Growth and Endocrine Issues after Surviving a Pediatric Transplant

Presenter: Michael Nieder MD, Medical Director and Senior Member of the Blood and Marrow Transplant and Cellular Therapy Department at Moffitt Cancer Center

Summary:

Growth and endocrine problems are common after bone marrow transplant. Yearly screening is necessary to detect the problems early. Lifestyle modifications such as exercise and diet can reduce the risk of heart disease, stroke and diabetes.

This is a recording of a workshop presented at the 2019 Celebrating a Second Chance at Life Survivorship Symposium.

Presentation is 30 minutes followed by 30 minutes of Q&A.

Highlights:

• Pediatric transplant survivors are at risk of lower than expected growth, particularly if they were less than 10 years old at the time of transplant
• Growth after transplant depends on the child’s age at transplant, whether there was radiation to the head or total body irradiation and other treatments the child received before transplant
• Growth hormones can help promote growth after transplant only if a child is growth hormone deficient
• An underactive thyroid is common after transplant, and can occur five to twenty years after transplant
• Loss of bone mineral density is common after transplant and seen most often in adolescents and adults.
• Transplant survivors have a higher risk of metabolic syndrome - heart disease, stroke and diabetes – earlier in life than the general population.

Transcript of Presentation:

00:00  Welcome to our audience here in Orlando on this May 4th, 2019 and, also a hello to the people who are going to be watching this on the internet. So today we're going to talk about growth and endocrine issues after surviving a pediatric transplant, and we're going to review growth, thyroid problems, bone problems, and something called the metabolic syndrome, which some people are aware of.

00:26  So, depending on where you look, how old the article is, 20 to 86% of children will have reduced adult height after transplant. Reduced adult height does not mean that they will be short. Reduced adult height means that looking at the mean height of each of the parent and predicting how tall the child might have been when they grew up, the children who've undergone transplant will likely be shorter than their maximum potential growth would have been.

That's not to say that 20 to 86% of children will have had short stature. They're more likely to be shorter if they were less than 10 at the time of the transplant, if they had radiation to the brain before transplant. So, that's more applicable to children who have acute lymphoblastic leukemia or ALL, and we used to use lots of cranial radiation for the treatment of those patients.

So, since we're talking about longer term survivors and what happened to their health, those were patients who received therapy in the 80s and 90s and early 2000s and underwent transplant. The treatment for ALL is a bit different now. If they had radiation as part of the transplant conditioning, so total body radiation is still an important component of transplant for children who have acute lymphoblastic leukemia, and low dose radiation is also used for other types of transplant as well, and if they had growth hormone deficiency or became growth hormone deficient after transplant.

02:07  So, this is a slide that shows growth after transplant, and it depends on the age of transplant, radiation to the head, other treatments before transplant, and total body radiation as part of the transplant. And just a few words about those things where it says growth depends on: obviously the age of the transplant, there's nothing you can do about that. There's also nothing that you can do when you get to the transplant if the patient already had radiation to their head or to their brain. You can't do anything about other treatments that may have occurred before you got to transplant. The only thing that you can modulate, if you will, is using total body radiation as part of the transplant. You can decide, let's try to do something else if it's possible. Usually, when total body radiation is chosen as part of the transplant regimen, it's chosen because it has severe or superior curative potential.

03:07  Children who are less than age 10 at the time of transplant will have a bigger discrepancy between actual height and projected height than older children:  If you look at this graph here, you'll see that the black bars are patients who were transplanted when they were younger than 10 years at transplant, and the light gray are patients who were transplanted older than 10 years.

So, the first one that says HCT at the bottom is at the time of transplant, and what you can see is at the time of transplant, zero means normal height, no deviation, is that really there was not much difference

But if you look, you can see that some of them had growth hormone deficiency that was diagnosed after transplant; and if they did, on this graph, the bars that go down or into the minus, mean that they're half a standard deviation shorter than normal kids for that age. So, you can see that if they had growth hormone deficiency after transplant, both if they were older or younger than 10 years, that they were going to have some decreased adult height. But if you look at final adult height, the black bar goes farther down than the gray bar. And that means that the children that were younger than the age of 10 at the time of transplant had more growth stunting or had a final adult height that was less than what would have been compared to the normal when you look at children who were transplanted above the age of 10. So, if you're less than 10 years old at the time of transplant, you're going to have a bigger height discrepancy compared to what you potentially would have been.

