Late Effects after a Pediatric Transplant/ Transitioning to Adult Care

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Late Effects after a Pediatric Transplant/Transitioning to Adult Care

Monday, May 2, 2022

Presenter: Robert Krance, MD, Director of the Pediatric Bone Marrow Transplant (BMT)/Stem Cell Transplant Program at Texas Children’s Hospital in Houston, Texas

Presentation is 39 minutes long with 16 minutes of Q & A.

Summary:  After a pediatric bone marrow transplant, patients are at risk of developing new transplant-related health problems. These problems may not appear until later in life. This presentation discusses the potential complications, available treatments, and the importance of a healthy lifestyle ongoing monitoring to detect health issues early, when treatment is most effective.

Highlights:

• Total body irradiation and some chemotherapy drugs can make young boys sterile. Males transplanted after puberty may retain fertility. Young girls may retain fertility if transplanted before puberty, but fertility is almost always lost if they are transplanted after puberty.
• The risk of other cancers after transplant is roughly double that of the general population and this risk increases over time. Since these cancers may not appear for 10 years or more post-transplant, annual exams and regular screenings are important throughout one’s life.
• Maintaining a regular exercise program can minimize the risk of many post-transplant complications. Pediatric patients should have a long-term health plan and transplant centers should help with this. Healthy lifestyle habits and behaviors are also important to maintain.

Key Points:

(04:40): Getting re-immunized after transplant is extremely important.  

(09:15): The incidence of heart disease in transplant survivors is ten times greater than seen in the general population

(13:05): Bone problems like osteoporosis or osteopenia occurs in a quarter of patients post-transplant.

(13:57): Kidney injury is common after transplant. It can be subtle and may not show up early on typical kidney tests for BUN and creatinine.

(16:14): Monitoring to catch lung injury early is crucial, because it is difficult to treat, once it becomes severe.

(17:59): Patients should be monitored regularly for skin graft-versus-host disease and skin cancer.

(20:06): Hormone failure can delay or inhibit growth in young patients.

(27:08): The liver is sensitive to drugs and irradiation and at risk for excess iron which may be treated through phlebotomy.

(29:11): Metabolic syndrome can develop after transplant and increase the risk of diabetes, stroke and cardiac disease.

(34:10): Young transplant patients who have received radiation should have regular neurocognitive testing, although most data suggest they will maintain average IQ and cognitive performance.

Transcript of Presentation:

(00:01): [Mary-Clare Bietila] Introduction.  Good morning. My name is Mary-Clare Bietila, and I will be your moderator. Welcome to the workshop, Late Effects of a Pediatric Transplant /Transitioning to Adult Care.

(00:12): I'd now like to introduce Dr. Robert Krance. Dr. Robert Krance is a Professor of Medicine at Baylor College of Medicine and the Director of the pediatric bone marrow transplant stem cell transplant program at Texas Children's Hospital in Houston, Texas. Dr. Krance has been involved in bone marrow transplantation for more than 30 years. His research interests include the use of alternative donors and less than fully HLA matched related donors for transplant, and the impact of viral infection post-transplant. Please join me in welcoming Dr. Krance.

(00:56): [Dr. Robert Krance] Overview of Talk. Good morning, everyone. I want to thank first of all, Ms. Stewart and the staff of BMT InfoNet for inviting me to speak today. I am going to be talking as was introduced, on the long-term healthcare issues of pediatric patients who have been transplanted. I want to say from the start that I use the word patients or survivors, because there's no better or easier word that would make sense. But I know some people may not want to necessarily be labeled or considered as that, but, as I say, there's no better term I have.

(01:37): I think this is a very important topic because long-term healthcare management is so essential to quality of life. And as clinicians we have two goals. We want everybody who has to have a transplant to basically successfully get through the transplant. And we also want to accomplish that without causing undue harm or delayed complications.

(02:04): And so for patients who've been transplanted, I think it's important to recognize these elements so that if they can prevent complications, they're aware of them and they can deal with them. Or if they do develop complications, that they do have effective treatments, an option that's available to them. And they receive that as soon as possible so that the benefits of the treatment can be before there's lasting injury.

(02:32): The other element of this talk is that we are encouraging people to develop lifelong healthy habits, because that is a big part of long-term healthcare management. And then take advantage of all the measures that you can use to improve quality of life. For instance, BMT InfoNet has a number of opportunities for patients who have been transplanted in the later years.

(03:01): The specific illness for which patients were transplanted as well as the treatment they receive prior to and during transplant determines their individual risk of developing late complications. So let me start off by saying it's important that each person recognize the specific circumstances of their treatment and their course. The illness for which transplant was recommended is one. If there was treatment pre-transplant, you should be aware of that. You should also be aware of the treatment that was used to perform the transplant. For instance now, not all patients get ablative therapy, which was the standard a decade or more ago. Some patients received non mild ablative or reduced intensity [treatment before transplant]. And that can make a difference in terms of the transplant-related complications, and post-transplant care. And also the graft-versus-host disease, preventive therapy and complications that may have arisen during the transplant course [are important to know].

