cancer? We’ve heard a lot about breast cancer and bone marrow transplant. It’s been up. It’s been down. It’s been all around. What do we know about the same arena for pediatrics?

And I just want to summarize, here, the things you should think about if this comes up. When you are thinking about whether an autologous bone marrow transplant is indicated for a disease, if you keep in mind how it might potentially work, you can figure out whether it is a good idea or a bad idea.

Remember always, when we do an autologous transplant, we take the patient’s own marrow. We store it. We give a big dose of chemotherapy. We give the marrow back.

What we are trying to do is just give more chemotherapy. We get a bigger dose in. We give them their own cells back. So that presupposes that the tumor that you are treating in the first place is sensitive to chemotherapy, and that if some works, more is better.

Now there are some diseases for which this is indubitably true. There are some diseases where it probably isn’t. In pediatrics neuroblastoma, this is an adrenal neoplasm. It is common in children under five. If it’s disseminated, it is associated with a very high mortality.

There are good randomized studies that show autologous bone marrow transplant improves outcome, and it gives you about a 20 percent improvement in survival. In combination with retinoic acid, you probably get a 30 to 40 percent improvement in outcome.

Here, it’s clearly a chemo-responsive tumor -- an autologous bone marrow transplant up front in first remission is an advantage.

In non-Hodgkin’s lymphoma and Hodgkin’s lymphoma, autologous transplants commonly used in the adult setting, these are very chemosensitive diseases. You would expect it to work here? It certainly does. There are a lot of good studies showing that particularly in those with advanced or relapsed disease. This is a good strategy. It works well.

Things get a little more unclear, as we move down the list. We look at brain tumors. Autologous transplant is usually offered for those with advanced or relapsed or unresectable disease. Brain tumors that are in a place where you just can’t remove them, even though they are not particularly large or that have come back or disseminated.

Again, it’s important to remember is this is a kind of brain tumor that is likely to be chemosensitive.

Many brain tumors in children are slow, slow growing. They divide very slowly. They are not very sensitive to chemotherapy. They progress slowly. If they are not chemosensitive when they are at an earlier stage, it makes no sense to move onto high dose chemotherapy -- stem cell rescue when they are worse.

So this is the key to think of. Is it chemosensitive? And in pediatric brain tumors, medulloblastoma, primitive neurectadomal tumors are usually chemosensitive and are good candidates for the strategy. Other slower growing but also lethal tumors like oligodendra gliomas, it really doesn’t make a whole lot of sense. And it should be considered still under investigation. People are still trying to clarify its role here.

Similarly, in advanced sarcomas -- rhabdomyosarcoma, Ewing sarcoma, the bone tumors that children get -- it is hard to find large series that tell you whether this is an appropriate strategy or not. So, even within an individual patient, it is appropriate to think is this chemosensitive disease? 

And, if I’m trying to decide, a child presents with a relapsed streptomyosarcoma, the doctor calls. He has given two rounds of chemotherapy. The patient didn’t respond. Couldn’t we do an autologous transplant? That makes no sense. He has not got chemosensitive disease. Didn’t respond to a moderate dose of chemotherapy. The increase in dose that we can give by doing autologous transplant is relatively modest. It doesn’t make sense to progress.

On the other hand a child with Ewing sarcoma -- more sensitive --had a relapse, got two rounds of chemotherapy, the pulmonary nodule has gone away. Should we try an autologous transplant to keep it away? Yes, that makes sense. Give a bigger dose and do that. So whenever you are thinking about autologous transplant, think, “Is this is a chemosensitive disease?” 

If it is not, it doesn’t make sense.

Just to finish up talking about the malignancies, which is not where I want to put my stress, because you will hear about that a lot from the adults, I want to talk about chronic leukemia in childhood, and I want to talk about it really to remind you that it is different from Chronic Myeloid Leukemia in adults.

In adults, Chronic Myeloid Leukemia is the commonest indication for transplantation. It is associated with the presence of the Philadelphia chromosome, and it’s associated with a fairly slow course. There is another disease, which is commonly called juvenile chronic myeloid leukemia, which people often mistake for a child with the same disease, with Philadelphia positive chronic myeloid leukemia. This is not the case. 

It is important to remember that Philadelphia positive chronic myeloid leukemia can occur in children. While the typical patient is 50 or 60 years old, the youngest patient with CML that I have transplanted was one year old, so it can occur. There is a curve in the age range. 

This is a different disease. It just happens to be named badly. And there is a move afoot to try and change its name to Juvenile Myelomonocytic Leukemia or JMML. And I just want to show you, briefly, the clinical features of this and a couple of the specific features of transplantation, because it is a very different disease.

This is a disease of very young children. Adolescents have been described in the literature with JCML. They probably didn’t have it. They were probably misdiagnosed. The incidence of this disease is essentially over by the age of five. It is associated with the presence of face rash, fevers. These children tend to bleed. They bleed more than the platelet count would make you expect. 

Their blood picture shows a monocytosis, and these monocytes are malignant. They are part of the malignant clone. They have an elevated fetal hemoglobin, and they do not have a consistent chromosome abnormality. If there’s a Philadelphia chromosome present, it is not this. It is the adult kind.

This disease has a very poor prognosis. Death usually occurs from progression of the disease or from infection associated with the disease being present, and these children do very poorly with chemotherapy. 

This is not a leukemia that we can generally cure with chemotherapy and, interestingly, children with the inherited condition neurofibromatosis have a 200- to 500-fold increased risk of getting this kind of leukemia. So about 30 percent of children with JMML also have neurofibromatosis.

This shows the face of a child who has JMML, and I like this clinical picture, because it tells you a lot about JMML. You can see this is a youngster who is about one. Look at the teeth. You can see the typical face rash. It is raised. It is usually not painful. It is papular. You can feel it. 

It almost looks like acne, and it’s almost misdiagnosed because this is a very infrequent disease. The diagnosis is usually made when somebody finally does a blood test or does a biopsy of one of these things. When you biopsy one of these things, there is a skin infiltrate with malignant monocytes. This is part of the malignancy that is here.

As this leukemia progresses, these children develop a massive disease burden. They develop very large livers, very large spleens, and the associated malnutrition that goes along with having an abdomen full of this kind of disease.