Now obviously, there's no way to exactly predict how tall a child's going to be at any point in their life, unless it's a week before they finish growing. So, these are what are called predicted models.

05:08  Growth hormones help improve growth, but only if a child is growth hormone deficient: But how about treatment with growth hormone? So, if growth hormone deficient, treatment helps a lot; but if you look on this graph on the right, you can see that the patients who were not treated had a much more negative score, which means that they were shorter than the ones who were treated. And what you can see from here is the ones who were treated were just a little bit below the zero mark, which means that they didn't have much of a height discrepancy from what their calculated adult height would have been. But if they're not growth hormone deficient, then growth hormone makes no difference. And it's just like in normal kids. If you give a normal child lots of growth hormone, you can't make them grow taller. So, growth hormone only works if you're actually deficient.

05:59  Test your child for growth hormone deficiency every 6-12 months after transplant if they are not growing well:  So what can you do? You can make sure your child or adolescent is tested for growth hormone every six to twelve months after transplant if they're not growing well. So, in pediatrics we have growth curves. If someone is tracking relatively close to the growth curve, there's no point in doing growth hormone tests and growth hormone stimulation tests because you're not going to give growth hormone to someone who is within the range.

Once a child reaches 14, there's no point in doing this, there's no point in doing this if they go through early puberty. But the point is that you really need to see an endocrinologist who specializes in growth hormone deficiency for those patients who are starting to fall off the growth curve for who they're worried. And it's obviously going to be more important for children under the age of 10.

And there's other things that we do. We can do x-rays of their hand, looking for bone age at different times, because your skeleton matures, and we can predict your bone age versus your actual chronological age. And the most important thing is be proactive. If you think that your child is not growing, or you're concerned about it, then you really need to push this with your pediatric oncologist, your pediatric oncology transplant provider, or with your pediatrician.

So, the key message from this slide is; don't wait. The other key message is: if you're not growth hormone deficient, growth hormone is not going to do anything. And it's also extremely expensive, and insurance is not going to cover it unless you prove a growth hormone deficiency.

07:42  Hypothyroidism is common after transplant:  The next topic has to do with the thyroid. And the thyroid is a gland in your neck that you normally cannot feel. It controls your metabolic rate: or basically how fast you burn up calories. It also controls heart and digestive function. It's importance for bone maintenance, and believe it or not, it's important for mood.

Problems after transplant occur, and the most common one is hypothyroidism. This can occur rarely in the first few years after transplant; but we do see it, and that's why we screen for it annually. It can occur as long as five to twenty years later. And so, what this tells us is if you've undergone a transplant, you need to be screened for thyroid problems basically forever. We should also point out that as adults age, many adults become hypothyroid. It's one of the most common chronic conditions in the United States.

08:39  Thyroid cancer occurs in less than 3% of transplant patients:  Even so, it occurs in less than 3% of transplant patients. It can be seen within the first year, this is thyroid cancer, occurring less than 3% of transplant patients, and it can be seen for the first year and many years later. It is rare. However, that's why we ask to feel the neck of patients after transplant.

What's way more common are these thyroid nodules, although it says it occurs in less than 3% of patients, it's probably more than that. It can be seen after transplant or much later. Often on imaging studies such as ultrasound, they can tell the difference between cancer and not cancer. The good news is that it's easy to diagnose with just a needle biopsy. The other good news is the thyroid cancer is very treatable.

09:28  Symptoms of thyroid problems:  So you have to know the symptoms. So, unexplained weight loss is obviously a symptom that can occur in lots of different reasons and lots of medical conditions but can occur in people with thyroid problems. As is excessive sweating, tremors, nervousness, rapid or irregular heartbeat, fatigue, sensitivity to cold, constipation, dry skin, weight gain, puffy face, hoarseness, muscle weakness.

The problem is that all those symptoms are pretty vague, and a lot of people have those symptoms anyway. And if you look, unexplained weight loss and weight gain are both symptoms of hypothyroidism. So, that's why we screen. Because usually, people who are screened annually for this, we can pick up the problem long before they become symptomatic. The ones who have symptoms are the ones who aren't screened and come in after a while of symptoms.