(03:59): Guidelines for long-term care plans are available. Unfortunately, although transplant has been available for over 50 years now, much of what we know about post-transplant care still remains unclear or uncertain. In many cases, there are data to use to develop a care plan. But in other cases, treatment is based upon what groups of physicians think might be the best. And in some cases, your individual center may have their own particular protocol. Listed here are three organizations that do have guidelines and people may be interested in looking at these to see if there's something that they find useful.

(04:40): Getting re-immunized after transplant is extremely important. Something that's extremely important and often not addressed or not fully managed is re-immunization. It's one of those things, which is sort of a no-brainer. But unfortunately, when patients, if they're not being cared for at their transplant center and are being cared for by a private physician, the private physician may not be aware of the need for a re-immunization schedule or may not have that, or may be skeptical of the need for it. So I encourage every person to obtain a schedule of re-immunization and make that available to their physician, so that can be carried out.

(05:19): The timing of immunizations may differ for each vaccine. When should immunizations begin? There's no set time. Some centers look for immune recovery by looking at particular populations of immune cells. Other centers don't do that. They wait for a year. Our own center looks to immune recovery, but also we will provide patients with a vaccination against pneumococcus, the Prevnar vaccine. and the detailed vaccine for diphtheria, tetanus, and pertussis. And we look at the pre and the post response to the vaccination. And if the response looks good, then we will proceed with the full schedule.

(05:56): Non-live vaccines may be given a year after transplant; live vaccines are usually given two years later. In the first year, and usually it's a year or more after transplant before starting the vaccinations, the vaccinations should only be for bacterial infections and for using non live viral vaccines. After the second year of transplant, it's possible to get live virus vaccines. Those include the measles, mumps, rubella, varicella and the human papilloma virus, HPV. The reason for that is with the longer time to immune recovery, we think it becomes safer for the use of live viral vaccines. Additionally, every patient post-transplant should get an annual flu vaccine. And I think you can probably look forward to getting vaccine against COVID on some regular basis in the future.

(06:48): Transplant may not resolve all issues related to genetic diseases, such as Fanconi anemia, for which a patient may be transplanted. Most patients who undergo stem cell transplantation do so for a malignancy, like leukemia or for a bone marrow failure, like aplastic anemia. But there are patients who undergo transplantation for certain genetic disorders. It's important that they keep this in mind, because while transplantation may improve some of the elements of their illness, it does not improve all of the elements, because the underlying disease is not totally cured by the transplant.

(07:19): So what's an example of that? Patients who have Fanconi aplastic anemia. That's a bone marrow failure disorder, but it also has a predisposition to cancers of the gastrointestinal tract, which are unrelated to the transplants or its therapy. Or patients who have another condition called Dyskeratosis Congenita, which is another marrow failure disorder. It also can cause liver and lung disease, and that's independent of the transplant. So for certain illnesses, transplant does not address the underlying genetic problems completely. And it's important to remain knowledgeable about that because that will make a difference in your long-term care.

(08:06): Oral care is crucial during young years of tooth formation. So taking this sort of by system, by system, starting out with oral care, pediatric patients are often transplanted early in life. And it's in the early years that organ systems are developing. One system is the teeth, the oral cavity. Treatments like radiotherapy delivered during these young years can cause interruption of tooth formation. Teeth can fail to erupt. They may have poor enamel formation or poor root formation leading to tooth loss. We think it's very critical that patients have annual oral care, at least, and of course, most people do see the dentist annually. But in this particular case, it's very important so that patients have the best possible outcome related to their teeth. Orthodontia may require specialists if there is a problem with teeth formation or teeth development. So be aware of this.

(09:15): The incidence of heart disease in transplant survivors is ten times greater than seen in the general population. Getting to the heart of the problem, talking about heart health. Heart health is something that's going to be a lifelong endeavor for patients who have undergone transplant, especially if they received certain chemotherapy or radiotherapy. The incidence of heart disease in transplant patients is approximately 10 times that of the regular population. It can lead to heart failure like a cardiomyopathy, but really any element of the cardiovascular system can be affected, including blood vessels. So maintaining a healthy heart lifestyle is currently very important.

(09:59): Some types of chemotherapy or radiation elevate the risk of heart disease. What are some of the risks for patients? Not every patient is at risk, but patients who have received anthracyclines such as doxorubicin, patients who have received total body irradiation, or patients who've received chest irradiation, say mantle irradiation to treat lymphoma, or the combination of those are more at risk than any other group. But again, you can contribute to your own heart health by avoiding unhealthy habits, such as smoking, diabetes, high levels of cholesterol and so forth. So this is a total health picture, not just related to your treatment.