This shows you an even younger child, and this can occur in infants three or six months old, again with the typical skin rash, and this is an infiltrate of malignant monocytes within the skin.

The only real effective curative treatment for JMLL or JCML is bone marrow transplantation, and the children are probably not helped by getting chemotherapy first. In a typical leukemia, you give chemotherapy. You get them in remission. Then you transplant them. In JMLL, the response to chemotherapy is so poor. There is so much toxicity associated with it. It is probably not helpful. 

The transplant is usually well-tolerated. These are young children, and transplanting young children, even babies, is actually a lot easier than transplanting older people. Toxicity is much less, and the transplant will work about a third of the time. 

Survival is about 30-40 percent, and the main reason it fails is early relapse. This disease comes back. It comes back early. It comes back often and the median time of relapse is two months after the bone marrow transplant. So it is a very depressing kind of disease to transplant. There really are very few other routes.

This is a disease in which the graft, versus leukemia effect may be helpful. You know, in bone marrow transplant, just as we can get a graft, versus host effect when we use marrow from two different individuals, you can also get a graft, versus leukemia effect that adds to the preparative regimen and makes the leukemia stay away.

This is a rare disease. There are about 40 cases a year in the United States, and we are working to generate an international study group to try and improve the outcome for this disease.

So I have covered briefly the malignancies, and we can talk more if people have questions about specific indications. I want to move on now to another area and an area that was real specific to pediatrics, which is the immune deficiencies. Immune deficiencies are quite varied. I want to cover three in particular.

Severe Combined Immune Deficiency, Wiskott-Aldrich Syndrome and HLH -- all of which are diseases that generally need transplantation for cure.

There are many other immune deficiencies; most of them are extremely rare, poorly characterized and we not infrequently see children who have a disease that is all their own. They don’t fit neatly into anyone of these categories, and, again, we need to be open-minded about how to treat them, depending on function.

So let’s start with severe combined immune deficiency. This is the common image of a child with immune deficiency -- the boy in the bubble. These are babies who essentially have no T-cells and no B-cells. They have normal red cells and platelets, but no lymphocytes to direct the activities of the neutrophils. 

They present, typically, with severe and multiple infections. They have diarrhea and they have poor weight gain and they have rashes. 

This shows you an example of a child with severe combined immune deficiency, and it shows you, quite nicely, the clinical features. This child is malnourished. The child has a rash. They have the scaly, peeling kind of eczema, and the children are commonly itchy and wear little mitts to prevent them from damaging their skin and getting invasive skin infections. They are very vulnerable particularly to Candida.

You can see this is an older child, despite the fact that he is just lying flat. He is developmentally delayed, and he has the worried, anxious look that ill children often have. These children have no lymph nodes and no thymus in addition to the absence of their immune system.

Severe, combined immune deficiency is a very important disease for bone marrow transplanters. It is associated with excellent results. If the children are diagnosed early, before they have gotten a really bad infection, they have an outstanding outcome. We expect better than a 95 percent survival rate, and, often, you don’t need to give any preparative regimen -- no chemotherapy, no radiation. You can just infuse in the cells that you have available, because these children don’t have the capacity to reject a graft. 

We give chemotherapy and radiation to empty out the host’s own bone marrow and to prevent the host’s bone marrow from rejecting the new cells. These children can’t do this. So you can just run the cells in and then sit tight and wait for them to grow and graft.

What will commonly happen is the children become mixed chimeras, so their red cells, their neutrophils, are their own, but their T-cells and B-cells are the host’s, and that works just fine. That is perfectly adequate.

The problem with kids arises when the diagnosis is not suspected, and this’ again’ is a rare disease. So, if you are the second child in a family, you’ll get diagnosed at birth. You’ll get whipped away into a clean environment. You will get transplanted right away. You are going to do great.

But more frequently these children present around three months. They have had a couple of episodes of croup. They’ve had bad RSV. They’ve always had diarrhea. They’ve never grown, and they present for transplantation when they are already on a ventilator for pneumocystis pneumonia. In that situation we do not have good outcomes.

The other difficulty that can arise is that these children have no capacity to reject foreign lymphocytes. They will commonly be malnourished. They will have gastrointestinal bleeding. They will have low hemoglobin. If these children receive unirradiated blood products as a transfusion, they can sustain lethal graft, versus host disease before they are ever transplanted, and that, again, is not a survivable event. 

So we do teach our residents, if you see a child in the ER, their hemoglobin is low, they have multiple infections, you are not sure, and it is always safe to irradiate your blood products. It doesn’t do any harm. If you didn’t need to, it doesn’t matter.

I just wanted to show this to remind you that this is where transplantation began. The first successful bone marrow transplant was performed in severe combined immune deficiency. It happened in 1968. It was at the University of Minnesota, and this child was a male child who came from a family, which reported 13 infants, who had died within the first six months of life.

This family had X-link, severe combined immune deficiency, which wasn’t known at that time, but they knew that their male babies had problems. So when this child was born, he was checked immediately.

We didn’t have the capacity then to measure T-cells and B-cells as we would now, and as he was being watched, he developed draining pus from his axillae. He had a draining infection in the back of his head, and it was clear that he was going to progress down the same path that his 13 preceding cousins, brothers and uncles had. And this child was his donor.

This was his older sister who survived. He was transplanted in 1968. Because we didn’t know how to do bone marrow transplants in those days and because we hadn’t figured out, if you run marrow in through an IV, it finds its own way home, he was given the bone marrow intraperitoneally. He had effectively a number 10 cuff catheter placed, and the cells were given, and he had to have three doses to get it in, but he did successfully in-graft, so he is now, of course, 32 years old.

This is him. He must have been about 10 or 11 months here. He lives in Connecticut and, because he didn’t need a preparative regimen, he is fully fertile, so he is the father of twins and one of the only surviving males within his rather large family. So this is where transplantation began.

Two other immune deficiency disorders that you may hear about and which are a good indication for transplantation, the first is catchingly named hemophagocytic lymphohistiocytosis or HLH. It also is called FELS or familial erythrophagocytic lymphohistiocytosis. You can see why you use the shortened version.