10:23  Annual thyroid screening. So, the medical provider feels the lower neck and checks the bump on the thyroid gland. And if your doctor or nurse practitioner or PA isn't doing that, you should say, "Can you feel my neck?" You really can't do this to yourself. If the thyroid is enlarged, then they're going to be doing some ultrasounds.

But thyroid function tests should be done each year, and those are blood tests called a T4 and TSH, and they're simple blood tests. An endocrinologist treats thyroid problems. Pediatricians and pediatric specialists can certainly do this; but we don't do it all the time, which is why we tend to send them to endocrinologists.

11:10  The next issue is bone problems. Loss of bone mineral density is common after transplant. It's more commonly seen in adolescent and adults. So much so that they get screened a lot. But because of this risk of osteoporosis, which is actually a medical diagnosis, and it's made by what's called a DEXA scan. And you have to have a certain number on the DEXA scan. More common is osteopenia, and -enia is Latin for poor. It just means weaker bones. And, the issue with osteopenia and osteoporosisis your increased risk of bones breaking.

Corticosteroid use with prednisone, dexamethasone before or after transplant can predispose for this. It's well known in patients who had acute lymphoblastic leukemia treated with high dose dexamethasone [that they] had a lot of problems with osteoporosis and osteopenia.

Low serum calcium can set you for that. Girls and women are at higher risk than boys and men, but as you get older, everybody develops some degree of osteopenia. Being underweight can also increase your chance of osteoporosis and osteopenia, probably because your nutrition is not that good. And a sedentary lifestyle can also do this. Your bones become stronger because of stress applied to them. So, that's one of the reasons why if someone becomes a paraplegic and you do scans of their legs, that you'll see that their bones are basically very, very weak.

12:59  How about the frequency of bone problems? So, at the top, we're looking at bone mineral density loss, osteopenia, which is weak bones, and osteopetrosis, which is very weak bones. So, when people are looking at different areas, they're looking at the spine, the hip, you can also look at the forearm, and you can see that transplant survivors, on the bottom, 76% have some type of bone mineral density loss, about 58% have weaker bones, and a smaller percentage, only 18% have osteopetrosis. So, it is a common problem to have somewhat decreased bone mineral density. It is an uncommon problem to have osteopetrosis, but this is why we check with DEXA scans.

13:50  So, what can you do? You should get screened with a DEXASCAN after transplant and then every few years. And the truth about this is that if you are a woman, yes, you should continue with this. If you're an adolescent male or a man and you're relatively active through your life, that's going to be less of a risk.

14:13:  Checking vitamin D levels once or twice a year. What we're finding in the United States is we're diagnosing more vitamin D deficiency than we ever thought was possible. And what's unusual is that vitamin D deficiency used to be more common in darker skinned people, because they didn't absorb the sunlight as well. But we're finding it in light skinned people who were tanned.

So, the reason for this is not really clear. But taking vitamin D if your levels are low is a very easy thing to do, and I'll put this one caution in here. Vitamin D is a fat-soluble vitamin, you can overdose it, it can make you extremely ill. So, you should be talking with your doctor, nurse practitioner or physician's assistant about what level of vitamin D you should be taking, more is not better. There is insufficient vitamin D in multivitamins, you actually have to take a replacement; and then the caveat, please remember that vitamin D toxicity can occur, so you don't want to be taking a whole bottle. More is not better.

15:25  You should take calcium as directed, that's probably more of an issue for women. And if osteoporosisis is actually diagnosed, patients should be treated with IV or oral medications. The class of medication is called bisphosphonates, they do have some side effects. And those are medications that have to be prescribed. But if you actually have osteoporosis and you're at risk for bone breakage, you should be on the bisphosphonates.

15:56  Bone strength is derived from stress on your bones: And then the bottom line in yellow says exercise. As I pointed out earlier, bone strength is derived from stress on your bones. Stress on your bones does not occur by sitting on the couch. And although walking is a lovely exercise for older people, for young people and children, the only benefit that walking really gives you is it gets you off the couch and away from the refrigerator. But as far as providing meaningful exercise which is going to improve your bone health, it is not.