(10:39): Patients can be classified as having high, intermediate or low risk for heart problems to guide the type of follow up care they require. The current recommendations try to stratify patients based upon the amount of therapy they've received. Patients can be labeled as high risk for heart disease, intermediate risk and low risk. And you can see the reference below, that you can look into for further details. The patients who are considered high risk probably should undergo an echocardiogram every two years. Whereas those that are considered intermediate should consider an echocardiogram every five years. And those that are considered low risk, it's probably not necessary that they have a regular echocardiogram performed. But being aware of heart health, I think again, is very important.

(11:23): Patients who received total body irradiation may develop benign, bony tumors called osteochondromas. The bone, the skeletal system. We typically don't pay much attention to that. But bone health is an issue for patients who have been transplanted. Patients who've received total body irradiation may develop bony tumors called osteochondromas. These are bony outgrowths that occur at the metaphysis or the growth plated bones close to the end of the bone. These are almost always benign. A simple x-ray can often be diagnostic. It doesn't require further evaluation. Typically they don't need any therapy unless there's some cosmetic issue, or if they cause some functional pain in movement of a joint. If so, they can be removed.

(12:17): Another condition that can occur after transplant is avascular necrosis. This is an unusual condition. It typically presents in the hip and patients have pain with walking or running. It's not clear to the etiology, but use of steroids for prolonged periods of time, and sometimes radiotherapy are implicated in this. What happens is that the head of the femur basically undergoes necrosis. It's thought to be due to a vascular injury. And as I say, it's not clear why this happens. An MRI is diagnostic and treatment can include symptomatic care, in some cases, surgery, and rarely it can require hip replacement.

(13:05): Osteoporosis or osteopenia occurs in a quarter of patients post-transplant. Osteoporosis or osteopenia is another complication. And it's present in at least a quarter of patients post-transplant. The way the diagnosis is made is by a study called the DXA scan, which is a nuclear medicine study. But because it's so common, most centers just recommend that patients take calcium and vitamin D to promote bone mineralization. Osteoporosis is more common among patients who've received total body irradiation and prolonged therapy with steroids, and other hormone deficiencies can contribute to that. Smoking and excessive alcohol intake can aggravate this condition and physical activity can help deal with it. So being active helps bone mineralization.

(13:57): Kidney injury is common after transplant. It can be subtle and may not show up early on typical kidney tests for BUN and creatinine. For the kidney. The typical tests are BUN and creatinine. And these are often normal, despite the fact that transplant patients can have endured injury to the kidney. And this kidney injury is quite frequent. Kidney, like many of the other organs in the body, has a certain redundancy of function so that there has to be a great deal of injury before a blood test like the BUN or creatinine might show up. But patients who received radiotherapy or patients who receive certain chemotherapy drugs like ifosfamide and cisplatinum, obviously patients who receive tacrolimus and cyclosporin, these are all agents which can contribute to kidney injury. And also patients who've had complications during the transplant phase, like transplant associated microangiopathy (TMA), or a patient who's required dialysis at some point during the transplant course, all have sustained kidney injury.

(14:58): The best way to evaluate kidney function is by a functional test, creatinine clearance or proteinuria filtration rates. So we usually will require one of these tests a year after transplant to determine what the ongoing baseline function is. Typically, kidney function doesn't decline after reaching a plateau. So that's a good sign. But conditions like hypertension must be managed aggressively and may require intervention by a nephrologist.

(15:28): To avoid kidney injury, transplant survivors should not receive chronic treatment with non-steroidal anti-inflammatory drugs such as ibuprofen or Naproxen. One important thing is to avoid further injury to the kidneys. So we are very adamant that patients should not receive chronic treatment with ibuprofen or Naproxen. These are called non-steroidal anti-inflammatories. A single dose here and again, not significant, but chronic use of these medications is discouraged. Likewise, when you see a physician for some condition and you are given up prescription, I think it's always important to tell the physician that you do have concern regarding kidney function and is this particular medicine a problem for you? And as stated we would recommend anybody who has proteinuria or hypertension to be seen by a nephrologist

(16:14): Monitoring to catch lung injury early is crucial, because it is difficult to treat, once it becomes severe. Lung injury, nothing frightens transplant physicians more than lung injury because there's so little you can do when lung injury becomes severe. In the immediate aftermath of transplant, the one condition is bronchiolitis obliterans, which is thought to be a complication related to graft-versus-host disease. It has many of the symptoms to suggest asthma such as wheezing and puffy chest and prolonged expiration, but it is different. And the therapy is not good and requires ongoing care. Later on, lung injury can be related to the effects of prior treatment from drugs like busulfan or bleomycin. or patients who received irradiation to the chest or TBI. They can develop basically scarring or fibrosis of the lung, which can lead to restrictive lung disease. The symptoms of that would be becoming short of breath with really minimal activity.

(17:14): The best way to monitor the lung is with pulmonary function tests. Usually children older than six years of age can perform these tests. We typically obtain pulmonary function prior to transplant, and then during the first year after transplant. If the tests are stable, it may not be necessary to repeat these in the future. But if there's a decline, certainly we would repeat them and follow them as long as there's ongoing decline in pulmonary function. No smoking, obviously. No smoking. And you all know about secondhand smoke. Again, we recommend flu vaccine and Prevnar vaccines to avoid the possibility of developing infections that you could avoid.