Again this is a disease of children under five years of age. It is a hard diagnosis to make, because the onset can be fairly insidious. These children present with fever. They have pancytopenia. All their counts are low. 

They have infections, and they have seizures and blindness. This is a disorder of activated histiocytes, so the children have infiltration of the optic nerves of their brain with these histiocytes that become activated for a reason that we generally don’t know.

It can be familial. More than one child can be affected in a family, and in some children, there is clear evidence that it is set off by a virus, and it’s not clear if this is a normal child having an abnormal reaction to a virus or if this is an abnormal child whose immune system behaves abnormally.

These children continue to have very high fevers. These are babies with temperatures of up to 106 and progressive neurological deterioration unless they are treated with chemotherapy. With chemotherapy that kills histiocytes, drugs like VP16, you can switch them off. You can put them into remission, but they are not cured unless you transplant them, and it is likely that they have a very basic immune defect that doesn’t allow them to handle viral infections.

So this is a good and immediate indication for transplantation. However, it is not a good idea to transplant them with active disease. You need to give them chemotherapy. Switch off the fevers. Return their blood counts to normal before you start. We learned the hard way that if you just blast in there, with the disease active, those children will not survive.

The last immune deficiency I want to mention to you, that is an important indication for transport, is Wiskott-Aldrich Syndrome. This is an X-link disease, so only boys get it. Girls can be carriers, and it is associated with a poor immune system, weak T-cells so that these children get multiple infections -- commonly pulmonary infections, pneumonia, sinus infections -- and these boys have low platelet counts. They have unusual looking platelets.

They are small and, curiously, they bleed much more than you would expect. These children can have spontaneous hemorrhage; platelet counts of about 40,000, where you really wouldn’t expect it to happen. And unfortunately they seem particularly prone to CNS hemorrhage, and many of these boys, if left untreated, will have an episode of sudden death around the age of five to seven. They will go to bed and be found dead in the morning from cerebral hemorrhage.

If the children survive these early events, and they are not transplanted, they are particularly prone to malignancy. They are prone to lymphoma, and the majority will develop, though not all will develop lymphoma between the ages of 10 and 20. These children are difficult to treat once they develop lymphoma and difficult to transplant at a later age.

Again, the results of transplant are very good if they are transplanted early, before these adverse events have happened. Once you have accrued multiple infections, these are things that will come back and be a problem during the transplant. Once you developed a lymphoma, it can recur, come back. You’ve got the toxicity of the chemotherapy. The boys are older. They’ve had more infections. The results are much worse in boys transplanted late.

When we look at the outcomes of BMT, there is a 95 percent cure rate in boys less than five. The cure rate is about 10 percent in those transplanted later than this, for these reasons. So this is an important indication for an early transplant. Don’t let these events happen and slip down.

Having said that; it is often much harder for parents to make the decision to take a healthy child to transplant. Your child has got leukemia. You’ve got to race forward. You know you are battling against time. You’ve got to get to transplant.

For a child with a diagnosis like this, you keep them clean. You watch them so they don’t bleed. You give them antibiotics. You keep them away from crowds so they don’t get multiple infections.

Going to transplant and knowing there is a possibility that the child will die right then -- and there is always is -- is very hard to do.

Now I just want to illustrate a little of what Wiskott-Aldrich means for families and start you thinking about what genetic diseases mean for families by showing you this family.

This is Tommy. Tommy was diagnosed with Wiskott-Aldrich when he was born. He was diagnosed when he was born because his mom knew it ran in her family. Three of her brothers were affected with Wiskott-Aldrich, and two of them died in middle childhood in the way that I have described to you -- going to bed well, having a spontaneous cerebral hemorrhage and being found dead in the morning -- clearly a very horrific event for the family.

So Tommy was diagnosed at birth. His family were very apprehensive about the possibility of transplantation and put it off and put it off. Eventually when he was about four years and ten months old, he would have multiple infections. It was clearly time to do it. He came and had an unrelated donor bone marrow transplant.

When Tommy arrived for his unrelated donor bone marrow transplant, his little brother Danny was about three months old. Danny had been born. Everybody was very excited because he was clearly an HLA match with Tommy and we had great hope that we would have a match donor.

Unfortunately when we sent the testing away, Danny was also affected with Wiskott-Aldrich Syndrome.

While Tommy was having his transplant, Danny, it became apparent, was much more severely affected than Tommy. Tommy had a reasonable platelet count of around 50,000 at the time we transplanted him. As we watched Danny, and he was really just there because his family were there, his platelet count became refractory, and you look at the bruises on his legs here. He had a platelet count, persistently, of less than 10,000. 

We couldn’t get him up. These children are hard to transfuse, so we felt very anxious that he was going to have a cerebral bleed and felt that it was an urgent need to transplant him, and you can see he is getting his Hickman changed. That is clearly what we did.
Tommy and Danny, I have already told you, were HLA identical. 

Danny was in trouble. His platelet count was real low so we knew where to find an HLA match donor. We asked Tommy’s donor three months after she donated. This is a stranger -- an unrelated donor. After she donated for Tommy, would she donate for Danny, and she never missed a beat. She indeed did donate to both boys.

This is Trish. She was allowed to meet the boys a year later. This is Tommy, maybe 18 months after his transplant -- Danny a year after his transplant. They actually met each other on the [a talk show], on a show on giving thanks, and they wanted the opportunity to give thanks Trish for the great gift that she had given to this family.

So this is a happy outcome. These boys are both fine. They are both almost three years out from the transplant now. But I just want to start you thinking about what kind of a burden this disease is -- of having to have more than one child go through a transplant. 

While we are talking about genetic diseases, I want to cover one more, I think, before we talk about metabolic diseases. I want to mention Fanconi [Fanconi’s] Anemia to you, because it is another disease in which it’s a challenge to transplant. They have specific difficulties, and it’s a challenge to decide when to do a transplant.

Fanconi’s Anemia is autosomal, it affects boys and girls equally, and these children have typically short stature. They have dark skin, and by dark skin, I mean a generalized even pigmentation. And this is a bit of a subtle observation, but, to make it, you need to stand the child next to his siblings and next to his parents, and then it can be extremely obvious. The child looks like he has got a significant suntan, compared to what is normal for the rest of his family.