So, you actually have to do something that is going to put stress on your bones. And that can be aerobic exercise, it can be going to the gym and using weights. And we're not saying that you need to become a bodybuilder, but resistance on the bones whether it be isometric or other is what is going to improve bone health. And this is not just for transplant survivors.

17:03  Transplant survivors have a greater risk of heart disease, stroke and diabetes earlier in life than the general population:  So metabolic syndrome in transplant. So metabolic syndrome is a group of conditions that occur together. It's extremely common in the U.S. High blood pressure, high blood sugar, excess body fat around the waist, high cholesterol or triglyceride levels is what constitutes the metabolic syndrome. You do not have to have all of those together.

The problem is that it leads to increase risk of heart disease, stroke, and type 2 diabetes. People who have had transplant are at higher risk for developing metabolic syndrome earlier in life.

Adult survivors of childhood acute leukemia, so this is not even transplant, this is adult survivors of acute leukemia have a higher rate of obesity as compared to adults who did not have leukemia. Have a higher risk of dying from cardiovascular disease, and have more insulin resistance, and increased prevalence of multiple heart risk factors. So, insulin resistance is one of the components of type 2 diabetes. So again, this is not transplant survivors, these are adult survivors of childhood leukemia.

But for allogenic transplants, or transplants from a donor in pediatrics, acute lymphoblastic leukemia is one of the most common reasons why we do a transplant. So, we know that without a transplant, our adult survivors are at risk for metabolic syndrome, and childhood leukemia transplant survivors are even at a higher risk for developing metabolic syndrome.

So this is a combination of your diagnosis that you can't do anything about, previous treatment that you had prior to coming to transplant, which you can't do anything about, and an awareness of "I'm at risk for this."

19:07  So, who's at risk? Up to 60% of patients who received total body radiation are at risk for developing metabolic syndrome. And up to 30% of patients who get chemotherapy alone in the conditioning regimen for transplant are at risk for metabolic syndrome.

19:27  Transplant survivors have less lean body mass than their siblings:  So, this is body weight and bone marrow transplant survivors, and this comes from the Seattle consortium, Seattle Cancer Alliance, and what we see. If you look at body weight per se and transplant survivors, you can see that there's not much difference in weight between transplant survivors compared to their siblings. So, this was a study in which patients had siblings, brothers and sisters, and they looked at all survivors of the transplant, those who had gotten total body radiation, those had gotten no total body radiation. And what you can basically see is that their body weight is not a whole lot difference. So, things look good.

However, there's more to the story. There's something called lean body mass, and now we can see the differences. As all of us age, human beings, as we get older have decreased amount of bone density, decreased amount of muscle mass, and increased fat. So, you can go onto the internet and you can see that as you get older that your fat content of your body increases, your muscle and your bone content decreases. This is a normal consequence of aging.

If you look on the slide in the light blue all the way on the left, you can see that the sibling's adjusted mean lean body mass is at one level. In the yellow, you can see all survivors of transplant, which is significantly lower. So, we're talking about lean body mass. And then in the red, you can see those patients who had total body radiation which was slightly lower. And all the way on the right, you can see the ones who had no total body radiation.

The point is that even though their weights might be very similar to their brothers and sisters, their body composition is not exactly the same. Put in another way, survivors have more fat. And this is actually the percent fat of their body. Now, we know we live in America, and we can make a lot of comments about this. But this is one study done in the Seattle Cancer Care Alliance. And you can see over on the left that they had about 28 and a half or 29% body fat in the siblings, and you can see how much higher it was in the survivors of transplant.

22:20  Survivors also have more insulin resistance. And insulin resistance... So, on the bottom, the controls have a certain level. HCT stands for transplant. TBI are those patients who had transplant and total body radiation, and then on the right, total body radiation plus central nervous system radiation. And you can see that those are the people that had the very most insulin resistance. And then people who didn't get total body radiation didn't have quite as much. So again, these are things that you can't really control. It's done. But those are the ones that have a higher risk of type 2 diabetes, if they have more insulin resistance.

So this is a picture of what I've been trying to show. So, on the left you can see a cartoon of what we'll call the sibling, and what we mean is the healthy sibling who was not transplant. And on the right, we have the one who is the transplant survivor. On the outside, they look the same. On the inside, what we're looking at is the body fat, and you can see that that is the red oval, or the pink oval. And on the right, the transplant survivor has more fat and lean body mass of 37 kilograms, compared to a lean body mass of 47 kilograms with a sibling. And both of them weigh about the same. So, the issue is, is that on the outside they may look the same, but the inside they're going to be different.