(17:59): Patients should be monitored regularly for skin graft-versus-host disease and skin cancer. Skin health. Chronic graft-versus-host disease could cause major changes to the skin, particularly scarring and thinning or atrophy of the skin. And these can be niduses, beginning sites for development of squamous cell cancer. But skin cancer, like melanoma or basal cell carcinoma, can also occur. We think that annual skin exam by your physician or by a dermatologist is important. Certainly if you have pigmented molds, they should be followed by a dermatologist because they have the potential for developing into a melanoma. So following these on a regular basis is very important. No tanning booths.

(18:47): Endocrine problems often occur in the first years after transplant. Some of the things we've just talked about, they develop over time. But changes to the glandular system, the endocrine system, are often present in the first years after transplantation. And particularly for children, where growth and development is so important, endocrine function is really critical.

(19:07): Measuring linear growth after a pediatric transplant is important. So the pituitary gland, the major gland for the endocrine system in the brain, which controls the thyroid and the adrenal gland and the testes also secretes growth hormone. It is very important that this gland has adequate function. So measuring linear growth and following that is quite important. The pituitary can be affected by irradiation to the brain obviously, or patients who've had disease involving a brain, like CNS leukemia or brain tumor.

(19:40): If a patient has growth hormone deficiency, this can be determined by looking at a number of things. There are blood tests, like the insulin growth factor. Obviously, following height over time, obtaining a bone age to compare that with height to be certain that things are proceeding according to the norm, are measures of that. You can perform a growth hormone test. That's a little bit more involved and usually is done by an endocrinologist.

(20:06): Hormone failures can delay or inhibit growth in young patients. Patients who have other hormone failure can also have delayed or inhibited growth. So the thyroid and gonadal function can be quite important. For patients who have growth hormone deficiency, it's possible to treat them with growth hormone. It must be started before puberty to have any benefit because once puberty occurs, bone growth is going to be stopped. And so starting before puberty is critical. There were concerns in the past about growth hormone causing the recurrence of the primary disease, so there was a cancer, but I think that's been pretty much excluded, and whether or not it could stimulate some other tumor. I think most endocrinologists and bone marrow transplant physicians don't believe that's an issue. You know, height is so important in today's society. So I think this needs to be addressed. You should discuss that with your care team.

(21:03): The thyroid gland may lose function after transplant but can be easily treated once it is detected. The thyroid gland, especially for patients who are receiving irradiation to the chest or total body irradiation may lose function. It could be related to the pituitary injury, but more typically it's due to thyroid, decreased thyroid function in response to thyroid stimulating hormone. It's easy to treat with thyroid hormone extract. The only point I would make here is that also other kinds of thyroid issues, including hyperthyroidism, where the thyroid is overactive can occur rarely. And thyroid cancer is something that needs to be considered. On an annual exam, patient should have palpation of the neck, looking for thyroid nodules. Some centers recommend ultrasound examination.

(21:54): Boys who receive total body irradiation, cyclophosphamide or platinum agent drugs before puberty often become sterile.  Sexual development, a very critical element, as everyone knows. For males the testes control development of masculinity and pubertal growth. We'll talk a little bit about the difference between testosterone secretion and germ cell function, but total body irradiation and certain agents like cyclophosphamide or platinum agent drugs can affect the testes. It's important to recognize that, for boys who are treated before puberty and receive total body irradiation, it's very likely that they will be sterile, because the effect of these agents on the testes are such that the sperm cells, germ cells are lost. They may continue to go through puberty, or they may have delayed puberty. And it's important to test boys early, 10 or 11 at the latest, looking for evidence of testicular failure. We'll discuss those tests on the next slide.

(22:59): Boys transplanted after puberty may retain fertility which can be measured by semen analysis. And for pubertal males, there is the potential for retaining fertility, especially if after several years post-transplant, it may be that the fertility will recover as sperm production returns. The only way to be certain about fertility though, is to do a semen analysis. As I mentioned, there are the germ cells, the sperm cells, and there are the Leydig cells, which secrete testosterone. The germ cells are very sensitive to therapy. And that's why for young boys, they often are eradicated. Whereas the Leydig cells are more resistant to therapy. And so they will secrete testosterone. So typically patients may masculinize, but they will be infertile.

(23:50): Young girls transplanted before puberty are more likely to retain fertility than those transplanted after puberty.  For females, the story is somewhat different. A female at birth is born with all of the follicles or ova that are going to be there for life. And they will decline over life, as a woman goes through puberty and menstrual periods. Each of those times, follicles are lost. When the number of follicles decline to a certain level, a woman goes through menopause. And the effect of radiotherapy and certain chemotherapy agents is actually to reduce the number of follicles. Young girls, because they have more follicles than females at puberty or post puberty who've already lost a number of those follicles through development, are more likely to retain the ability to go through puberty and may retain fertility. Whereas fertility is almost always lost for pubertal or post pubertal women.