These children also have splotchy abnormal pigmentation, which is different. They can have big café au lait spots or areas of hypopigmentation. The typical diagnostic sign is abnormal thumbs, and these children will often have absent thumbs, malformed thumbs, thumbs with one bone in, … thumbs, little small ones or lobster hand. Abnormalities of the radius, sometimes with normal thumbs, and abnormal kidneys, a horseshoe kidney or a pelvic kidney, are common.

These children are mentally normal. This is not associated with retardation. And, importantly, about 30 percent of children with Fanconi’s Anemia don’t have any of these typical signs. They can look completely normal, and, curiously, it doesn’t run true in families. 

So you can have two siblings, one of whom will be tiny, dark skinned, very pixy-like face that is typical of Fanconi’s Anemia, and the affected sibling -- I have one family where the first diagnosed child is exactly like this he had no thumbs. He is very short. Had dark skin. His brother is the quarterback on the high school team, and he is just affected.

What is important about Fanconi’s Anemia is that it is associated with progressive bone marrow failure, and the typical time of onset is around the age of five years.

The first signs are, typically, a raised mean cell volume, just showing that the red cells are not forming normally or a somewhat low platelet count. And these changes can be quite modest, and you can sometimes watch them for a number of years, but they will almost all eventually bone marrow failure.

For those who do not develop bone marrow failure, this is a DNA repair disorder. It is associated with malignancy. Forty percent of those will go on to develop Acute Myelogenous Leukemia.

This shows you some children with Fanconi’s Anemia, and this shows a pair of brothers. These brothers are only about a year apart. This is the affected child who is very short.

This slide is actually to show you that one of the typical treatments that adds about two years to life expectancy is androgens. These children’s marrow responds to androgens, but it does lead to virilization, deepening of voice. It is often unacceptable to the girls and is associated with development of hepatic adenomas or hepatic cancer. So it is of limited benefit.

More children with Fanconi’s Anemia, and you can see the typical little pixy-type face, a very small midface, kind of pointy low set ears, and here thumb abnormalities, and here a café au lait spot, and additional pigmentation. Here is loss of pigmentation. Both of these are part of Fanconi’s Anemia and the short stature

More thumb abnormalities -- you can see an abnormal thumb here – short, spade-like hand and again a somewhat pixy-like face.

Fanconi’s Anemia patients are challenging to transplant. Again, like everything else, if you are transplanted early in the course of the disease and you have a well-matched sibling donor, you can expect to do quite well. In that circumstance, survival will be 80 to 85 percent. 

However, in Fanconi’s Anemia families, you are not only looking for a sibling who is an HLA match, but similar to the Wiskott-Aldrich family, you have to have a sibling who is also not affected with the disease. 

So most of the kids who need transplant don’t have an available sibling donor, so you are talking about a mismatched family member -- an unrelated donor, or cord blood, which are much more difficult to use.

These children are hypersensitive to treatment with radiation or to chemotherapy drugs like alkylating agents. And these are exactly what we use during the transplant to empty out the bone marrow and get the new marrow in. Not only are they sensitive, they are not all the same. Some are more sensitive than others. The early history of transplanting Fanconi’s Anemia was a disaster because we didn’t understand this. We gave them the regular doses that we give to normal children and they would fall apart.

We have now figured out that we need to give them about a fifth of the dose that we give to a regular child, but, for some, that is still too much and for some it is too little, so they will reject the graft. So this is an important area of investigation -- trying to understand how to target the dose and get it right for each child.

Additionally, these children have other congenital abnormalities. They have cardiac abnormalities that make it hard to transplant them, and they have the effects of their prior therapy. Many of these children have had multiple blood transfusions, because they have been watched in bone marrow failure for many years, because people have been unwilling to take the step of bone marrow transplantation -- often with good reason. It is not an easy thing to do.

The androgens that I have showed you can have adverse effects. It damages the liver. It can make you prone to bleeding in the liver, and people will often use steroids. You probably shouldn’t, but it makes them very susceptible to diabetes during times of stress. When we transplant children with Fanconi anemia, they will commonly need insulin drips and special management.

So again I want to remind you that for patients with Fanconi anemia, being transplanted early is good, but you need to be careful. They are different from everybody else, and they should be transplanted somewhere that has a particular interest in this disease. It is not something for the occasional transplanter.

So I’m going to change directions now and talk about a different category of diseases. I’m going to talk about the inherited metabolic diseases and talk about where transplantation is going in these areas.

This is something really quite different that is being used much more extensively, talked about more, and I think you are going to hear about more.

I am going to talk about two categories of diseases --firstly, the mucopolysaccharidoses and, secondly, the leukodystrophies. They are diseases with similarities and differences. 

There is a group of different diseases in these categories, and I am going to focus on Hurler’s syndrome for the mucopolysaccharidoses, because that is the most frequent one of those, and it illustrates some of the decision-making things that you need. And I’m going to talk about Adrenal Leukodystrophy and Metachromatic Leukodystrophy in the leukodystrophies.

So let’s start with Hurler’s Syndrome. Again, it’s a genetic disorder. It’s a single-gene defect. It’s an inherited deficiency of alpha-L-iduronidase. So children are born without alpha-L-iduronidase. This enzyme metabolizes glycosamine and glycans within your body. This is a waste produce of metabolism. If you don’t have it, glycosamine and glycans accumulate throughout your body, and I’m going to show you what the clinical effect of that is.

This is an autosomal recessive disorder so both parents are necessarily carriers. The affected child has two abnormal genes.

This slide shows you a picture of a child with Hurler’s Syndrome, and I want to show you a few pictures, because the outward appearance of Hurler’s Syndrome is very important. It is important that these children are transplanted early in the course of the disease. It cannot be done late, and we’ll talk about why. 

The diagnosis is often missed. Because these children look normal at birth, the typical appearances come as the glycosamine and glycans accumulate within your body. 

If you look at this child, I draw your attention to the relatively course facies, thick hair -- very characteristic, thick course hair. She has an enlarged liver and spleen -- very typical. You can see she has knock knees. The knees are pointing in. 