23:58  So, this metabolic syndrome can lead to what's called sarcopenic obesity. Sarcopenic obesity does not mean you’re fat. It's a medical term that we use to describe what happens when people get older. All people, when they get older are going to have some degree of sarcopenic obesity, and that's just what we've been talking about. It's a loss of muscle mass, and increased fat mass.

So, even with a normal weight, if you have this, it can result in increased insulin resistance and increased risk of type 2 diabetes. Transplant accelerates sarcopenic obesity and insulin resistance, which means in another sense, transplant can speed up the aging process. That's what this really means. Which means that it increases the risk for heart disease, stroke and type 2 diabetes, and transplant survivors are at high risk of developing metabolic syndrome.

25:05  Maintaining a healthy weight and exercise can reduce the risk of metabolic syndrome:  So, what can you do? So, we talk about this because we can change the course of history. Maintaining a healthy weight is important, but as I've showed you from the previous slide, that's not the whole story.

Exercise. There is a good amount of research now to show that exercise can reverse this. This research has been done at the Dana-Farber Cancer Institute in Boston as well as Saint Jude. So, we know with PhD physical therapists who have published research that exercise can reverse most of this.

Eating a healthy diet that's low in sugars and carbohydrates is another component. And I'm not here to be an advocate for the keto diet or the paleo diet or for Atkins diet, or whatever other diet is out there. But I think most of us know that we shouldn't be eating key lime pie every single die. And we all know what a healthy diet is.

And I'll just take a moment to say the sad truth is, a healthy diet is way more expensive than an unhealthy diet. Carbohydrates are much cheaper than protein. And because of socioeconomic status, it's not often easy for people on low incomes, or as you get older on fixed low incomes to eat as healthy as they would normally like to.

26:38  We can screen and should screen annually people for cholesterol and triglycerides. Not something that's done for most teenagers and young adults, because they don't see the doctor often. But transplant survivors are being seen annually should be coming in for fasting levels of cholesterol, triglycerides and a lipid panel, and they should be treated aggressively. That's the best recommendation we have right now.

So, getting yearly physical exams, carefully measuring blood pressure, cholesterol with the lipid panel and glucose levels are extremely important to do. So, especially in transplant survivors, because they have increased risk of developing metabolic syndrome, and other problems.

27:25  So, in summary, growth and endocrine problems are common after bone marrow transplant. Yearly screening is necessary to detect the problems early because prevention of some of the problems is up to the survivor. It's up to the survivor to actually show up for the annual visits. It's up to the provider to recognize all that. But empowering the survivors to know what to ask about and know what to do is really important. And for those of you that are out years after your transplant and just seeing your physician once a year, obviously the exercise and the diet issues are not up to the medical provider. They're up to the survivor.

28:10  My last slide is a picture of me in 1989 holding a patient who was one-year post-transplant at this point. And in 2018, this is the same patient with his biological child. And he had undergone an allogeneic transplant, and of course we told his parents that he probably wouldn't be able to have children. Not everything we say is true.

And so, he is now, as I give this talk, 31 years post-transplant. And on the slide, at the time that the slide was done, he was 33 years old. And I would say, notice his gray hair. He has had some premature aging, but he actually played football in college. He is 33 years old when the picture was actually taken, and he does exercise and follow a healthy diet, and he's doing extremely well.

So, he's sort of my inspiration, because he was the first patient I transplanted in November of 1988, very early in my career. And it inspires me to just keep going, and hopefully inspires you, that you can have as good of life as you want to make it. So, thank you very much, and I'll be happy to take any questions.

29:26  Thank you Dr. Nieder.

Question and Answer Session

29:35  [audience] How do you define a lot of radiation:  One question is, when you're talking about levels of radiation and what our son’s body would have gone through, how much is a lot? When you were talking, I think it was more in the thyroid, and I think you were talking more about the cranial radiation. When you say... Does a little versus a lot-

30:03  [Nieder] Make a difference? So, with respect to cranial radiation, the children that had the most cranial radiation were those children with acute lymphoblastic leukemia, or acute myelogenous leukemia who had central nervous system leukemia at the time of their diagnoses or relapse. So, most children with leukemia do not have leukemia cells in the spinal fluid either at the time of diagnoses or at the time of relapse, but some do.