(24:48): If a woman remains fertile after transplant and wishes to bear children, she should do so sooner rather than later, as fertility may be lost over time. The only point I'm going to make here is that if a woman retains evidence that they may be fertile, it's important for family planning to consider that earlier, rather than later, because over time, fertility may be lost and menopause may occur. For those patients who are fertile and do have offspring or who are able to become pregnant, there is no evidence that there is an increased risk for congenital anomalies or genetic disease in offspring. So that's, I think a comforting thing. The risk for infertility is high, but for those that are fertile, they can be comforted by the fact that there's no evidence that there's increased risk. There are risks for transplant survivors who are female. Going through the pregnancy, they may have miscarriage, or they may have some difficulty with delivery due to the changes to the uterus, but infants have always been healthy.

(26:01): Hearing is usually not affected by transplant, except in children who received high dosages of cranial radiation or certain drugs that contribute to hearing loss like cisplatin. Eye and ear health. Obviously seeing and hearing is, without a doubt, very important, but it's important beyond just the senses themselves. It's important in terms of schooling and occupation. and so many things. Hearing is usually not affected, except for patients who have had higher doses of cranial irradiation, over 3000 gray. Certain drugs can also contribute to hearing loss like cisplatin. We do an audiogram in the first-year post-transplant to have a baseline, but in general hearing is preserved.

(26:37): Cataracts often develop after transplant. An eye exam is necessary at least on an annual basis, because of the risk for cataract development among patients who've had total body irradiation, and in some cases, for patients who only had chemotherapy. Cataracts can develop, they don't always necessarily need surgical removal. But if, for instance, there is cataract formation in one eye that leads to a greater loss of vision, it is important to correct that.

(27:08): The liver is susceptible to iron overload after transplant. The liver, like many of the organs we've already discussed, is sensitive to drugs and irradiation. Complications during the transplant phase, like veno-occlusive disease, may cause permanent changes in the liver. The liver also is more susceptible to iron overload. So with transfusions of red cells, iron accumulates, and it's stored in the liver. And if the accumulation of iron is significant, it can lead to liver injury, even to liver cirrhosis. We use the protein ferritin as a way of assessing the storage iron. And if it exceeds a certain amount, we recommend that patients get an MRI of the liver, which lets you quantify the amount of iron in liver. If it's high, then it should be removed. The current favored way of removing it is by phlebotomy, just withdrawing blood. It allows the iron in the liver to be withdrawn and used to make new red cells. You can also use certain drugs to chelate iron. Besides the liver, the heart and the pancreas can also be sites of accumulation, but usually they're less susceptible to iron accumulation than the liver.

(28:30): Non-alcoholic fatty live disease can occur after transplant which can lead to liver cirrhosis. Patients who have abnormal liver function tests, unrelated to iron, can have a condition called non-alcoholic fatty liver disease. These patients usually suffer from obesity, and in this condition, fat gets deposited and stored in the liver. As it gets worse, it can cause steatohepatitis, fatty hepatitis, which also can cause cirrhosis. And actually it's one of the leading causes for a liver transplantation. It can be dealt with by controlling diet. And so that's another of those areas where lifelong habits can be very important in preventing certain complications.

(29:11): Metabolic syndrome can develop after transplant and increase the risk of diabetes, stroke and cardiac disease. Metabolic syndrome is often associated with non-alcoholic fatty liver disease. It's a compendium of symptoms and signs. It usually includes hypertension, abdominal obesity, waist circumference is large, abnormal cholesterol and triglycerides, and usually abnormal glucose metabolism which can ultimately lead to diabetes, which is a complication that is all too frequent among patients who have this syndrome. Apart from leading to diabetes, it can cause cardiac disease, and stroke and infarction are also part of the side effects of this syndrome.

(29:56): The most effective way to control metabolic syndromes is with a healthy diet, weight control and maintaining physical activity. The cause is not clear. It seems to be more common for patients who receive steroids and perhaps irradiation therapy and certain drugs. Patients who are growth hormone insufficient may also be susceptible to the development of this metabolic syndrome. But by and large, it's not clear how it happens. Obesity can lead to inflammation. We know that. And so there may be some element of inflammation. But the way to manage this, and it's shown to be effective, is by controlling diet, maintaining weight and maintaining your physical activity. So these seem obvious, but they do lead to improved quality of life. And so we it's a very important step in terms of post-transplant care.

(30:50): Transplant survivors have twice the risk of developing another cancers after transplant than the general population. Malignancy. It seems unfair after somebody's treated for leukemia or lymphoma, that they need to worry about malignancy. The exact incidence of cancer in post-transplant patients is unclear. There are many elements that could be involved in that, you know, exactly what populations are you comparing, things like that. Some of the best reports say that it may be about twice as common in the [transplant] population as non-transplant patients.