If you look at her back, you can see she is starting to develop a gibis. Children should normally have a lumbar lordosis, a bend in the back. You can see her tummy sticking out, and there is a little hump developing in her back. And a gibbous deformity, a widow’s hump, a kyphoscoliosis is very typical for the mucopolysaccharidoses, and the diagnosis should always be countenanced in any young child with that.

Note that the heavy eyebrows, the Brooke Shields eyebrows are very typical of mucopolysaccharidoses. Look at the shape of the face, because I’m going to show you some more pictures, and you’ll notice the commonalities between all the children with storage diseases. It is very striking. These children all look fairly similar.

As the disease progresses, this is a fairly mild version, this coarseness of facial features progresses further and becomes much more marked. And I’m embarrassed to say that in Europe, up until recently, this disease was known as gargoylism because of the very marked facial abnormalities in the advanced cases.

You can see these children here. Again see the thick, heavy hair? The heavy eyebrows? Here the tongue is starting to get large, and the course face with the little snub kind of Hurler’s nose. Because the glycosamine and glycans accumulates in the nasopharynx, these children always have runny noses. Hurler’s kids always have runny noses. It runs out instead of back.

Again, in this child, see the thick hair and the course face.

One of the early signs that can help a child with Hurler’s be diagnosed before any of these prominent manifestations occur is corneal clouding. If this is noticed and detected, these children can picked up early and it is always abnormal. You can see this cloudy cornea.

Children with Hurler’s who are untreated, and there is no available treatment other than bone marrow transplant, will have a median survival of about five years. Fifty percent of them are dead at five. They are virtually all dead by ten years of age.

You will notice here that the pattern of this curve, the children do well for the first year of life. Often the diagnosis is not made in that first year of life. You will notice that the things that I’ve told you about, a large liver and spleen, a funny looking face, thick eyebrows, none of those are things that you are going to die of. The children with the real adverse effect of the glycosamine and glycan is the deposition in two places.

The first is within the myocardium and the coronary arteries. So these children get a dilated cardiomyopathy, and the get coronary artery disease, and these early deaths, here, and the children usually who are severely affected with cardiac disease.

In the early days of transplanting them, we weren’t aware of quite how profound the effect on the myocardium and on the coronary arteries were, and we were seeing sudden death in children who clearly had a myocardial infarction at the age of 18 months, which is not something that we never thought to look for.

Now we are aware of it. We are very careful with these children. We don’t stress them. We check them cardiologically, very thoroughly, and we keep in mine those early deaths, during the transplant procedure.

In the children who do not have cardiac involvement and do not get transplanted, there is a progressive dementia. This is a dementia of childhood. The leukodystrophies also are dementias of childhood. And people always associate dementia with old age, but there are specific groups of dementia in childhood, and they look different from the typical patient with Alzheimer’s.

A child with dementia presents with loss of milestones -- loss of abilities that they previously had. So a child, who used to speak, gradually goes back to one word and then loses those single words. They lose their ability to stand, walk around and gradually lose those milestones.

However, it is a subtle process. When you see a child at 18, 19, 20 months with big eyebrows, a big frontal bossing, course features, who used to talk and no longer does, you think “Where have you been? Why didn’t you notice this?” 

But, when you are with it everyday, it is a lot harder to see, and often it will be the aunt from out of town who comes and says, “My God what has happened to Susie?” who will make the diagnosis and say there is something wrong with that child.

It is subtle, and it does creep up on you gently. It really does.

And we see children who come and you think, “How could it have been missed?”

But then, when you talk to the families and look at the pictures back, you can understand that you don’t see these things.

The later deaths up here are the consequences of the dementia and the loss of mental functioning. So their children will develop pneumonias, aspiration -- those kinds of events.

The children who are transplanted -- this is 69 patients who we have transplanted over time at the University of Minnesota, others have been transplanted elsewhere, and we have an international group to share knowledge, because we all want to learn together -- shows you that there is significant mortality in the early times.

When we first started transplanting these children, we really didn’t know how it was going to work. The idea is that the new bone marrow will carry in alpha-L-iduronidase and its white cells. The white cells will make it, and the alpha-L-iduronidase will soak into the areas of the body that needs it.

One of the things that we learned is that doing this in children with very advanced dementia, children with Hurler’s really beyond the age of two years doesn’t work. The CNS damage is so severe that it can’t come back, and it’s not a reasonable thing to do.

You know that neurons have very limited capacity to recover so what we do, by doing a bone marrow transplant and providing the enzyme, is generally halting the damage at the level to which its got. So the child is already severely damaged. 

You are not going to retrieve a vegetative child back to normality. So again you want to make the diagnosis early and move to transplant early. If the child is severely affected, generally over the age of two, though there are a very who are okay, it is not indicated.

Some of these early deaths, we didn’t appreciate also the degree that glycosamine and glycan deposition affects the nasopharynx. These children are really hard to intubate, and you need to have an anesthesiologist who knows what they are doing -- is used to Hurler’s. 

You cannot extend the neck very vigorously, or it will damage the spinal cord. You need to be careful. So a survival now is improved because we have ironed out some of those early events but, as with all bone marrow transplantation, there is always a risk of mortality.

How does it work clinically? If you get good engraftment, and these children need good engraftment, how does it resolve?

This is a picture of a Hurler’s child taken about two…

The cardiac abnormalities, by-and-large, go away. The myocardium returns to normal. The dilated cardiomyopathy, the deposition of glycosamine and glycans within the coronary arteries improves, and we have not seen late sudden coronary death, so we don’t see later myocardial events.

What doesn’t improve is we are only providing enzyme by having it soak in. So, if white cells don’t go there, it isn’t a well-vascularized area, it won’t improve. The areas in which we’ve seen problems are the cardiac valves. Cardiac valves are involved and can progress, because they are not very vascular. They are just kind of fibrous structures so you don’t get good delivery of enzyme there, and we continue to monitor the children cardiologically. One or two have needed valve replacement as they enter their teenage years, but that is a manageable complication.

The other is that orthopedic complications also continue. The abnormalities of cartilage, the hump back, the knock-knees that I showed you, you don’t deliver good enzyme there because it is not a very vascular area. 

You see this child’s wrists here, you can see that he’s got little thickened wrists, and the majority of children will develop carpal tunnel syndrome and need a decompressing. Many will need orthopedic surgery to their back, their hips, or their knees. 