Those patients who have that at the time of diagnoses or relapse will be treated more aggressively. And we used to use radiation to treat them, much more than we use now. So very often, now those patients are not getting radiation. So, in the transplant itself, we use a pretty fixed dose of radiation that does range between 1200 centigray and about 1400 centigray depending on the center you go to. Those amounts probably don't make any difference.

When you do total body radiation, obviously your thyroid is going to be in the field. But patients who would receive what we call a cranial spinal radiation as part of the treatment for the central nervous system disease not only got radiation to their head, but they got radiation to their spine. And that scatter from the spine radiation did affect the thyroid. People are no longer doing cranial spinal radiation, or at least not very much anymore. So, luckily in our transplants that are going to be in the future, we won't have that problem.

31:39  So, people, when they were getting this cranial spinal radiation, were getting anywhere between 1200 and 1800, on top of the other 1200. So, some of these people after transplant have a total of 3000 in the measurement unit we call centigray, or 30 gray of radiation, and that is fairly high dose radiation. So, the amount of radiation definitely can put you at higher risk for all of these problems.

32:07  [audience] How do you tell the difference between recovery transplant and long-term side effects: I guess right now too, my son is just about six months post-transplant, so we're relatively new. So, as he's rebounding from the transplant, we're still working on weight gain. We're still working on a lot of these things that kind of could have fallen into those categories. But part of me feels like it's still rebounding from transplant, just everything.

And at what point do we say, "Well, some of these things look like more symptoms than recovery?" You know? At what point do I start looking at... Well, and I'll even ask. I'm not even sure... I'm sure the thyroid is being looked at, or those numbers, because we're still doing every two to three weeks of blood work, so I'm sure that's being looked at. But, the weight gain is a big thing. Some of the thyroid. So, at what point do we make that transition?

33:08 [Nieder] That's a great question. So how do you tell the difference between recovery from transplant and long-term side effects. So, one of the big ways that we make the difference is time. So, most of these long-term side effects, the earliest you're going to see them is about a year after transplant. And that's really, actually, very, very early. So, what I tell patients, and especially children and adolescents is, let's worry about your recovery. Let's work on your recovery; because there's a whole difference between strategies to improve recovery post-transplant versus strategies that are going to have to deal with long-term side effects.

So, with my patients that I take care of, which are both children and adults, we talk about long-term side effects before transplant as part of a consent process. And then we pretty much don't talk about them again until they're at their year visit. Because there's way more fish to fry between that time. It's unusual for someone to have hypothyroidism in the first year of transplant unless they had cranial spinal radiation, cranial radiation, acute lymphoblastic leukemia, they relapsed years later. And now you're talking about long-term side effects from the original chemotherapy, which can predispose you to all these things. Versus long-term side effects from transplant.

And the important thing to remember is, those patients who had cancer, leukemia, neuroblastoma and who underwent a transplant, we don't separate the long-term survivorship issues because they had a transplant. I mean, you're the person, you have all this. So, we have to consider everything.

35:03  [audience] When does growth hormone testing begin after transplant?  My son was six years old when he had his transplant. At what age does growth hormone start being tested? The levels?

 [Nieder] So that's an excellent question. So, your son is one of those patients who is at the highest risk for growth problems. So, those patients need to be tracked every few months to see where they are on the growth curve. And as soon as there are deviations in the growth curve, then the child should be sent to an endocrinologist and screened for growth hormone deficiency. Because the earlier that you intervene, the better.

Now, if the survivor doesn't have growth hormone deficiency and is not growing well, then growth hormone is not going to be the solution, and then the question is going to be, are there other things contributing to the poor growth besides growth hormone deficiency? Because growth hormone deficiency is not the only reason that people have short stature, or don't reach good adult height. Nutrition, chronic disease also plays into it.

So, the best advice that I can give to patients who were transplanted, and they're less than 10 years old is that you really have to get growth plotting every three months. And then as the deviation is occurring, then go to a pediatric endocrinologist to determine if you have growth hormone deficiency, and obtain follow-up from that person, because then you'll be plugged into a system in which you can be monitored well. How old is your son now?