(31:20): The risk of secondary cancers increases over time. It's also true that for many of these, the risk increases over time, meaning that, for instance, we see below that MDS, which is myelodysplastic syndrome and AML, those are usually seen fairly early in the post-transplant period. And they're really limited to patients who've undergone autologous transplant, using their own bone marrow. And so it's assumed that there's some injury in the treatment that leads to the developments of AML. And lymphoproliferative disease is a viral disease that can occur in the post-transplant setting, which is fairly easily managed.

(32:00): Since these other cancers may not appear for 10 years or more, annual exams and regular screenings are important throughout one’s life. But other cancers are more common and do not usually begin to appear until 10 or more years after transplant. So this is the argument for ongoing care, because an annual exam and an annual history can be very important in discovering these cancers and getting the appropriate testing. As I said, it's not clear why it happens in transplant patients. There are a number of variables. It may be related to the patient's own genetics, or it may relate to the treatment that they receive like radiotherapy or certain chemotherapy agents. The diagnosis may be one that, like lymphoma, is associated with a higher occurrence of cancer in the post-transplant period. And the younger patients at time of transplant are more likely to have a cancer later in life.

(32:57): Chest or total body irradiation and treatment with anthracyclines increase the risk of breast cancer. The annual exams we talked about are important for discovery, but there are particular studies right now that should be done. So breast cancer for women who receive chest irradiation or receive total body irradiation with anthracyclines, seem to be at more risk for breast cancer. And currently, now, it's recommended that certain patients, and you can discuss this with your physician, should begin with a mammogram and a breast MRI at 25 years of age annually or eight years after the completion of therapy, whichever is longer. Some centers are not familiar with this. So your team is going to have to reach out and explain why this is being done. But this is recommended.

(33:50): We've already talked about squamous cell carcinoma related to chronic GVHD, and then patients who have CNS leukemia or cranial radiotherapy may also be more likely to develop a CNS tumor.

(34:10): Young transplant patients who have received radiation should have regular neurocognitive testing, although most data suggest they will maintain normal IQ and cognitive performance. In my own experience, probably the one item that the parents are most anxious about is, will irradiation affect my child's ability to learn. Will this somehow make them uneducable or make them in some way delayed. And there's a lot of data out there both saying yes and no. But the largest compendium of data says that the patients who had these treatments maintain IQ and performance within the average population range. However, we do think it's very important that patients have neurocognitive abilities examined, especially patients who've had TBI and cranial irradiation beyond the usual amount, or patients who have been transplanted at a very young age. And so neurocognitive testing can be quite informative in that respect. It's ideal that neurocognitive testing should take place before the patient starts transplant, but that's not always possible. But certainly in the first year after transplant, if they've had some of these treatments like irradiation, they should undergo a neurocognitive testing.

(35:21): And it's probably important that this testing be repeated at various time points along the child's life. Here, I recommend doing it as they move from preschool or into first grade, or when they go to junior high or middle school. And maybe again, when they go to high school, because the neurocognitive testing may show that there are problems in certain areas like memory or concentration or organizational skills. But these can be dealt with if they're recognized, and there are many ways to deal with this so that the child does not suffer because of not having the opportunity to have the appropriate education. So timely and appropriate intervention is important.

(36:04): Fatigue is a common problem that can lead to withdrawal, depression, or anxiety. Fatigue. Fatigue is very common among transplant recipients. Usually it begins to improve after several years, but not for all patients. Fatigue manifested by daytime sleepiness has been documented in almost 25% of post-transplant patients. Unfortunately fatigue can lead to many things. It can lead to withdrawal from being active in life. It can be associated with changes such as depression or anxiety. And there are things that can be done to help people who have fatigue, and if recognized it should be dealt with. We do want people to be aware of fatigue as being a prevalent complication in the post-transplant setting and reach out for help.

(37:03): Maintaining a regular exercise program can minimize the risk of many post-transplant complications. Finally, I made the point throughout this presentation about maintaining an exercise program. Being active is so very important. The only point I want to make here is that because of the issue of cardiac and pulmonary complications, that prior to embarking on an exercise program, you should have a clearance based upon your cardiac and pulmonary function. And that's easy to obtain from your transplant physician or from your caregiver. And I think as long as that, the function of the heart and lungs are sufficient, you should be able to have an exercise program. I would recommend that you not begin training for a marathon, but work into it gradually. You should have an organized program, perhaps with a buddy, so that you use that as a way of sustaining your exercise program.

(37:55): Pediatric patients should have a long-term, lifelong health plan. Transplant centers or knowledgeable providers can help with this. So the final thoughts I have are, it's very important that pediatric patients, as they age, and their parents, as they help them age, create a mindset of establishing a long-term lifelong health plan. As part of that, you should have contact with your transplant center, if that's the available to you. If not, you should find a knowledgeable provider in your locale. I think, in most cases, your transplant center can help you with that. You certainly can now provide the right information to your caregivers, so that there's some coordination.

 (38:42): Diet and exercise are important components of a healthy lifestyle, as are avoiding unhealthy behaviors such as obesity, smoking and use of recreational drugs. The second part of this is having healthy habits: diet, exercise, two of the most important ones. Avoid unhealthy behavior habits like obesity, smoking, drugs, and treat symptoms such as anxiety or depression, especially if it inhibits or restricts your life. I think healthy habits are essential to promote healthy adults. And with that, I conclude my presentation.