This is something important for the parents to appreciate as part of the commitment to the BMT process that we need to tell them what we can achieve and also what we don’t expect to achieve, because there are still hurdles ahead for the children.

So this is just to remind you of some of the challenges in transplanting Hurler’s syndrome. You need to diagnose them early. In very advanced cases, it is not appropriate to transplant, and we get more hostility and have more difficulties with the press and with publicity, the children we chose not to transplant than the ones that we do.

You need to worry about their comorbidities, cardiac disease -- hydrocephalus can develop and they have interesting airways. It is important to achieve full engraftment and keep it.

As I have told you, the orthopedic outcomes are not as good as we would like, and we are currently working to try and provide these children with additional mesenchymal stem cells, instead of just providing the white cells. Give them the stem cells that make bone and cartilage, and that is something that is still in development but starting to take place.

It is also important to monitor these children’s long-term neuropsychological outcomes. Give them intensive schooling and all the help they can get because, if we don’t, they won’t regain the neurological gain that we lost before the transplant.

So let’s turn to the leukodystrophies. This shows you where the thinking about bone marrow transplant in leukodystrophies started. There is a spontaneous animal model of leukodystrophies. This kind of dog spontaneously gets a leukodystrophy somewhat similar to metachromatic leukodystrophy.

When people first thought about transplantation, they used this dog as a model. These guys are litimates. This dog was transplanted from a normal bone marrow donor. This dog has not been transplanted, and you can see he is unable to walk and has the progressive loss of motor function that happens in leukodystrophies. This guy is just fine, and these dogs will live a normal life.

So this demonstration in a dog model that bone marrow transplant can cure leukodystrophies has led to an interest in using transplant in this area.

Two leukodystrophies I want to talk about. Firstly adrenal leukodystrophy, ALD -- this is an X-linked disorder, so only boys are affected, females are carriers. It is associated with elevated, very long-chain fatty acids in the blood and tissues, so you can diagnose it with a single blood test if you think about it. You have to think about the diagnosis to do the test. 

This is the disease that Lorenzo’s oil was designed to treat. Lorenzo’s oil is a fatty acid combination. It was made in a very intelligent way by parents of an infected child, Lorenzo, and it is effective in lowering the very long-chain fatty acids within these children’s blood. 

So, if you give it over about a month, with a low fat diet, it tastes okay, the boys will take it. With a very low fat diet, you can get the very long-chain fatty acids back to normal. The disappointing thing is that it doesn’t affect the course of the disease. I think that shows us that this is an epiphenomenona. 

It is a marker of the disease, but it doesn’t cause the disease. Similar to the way that anemia is a marker that you might have leukemia and giving a blood transfusion doesn’t fix leukemia. Fixing the very long chain fatty acids doesn’t fix adrenal leukodystrophy.

Adrenal leukodystrophy happens in two kinds, and this is important to know because it’s important for the distinction, the decision to do a transplant. There is the cerebral kind that has onset in childhood usually and is the very severe kind, and there is adrenalmyeloneurophathy, which just affects the spinal cord and generally occurs late -- 40 or 50 years old, and can be very mild, just a limp, need to walk with a stick, not a big deal.

These types cannot be distinguished biochemically. So, if we diagnose a child as affected maybe, because his uncle has been diagnosed, we don’t know whether they are going to get the very severe catastrophic childhood kind or this mild kind, which will just happen in later life and not hold them back. And for reasons we don’t understand, these two types coexist with a family, so how your brother behaved doesn’t predict how you will behave. How your uncle behaved doesn’t predict how you will behave.

This is a sort of cartoon demonstration of the clinical course of cerebral adrenal leukodystrophy and one of the first events may be adrenal failure. Isolated adrenal failure in a young child, it is usually misdiagnosed as Addison’s disease.

These children commonly come to attention around the age of six or seven years and they often will have a history of about a year of declining school performance. They become emotionally labile. They become temperamental. Their attention span dwindles. Commonly they have been seen, put on Ritalin, diagnosed as ADD.

As the disease progresses, they will develop a gait abnormality, and they also will progress to a dementia. It is often the abnormalities in walking. This is a white matter disease. These children develop spasticity and abnormal gait, spastic arms and legs, sometimes a hemiplegia that it becomes apparent that this wasn’t attention deficit disorder. It was progressive adrenal leukodystrophy, and a single MRI examination is absolutely diagnostic, and that is often what will happen when the gait eventually becomes abnormal.

Untreated, these children will progress fairly vigorously. They develop dementia. They become blind and deaf, and sensory input is very severely affected in these boys, and they become vegetative usually for about a year before the end of the illness. So this is clearly a catastrophic course at the end of the disease, and we’ve learned that transplanting children again when they are down here with this very severe affectation is too late. 

Your brain does not have a good capacity to recover so even delivering the missing enzyme in adrenal leukodystrophy does not reverse the damage you have, and these children continue to progress. So, what we aim to do is transplant children up here when they have visual processing deficits, memory loss, changes that are very subtle that you need regular neuropsychological testing to do.

And people often say, “Why don’t you want to transplant them up here when they are perfect?” 

Well, I don’t want to transplant a child of two who has adrenal failure who may go on to develop the mild adrenal myeloneuropathy version and just have a little limp, when he is 50 and expose him to a procedure with an upfront mortality of at least 20 percent.

So what we try to do, if children are diagnosed here, we try to transplant them immediately before we move down to this part of the disease. Commonly, a child will be diagnosed here; he is seven or eight years old. 

He will already have two or three little brothers, and we have families with as many as five affected children with this disease. And it’s important to take each of those children, test them very carefully, and then test them sequentially. And we test them with careful neuropsyche testing, with regular MRIs and, as soon as there is evidence of progression, we will move to transplant then. And those children, who are transplanted early, at just the right time, have excellent outcomes. They have normal IQs. 

They do not progress to any of these abnormalities, but it is very important that one is careful, because it’s just as important not to transplant somebody who doesn’t need it, as it is to transplant somebody who does. And again, these are emotionally, very draining diseases for families. It is very distressing.