36:42  [audience[ He's nine years old now.

36:44  [Nieder] Okay. And how is he growing?

36:47  [audience] Last time he went for an annual checkup, they said that it's average. So far.

36:54  [Nieder] So if your son is truly average, that would mean the 50th percentile in the growth curve, then there's no reason for any screening, because they will not do growth hormone replacement for someone who is following a growth curve.

37:10  [audience] How's the test being done? Is it just a blood test?

37:13  [Nieder] Right. So, the growth hormone can be gotten at a resting level, but then there's actually a stimulation test to find out if you give something, can their body actually make additional growth hormone. So, if your growth hormone is low, then you do a stimulation test. If the stimulation test shows that you can't really make growth hormone and you're deficient and your height is low, then those are the patient's that would get growth hormone.

37:40  [audience] Can I ask one more?

37:40 [Nieder] Sure.

Did he have total body radiation also when he was-

37:46  [audience] No, he did not. So, he had acute myelogenous leukemia back in the day, we still use this, he had a combination of busulfan and cyclophosphamide. He had plenty of chemotherapy before coming to transplant, but no radiation.

The one, when again talking about radiation and looking at the charts, I would see the TBI and it was CNT?

38:20  [Nieder] CNS. So those patients who had central nervous system radiation in addition to total body radiation.

38:28  [audience] So is that what they called a brain boost?

38:32  [Nieder] Yes.

Yes. So sometimes people will have boosts to their central nervous system during the conditioning regimen for transplant. So, they get total body radiation, then they get extra radiation to their heads at the time. Some patients have already had it.

38:53  [audience] For like their treatment of leukemia?

38:55  [Nieder] It's part of their treatment.

38:57  [audience] So then, and not to give things a number, but to say three... for the prep regimen, if there's three days worth of TBI and then additional brain boosts for those three days, would you say that's probably on the scheme of things with all of the radiation with leukemia survivors, that that's a lower amount of central nervous system radiation, or that's average, or that's a lot in a small period of time?

39:33 [Nieder] So, what your question really is, is how much central nervous system radiation in addition to what somebody would have gotten as part of the prep or conditioning regimen is going to make a difference? And the answer is, we don't know, and why don't we know? It's because all these studies that had been done had been done on patients who had any amount of central nervous system radiation, and those boosts could have been 600 centigray or 6 gray at the time of the transplant, or 1800 up to 2400 centigray, or 18 to 24 gray, which used to be given in the 80s and 90s.

So, things have really changed. And the good news is that we're using far less radiation and in lower doses than we used to. And for those people listening on the internet, the reduced intensity chemotherapy transplants which are starting to be used may result in less long-term problems. But we don't have the information at this time to be able to say that. We are hoping that by reducing the dose of chemotherapy and reducing the dose of radiation that perhaps some of these long-term side effects can be either lessened or avoided.

However, all of this really good data and the information that I was able to share today is based on people who are long-term survivors. And by definition, long-term survivors were treated in the 80s and 90s and early 2000s. And they did not have the benefit of these lower doses of radiation and chemotherapy. So, in five to ten more years, somebody else will give this talk and be able to give you a more reasonable discussion of transplant in the modern age, and what happens to the patients. But unfortunately, whenever you're talking about long-term survivors, you're always talking about a lag between what was done versus what is still being done.

41:36  [audience] You mentioned about lower levels of radiation and chemotherapy. My son, his transplant actually failed. His own bone marrow grew back.

41:50  [Nieder] Right, so he rejected it.

41:51 [audience]  It has something to do with, I think it was a lower dosage that he had?

41:55  [Nieder] So, transplant rejection or graft rejection can occur in people who had full-blown high dose chemotherapy radiation transplants, and it also occurs in the reduced intensity transplants. It occurs more often in reduced intensity transplants than it does in people who had full-blown transplants. And depending on if they had to have the second transplant, obviously you can increase the risk of problems if you had to give them more chemotherapy for a second transplant.

Okay, well thank you very much, and a salute to our survivors out there, and I hope that you found the information useful today. Again, this is being talked about in May of 2019, and new information is coming out all the time. So, keep looking for that.