Question and Answer Session

(39:11): [Mary-Clare Bietila] Thank you so much, Dr. Krance, that was an excellent presentation. We're now going to take questions. Our first question is what diet, exercise, or even hormones do you specifically recommend for pediatric patients after a BMT?

(39:45): [Dr. Robert Krance] So obviously that's the critical question. So exercise we recommend is basically whatever the patient feels like they can maintain. And I think it should be a combination of cardio as well as a muscle development. But whether you choose say a treadmill or bicycle, or even running, as your cardio, and whether you decide to lift weights or do resistance type training, I don't think that matters. It could be swimming. I just think the important thing is that you have something that you do on a regular basis. Doesn't need to be every day, but it should be on a regular basis. You say, I can do this three or four days a week.

(40:32): The diet should be, the diet that most people hear is the Mediterranean diet. So it should be a diet that's low in processed foods, obviously low in fats that are not considered healthy fats. And it should be caloric appropriate, not caloric dense. So I think if the caloric content meets your physical activity and your weight needs, and you're doing physical activity on a regular basis, that's what we expect.

(41:09): I take care of primarily children and adolescents, and eating fast food and processed food, it's sort of a way of life, especially when patients go away to school and are not under parental supervision. But I think if that starts at an early age, I think that children, as they grow older, are likely to pick that up and understand it as being important. So that's my recommendation. If you need more formal instruction, I think consulting with a nutritionist at your transplant center can be very helpful in that respect. Now for patients who have diabetes or have cholesterol or triglyceride issues, that's a more specific thing. And I do think they should discuss that with a nutritionist.

(41:56): [Mary-Clare Bietila] Okay. And they also asked about hormones, are there specific hormones that you prescribe to patients? And then what? Can you say a little bit more about that?

(42:11): [Dr. Robert Krance] Generally, we find that if patients are hypothyroid and need thyroid replacement we will do that in conjunction with the endocrinologist. But the common drug is Levothyroxine or Synthroid, and it's based upon weight and then response. So that's fairly simple, and there's no brand name that stands out there.

(42:33): For hormone replacement therapy, the options are much broader. Let me talk a little bit about female. I mean, hormone replacement therapy, we favor the use of patch over oral estrogens, because that seems to be, I guess, safer for the liver in terms of the estrogen dosing, than does oral estrogens. But sometimes that's not sufficient. The one caution there is that, generally speaking, patch hormone replacement therapy is not sufficient for contraception. So if fertility is present or at least it's being considered, that may not be enough to prevent pregnancy.

(43:16): We work with endocrinology or in some cases with gynecology. And gynecologist and endocrinologists, don't always agree on the best way to do this. Some advocate not using a combination with estrogen and progesterone, so that patients don't have menses. Others feel like menses are important as part of a protocol. So I would not want to make a categorical claim here but would want you to discuss that with your care providers.

(43:51): For males, the treatment is testosterone. One of the slides there talked about cryopreservation of sperm. So if fertility is a consideration, but hypogonadism is still a concern as well, and testosterone replacement is considered, patients should probably cryopreserve sperm. Because if you do receive testosterone therapy, you will lose spermatogenesis at least for a time. And it may not recover.

(44:22): [Mary-Clare Bietila] All right. That's really helpful. Our next question is from a parent whose child received a cord blood transplant for ALL at around 10 months old. They are curious what are the significant things they should be on the lookout for as far as late effects? And how can they help their child thrive?

(44:49): [Dr. Robert Krance] It's very good question. And my advice is going to be a little bit generic because without knowing specifics, for instance, I would suspect that at a 10 month of age, perhaps the center eschewed using irradiation and used a chemotherapy only regimen, trying to avoid the effects of cranial irradiation on pituitary and growth. But if not, and they did receive irradiation, then growth is going be one of the major concerns. And I think that they should see it an endocrinologist relatively early in the post-transplant course, even before any symptoms or signs of growth failure have developed. If it was a chemotherapy-based regimen, it depends a little bit again then on the drugs used. A drug like cyclophosphamide is very likely to lead to a loss of sperm production. And it also may delay puberty.

(45:54): So I don't know what the age of the child is now, but as the child approaches a pubertal age, they should be studied for whether they're going to actually begin puberty. If not, treatment should be started right away, it should not be delayed. You don't want to add delayed sexual development on top of all the other issues that a patient who's been transplanted can face.

(46:19): The annual exam should also look at adrenal gland function and thyroid function. Those are pretty straightforward, and generally can be quite easily dealt with. Beyond that, depending again, on what the pre therapy was before transplant and what drugs were administered, were there anthracyclines? Daunomycin would be a common one used for patients with acute leukemia.