If they are transplanted early, we can stop the course of the disease, but there is often still significant loss in the child that they had. People have expectations of a normal child in a normal school. Within six months, they can be left with a significantly delayed child and many times we’ll have a child who is diagnosed late, we’ll be transplanting the younger brother at the time that the older child is moving towards the end of his illness. And this is a really, very draining stress on family resources, their emotional and financial resources of having two children going through this kind of situation.

Briefly, I want to mention metachromatic leukodystrophy to you because it is perhaps the most frequent leukodystrophy. It has some features in common with ALD, and it has some differences. It is autosomal recessive, so females are affected as well as males. It is a deficiency of arylsulfatase A and, again, symptoms start at different ages in different families. 

Here the disease tends to be more true within families, but it looks different at what age the child presents.

There is a very aggressive infantile version. The child presents, in infancy, usually before one, and will have very severe spasticity. This class of disease progresses very fast so, unless there is an immediately available donor, if it’s a severely affected child, it is often not appropriate to move ahead with transplant, because you are not going to reverse that damage.

The kinds that are more commonly transplanted are the juvenile or adult kind and again presents between five and twenty years. It is a dementia. Loss of abilities that you had before, but often with prominent features of a psychosis, and many of our patients have spent as long as six months in a psychiatric institution before they develop neurological signs, abnormal walking, a limp that got them an MRI scan and made the diagnosis.

Again, in older adults, this can present. It can be relatively slow in its progression. Very prominent features of psychosis often misdiagnosed as a psychiatric disease. It can be transplanted in both of these cases. Again you halt the damage. You don’t generally regain function.

I just want to dwell for a moment on the psychosocial aspect of BMT for all these genetic diseases. They are more difficult in many ways than treatment of leukemia or malignancy. There is a lot of guilt, a lot of family involvement in genetic diseases. Not only is your child affected, you have to bring in your brothers, sisters, involve everybody. You may find out that there are many affected children within the family. 

More than one affected child within a family, needing bone marrow transplant, or a child dying at the time that other children are needing bone marrow transplant provides extraordinary pressures on these families, and they often get a lot of support from many from the Internet, many from other families with similarly affected children. 

The Hurler’s families in particular are all very close and seem to know each other very well, but it really is an extraordinary burden, and we spend a lot of time trying to help people get through this very difficult situation.

I also want to remind you that when we are talking to families about outcomes of bone marrow transplant, the context is important. So if you are talking about a bone marrow transplant for Hurler’s, it is appropriate to review the likely risk of dying from the procedure -- the likelihood of needing orthopedic interventions thereafter, but there are no other therapies. Even though this isn’t perfect, the other choice is to let the child have a progressive dementia.

In a child with acute lymphoblastic leukemia, there may be a very realistic choice. There may be a situation where outcomes you may expect 50 percent survival, with three years chemo or you may expect 50 percent survival with a bone marrow transplant, and people need to feed into their decisions what their choices are, and we need to offer these things when we are advising patients. And the choice between chemo and bone marrow transplant is often a very personal one. 

In my experience, the older adolescents often prefer bone marrow transplant. Do it now. Get it over with. Get on with your life. For younger children, often, parents are more comfortable with less immediate risk, but it is a very personal decision, and the context and the alternatives are very important.

It is important also with genetic diseases, metabolic diseases, to talk about quality of life. What to expect if the best happens, and people need to be realistic about whether they are going to get back the child they had two years ago -- whether they are going to just hold the damage at the point at which it is -- and it is important that we are honest and clear with families about what we can and cannot achieve with transplantation.

So I am going to finish by talking about a completely separate topic, and that is the use of umbilical cord blood for transplantation. 

And I want to remind you that, when we do a bone marrow transplant, what we are harvesting from the bone marrow are stem cells, the cells that can repopulate the marrow. These are immortal cells that can grow a whole new immune system probably from a single cell. 

It was realized in the 1980s that, for unclear reasons, there are a large amount of stem cells in umbilical cord blood that are just sitting there. Collecting umbilical cord blood is a very easy thing to do. 

It is all done after the baby is born. So this is a clamped cord. This is a placenta in a bucket. To collect the cord blood, you make a kind a gallows out of a chucks. You put the placenta in it. Drop the cord down -- this is the umbilical cord -- and this is just a blood collection kit, like you would use if you were going to donate blood. 

This is the easiest venipuncture you ever did. It is a huge vein, and it stays still. It just drips out and is easy to collect. You usually get between 60 and 250 cc’s of umbilical cord blood, which is very rich in these hematopoietic stem cells.

Algibens raged in the literature during the 80s and early 90s over a number of points. People had shown, in animal models, that you could use this product for transplantation. A lot of people believed two things. One, there wouldn’t be enough stem cells in a bag of cord blood to repopulate a human. Secondly, that there would be maternal cells or contamination from the perineum at delivery that would be a problem.

Arguments waned to and fro and, in the end, everybody got fed up and just did it and this is the first ever recipient of an umbilical cord transplant. This is a picture kindly provided by Joanne Kertzburg from Duke University. This child has Fanconi’s Anemia, which we talked about. He was known to have it. It was known that he was going to need a transplant, and his Mom was pregnant. 

The cord blood was collected in Indiana and tested, found to be a perfect HLA match. Because of issues related to the FDA and regulation, the child actually took the cord blood and went to Paris, and the transplant was done there. He received the umbilical cord blood 12 years ago, in 1988, and he answered those questions for the first one. One, yes there is enough stem cells in cord blood to repopulate a human, at least in this one case. And two, you wouldn’t necessarily get overwhelmed with graft-versus-host disease from the maternal cells that were there.

Once this proof in principle was done, more people did this. When we look at the results of sibling donor umbilical cord blood transplant, what you see is quite interesting. Firstly, the probability of engraftment is 91 percent. So the answer is, most of the time, there are enough cells there in a sibling cord blood graft to engraft a human, but not always.

Interestingly, graft-versus-host disease was very low, hardly any, and no chronic graft- versus-host disease. Now this is biologically interesting, but in terms of people getting transplants, it isn’t that much help. The commonest indication for a bone marrow transplant is adult type CML, and not many people, who are 40, have a pregnant mother who is going to have a match sibling to be a donor. 

So, in terms of providing a source of stem cells for most people who needed transplants, this wasn’t going to work. But it was supportive data for the establishment of unrelated cord blood banks and for testing of whether collecting and storing frozen cord blood could work.