(46:46): It may be necessary that they have an annual echocardiogram, or at least a bi-annual echocardiogram performed. The child is probably too young for pulmonary function [tests], but as the child comes closer to six, we would recommend pulmonary function studies. And they should have a sense of what the renal function is, so that they're aware of anything that might develop related to renal function and what drugs they need to avoid.

(47:16): Apart from that, I think just ongoing good care, re-immunization, going back to my third or fourth slide. That's really, especially at that age, to make certain that the patient is adequately immunized as they get closer to school age. Those are the most important issues. Eye exam, dental exam. Those are things to also to follow.

(47:44): [Mary-Clare Bietila] Wonderful. Our next question is along the same lines, this questioner would like to know if there are particular types of cancers that have the most late side effects or most likely to have secondary cancers? You talked a lot about the exact treatment protocols that people had are big indicators, but are there specific cancer diagnoses that are more likely to have complications down the line?

(48:16): [Dr. Robert Krance] So, yes, that's a good question. I think most of the issues related to late cancer are probably most dependent upon the therapy that the patient received pre-transplants and during the transplant. So right now it's not clear whether patients who have had reduced intensity or non-myeloablative therapy are going to be spared some of the risk for late cancer. But that's an ongoing question. Patients who've had lymphoma, at least in some studies, seem to be more at risk for late cancers. But the differences are not so great that somebody who's had treatment for lymphoma needs to be particularly more worried than somebody who's been treated for leukemia, or for somebody who's been treated for another type of tumor.

(49:19): I think, and actually in most cases for patients with lymphoma, it may be related to the fact that they've received radiation to the thyroid and to the breast, which may be the reason for the increased incidence there. And then for patients, who've had involvement of the brain by CNS leukemia or brain tumor, who've received higher doses of irradiation to the brain, they may be more at risk for brain tumors. Apart from the ones that I talked about earlier, the genetic disorders that are prone to certain kinds of cancer, I don't think that there's a real differential in terms of risk.

(50:01): [Mary-Clare Bietila] Okay. Thank you. Our next question is if you were diagnosed with TA-TMA after transplant, are there any long-term effects to look out for?

(50:20): [Dr. Robert Krance] So yes. I think that's an excellent question. It's a bit hard to answer because I think individual patients are going to have a different risk. But I think that the risk for ongoing renal complications, not complications, but I think renal function is probably more impacted by somebody with that diagnosis. And so going forward, they probably have less kidney reserve than somebody who did not encounter that complication. Here again, I would recommend that the patient be studied by a functional test, like a 24-hour creatine clearance or a GFR, a glomerular filtration rate to see what the baseline function is. If it's reduced, then I think it's really important that any other issue related to renal function be aggressively dealt with.

(51:20): So if there is residual hypertension, that must be managed very carefully. If there is residual proteinuria, protein in the urine, that must be managed very aggressively. I think a patient should probably be followed in conjunction with a nephrologist who's familiar with the condition and is able to act on that. We have patients who've had TMA, and some of them have recovered and don't seem to have any particular decline in renal function and have had no major change to their management. And we've had other patients who have ongoing issues, even some patients who've had to undergo kidney transplant. So there is a gamut here. I think in conference with their physician and maybe their nephrologist, they can have a much better understanding of what's in store for them. I did make the point that, in general, if the hypertension and proteinuria are not issues, and even if the function is reduced, it seems as if that will remain stable, provided there's no further injury. Avoiding injurious drugs to the kidney is important.

(52:30): [Mary-Clare Bietila] Okay, this is going to be our last question. For those that are 10 plus years post-transplant, and they're no longer under the care of their oncologist, they need to advocate for themselves. And they're curious when they're working with their primary care provider post-transplant, what are the tests they need to be asking for? What do they need to make sure when they have that annual exam that they're getting?

(53:00): [Dr. Robert Krance] That's a great question. I think if they want to download that slide set. The third one, the NMDP organization has a website and on that website there is a patient link for long-term studies. And it points out what is important in the post-transplant period for follow up. It tells you what testing, at what interval. It's even available on iPhone and for Google phones. There's an application for that, that you can use and take it to your doctor and show them what you need to have.

(53:46): I would recommend for that individual, if they're not being followed by their pediatric transplant center, that they either ask their pediatric transplant center, is there an adult group that they could be referred to? Here in Houston, we have an adult team. They're not in our hospital, obviously, but we do refer some to that. And then for patients that have moved to other cities, I often will call the adult programs in those cities. And they're usually willing, almost always, to see a patient who's had a transplant and follow them. Because it's really one of the important things that we do to try and prevent complications or treat them early so that the quality of life is not impacted in a major way.

(54:31): [Mary-Clare Bietila] Closing. Excellent, excellent. Yeah. Survivorship clinics are becoming more and more prevalent, and that is wonderful for our long-term survivors. Well, I would love, on behalf of BMT InfoNet and our partners, I would really like to thank you, Dr. Krance for your helpful presentation and remarks. And I'd like to thank the audience for these excellent questions. Please contact BMT InfoNet if we can help you in any way. And enjoy the rest of the symposium.