People were interested in potential advantages of umbilical cord blood. The laboratory studies suggested that cord blood had higher proliferative potential than marrow. It could grow faster so you needed fewer cells; doesn’t transmit virus like CMV or Epstein-Barr virus. 

We thought it might take less time to find a cord blood because, you know, it’s in a freezer, compared to searching a registry for a human. You could augment the donor pool by targeting racial minorities, and people didn’t quit on you. You could always find them once your cord blood was there in the bank.

Why do we worry about people quitting? Where we normally get unrelated donors from is the National Marrow Donor Program. This is it. It is in Minnesota. It is the top three floors of this building, and this is basically a mainframe computer with the tissue types of a lot of people who are willing to donate. We are up to almost four million now -- 396 thousand people are willing to donate?

Despite this large number of people who are willing to donate, the likelihood of you finding a match when you search the NMDP is still nowhere near 100 percent. This is a preliminary search. The likelihood of match finding at least one potential, only potential match donor, if you search the NMDP -- in 1990, not many donors enlisted -- about 32 percent chance. Now it’s about 80 percent chance. If you are African American, it’s about 58 percent. If you’re Caucasian, it’s about 80 percent. So there is still a gap, because we need that match. 

An 80 percent chance of finding a match -- much less chance than that of actually getting a transplant, because a lot of these people, when we look for them, we can’t find them. They decide they don’t want to do it. They are busy that day. All of these kinds of problems come up. So, while the registry has been extraordinarily important to us and is a very valuable resource, we need something additional for this 20 percent of people with really rare tissue types or for the people whose donors don’t come through for us.

Cord blood is still associated with some important ethical issues, and I’ll just put these in your mind, and you can decide for yourself. This has been typically regarded as discarded tissue. When it was originally collected, there was no consent given to its collection, because, when you sign that ticket when you’re admitted to hospital, you’re in labor, one of the things it says there is that the hospital owns your placenta and can dispose of it. So it was considered pathological waste, and consent wasn’t gained.

It’s now the mother who gives informed consent. There is a lot of discussion about what if the baby decides it wants its cord blood back. That’s never happened to us yet. There has been commercialization of the technology, and there are commercial cord blood banks that will offer, when you are pregnant, to store your cord blood for you, and we can talk about whether you should do that or not.

One additional use of cord blood is that it raises and encourages the possibility of families deliberately conceiving for the purpose of generating a cord blood donor. And this has always happened. Families with children affected with diseases like Fanconi’s Anemia, where you know you are going to need a transplant maybe in five years, why not get pregnant now and hope that the child will be a match.

With cord blood, if the child needs a transplant immediately, once the infant is born, the cord blood could be collected and used immediately. I think it’s a societal issue how we feel about whether that is okay or not.

Similarly the technology is now available for selecting embryos specifically for this purpose, and it’s technically certainly possible to undergo IVF, select an embryo that is not affected with the genetic abnormality that affects your family, remember we talked about that for Wiskott, for Fanconi’s Anemia, and which is also an HLA match with your affected child who needs a donor, and that technology is available up and running, and we have a couple of ongoing pregnancies now. 

Again it is an issue for societal discussion what that means.

So how well does cord blood work? To look at that, I just want to show you data that is combined from our own institution and from Duke University, again kindly supplied by Joanne Kertzburg. These are 165 cord blood transplants, and I just want to show you there are a bunch of different diagnoses here, so the individual experience with any one disease is still relatively small -- again, a bunch of the diagnoses that I have already talked to you about, relatively small number of each diagnosis.

So are there enough cells to engraft? Usually yes, but rather slowly. The median time of engraftment with cord blood is 26 days. If you look at similar unrelated donor marrow, the median is about 19 days. Twenty-six days, clinically, is perfectly acceptable, however, the range is quite great, between ten days and 59 days. Fifty-nine days is not acceptable. 

You can’t remain neutropenic in a hospital bed that long, without very significant risk.

This was the early days again of us using cord blood. We understand better now how to pick units, and I will show you that. So, this is now more like 93, 95 percent. So, it’s better, but it’s still not perfect. Some children will not engraft, and that is a bad thing.

Just to show you that cord blood grafts have a greater degree of mismatch than we tolerate with bone marrow. These grafts were largely a one-antigen or a two-antigen mismatch. We wanted to ask, could we use two antigen mismatched cord blood. We know we can’t use two-antigen mismatched bone marrow, that’s why we need such a big registry of people because we need a good match. 

For reasons we can discuss, we thought we could get away with a greater degree of mismatch with cord blood. If we can, instead of needing about four million people in the registry, we would need about 100 thousand cord bloods, so it was a big advantage if it works.

Cord blood units are about a tenth of the number of cells that we use for marrow, they are tiny, and we get less graft-versus-host disease. This is about half the incidence of graft-versus-host disease that we see with marrow.

Low incidence of chronic graft-versus-host disease also, so these are all good things.

Can we get away with HLA mismatch? Yes we can. Two-antigen mismatch is no worse than a one-antigen mismatch, so that was an important finding. You don’t need to match so closely, and that changed the way we picked our grafts, because what you do need is a big cell dose. 

This is how many cells you’ve got. The kids who got bigger cell doses did much better than those who got lower cell doses. The implication of that for the utilization of cord blood is very important because, what you’ve got in the cord blood bag is all you’re ever going to have. 

So what importantly influences the cell dose is how big the patient is, so that means this is more difficult for adults. So the cord blood bankers have been focusing on getting big cord blood units and, over the last two years, it has gotten much easier to find a large unit, but we used to accept a unit down to about one. We do not accept that now. We are looking for bigger units, but not worrying so much about the degree of match.

This is a multi-variant analysis showing you that match didn’t matter. That cell dose is very important; importantly influence the likelihood of you surviving the bottom line.

Being younger is always better. Getting a big cell dose is the most important thing. This means that there is going to be a limit to the applicability of the use of umbilical cord blood in adults, unless we can target collecting larger cord blood units, unless we can grow them in the laboratory and make them bigger, or unless we can use more than one at a time. And those are all areas of investigation in umbilical cord blood transplant.