Clinical trial: NCT00968864
Section: Confidentiality
Subsections: Confidentiality

The records of this study will be kept private. In any sort of report we might publish, we will not include any information that will make it possible to identify a patient. Your record for this study may, however, be reviewed and/or photocopied by Miltenyi Biotec, Inc., the manufacturer of the CliniMACS device, by Carolinas HealthCare System, or by representatives of the Food and Drug Administration or other government agencies. To that extent, confidentiality is not absolute. Medical records are considered confidential and records are kept in a secured area accessible to those involved in your treatment. All data entered into a computer will be coded. No data that may be linked with you will be entered on any network computer allowing access to confidential information. The master list (linking your name to your health information) will be stored offline and available only to the principal investigator and his or her designee(s). Although we will make every effort possible to maintain confidentiality, there is however, a slight risk of loss of confidentiality. A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
Clinical trial: NCT00968864
Section: Duration of Study Involvement
Subsections: Length Of Study

Your participation in this study will include a hospital stay of approximately 4-5 weeks. Following discharge, you will be seen in the BMT Clinic until 5 years after transplant.
Clinical trial: NCT00968864
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Risks|Short Term Effects Of Chemotherapy And Radiation|Long-Term Effects Of Chemotherapy And Radiation Likely: Sterility (Inability To Have Children) Effects On Growth Less Likely:|Specific Side Effects And Complications For Each Drug And Radiation Not Listed Above Include: Total Body Irradiation (Tbi) Likely: Dryness Of The Skin. Less Likely:|Likely:|Likely:|Thiotepa Likely:|Rabbit Anti-Thymocyte Globulin, Ratg, Thymoglobulin® Likely:|Cyclophosphamide Less Likely:|Rituximab Less Likely:|Risks Of Transplantation|Likely:|Likely:|Complications Seen With All Types Of Transplants Rare But Serious:|2. Anesthesia **(Being Put To Sleep For Surgery)**|Reproductive Risks

This study has several risks. Many of these risks are seen with any type of stem cell transplant. The use of T cell-depleted PBSC may be associated with a higher risk of infection and lower risk of GVHD than some other types of alternative donor transplants. In addition to the known risks listed below, there may be uncommon or unknown risks that might occur.

Many side effects are common to the high-doses of chemotherapy drugs used for transplant. These include:
Likely:
Anemia (decrease in red blood cells) and a severe decrease in white cells and platelets.  
You will require intensive treatment for these problems including frequent transfusions of red cells and platelets, as well as antibiotics (drugs) for infections.  
Hair loss Nausea Vomiting Loss of appetite Mouth sores Diarrhea  
Bleeding and/or infections that can be fatal (causing death).  
Damage to the lungs, liver, and/or kidneys. This may result in mild temporary decreased function of these organs, chronic (long term) decreased function that may limit your normal activities, or progressive severe deterioration (worsening) and death.  
Damage to the heart and/or brain. This may result in mild temporary decreased function of these organs, chronic dysfunction that may limit your normal activities, or progressive severe deterioration and death.  
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10-20% likelihood of cataracts (clouding of the lens in the eye)
Decreased thyroid function (thyroid gland makes less thyroid hormone)  
Slowed mental development There is an increased risk (1-15%) of another cancer (leukemia, lymphoma, skin cancer)
in the future. Leukemia or lymphoma may occur as a result of the transplant. Skin cancers may also occur as a result of the transplant, especially if total body irradiation is used. The risk for this is approximately 1 in 100 for every ten years you live after the transplant.

Dryness of the mouth, sore throat and/or thickened saliva (spit)
Swelling (like mumps) of the saliva glands in the cheeks Fever Sunburn appearance of the skin starting several days after radiation therapy  
Damage to the brain Irritation of the lungs (pneumonitis) and the sack surrounding the heart (pericarditis).  
Fludarabine

Increased risk of infection from viruses and other germs  
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Inflammation of the liver  
Damage to the nerves causing tingling or pain and/or weakness At higher doses than used in this study, has been associated with brain damage, causing blindness, confusion and coma (unconsciousness)
Disorders of the immune system causing damage to red cell or platelets

1. **Cytomegalovirus (CMV) infection:** A relatively common complication in BMT patients is CMV infection. CMV is a common infection in the first several years of life. About half of all people have been infected and CMV remains in a quiet state in the body. CMV can be also be passed in blood and bone marrow infusions. The chance of passing CMV
is decreased by the CD34+selection process. During the transplant period, CMV that is already in the body can become reactivated (referred to as infection) and result in disease of the lungs (pneumonia), eyes, brain, liver, and/or intestines. In recipients of T cell depleted transplants who have previously been infected, the risk of having CMV reactivation (having the infection again) is 50-60%. You will be given anti-viral drugs that may include ganciclovir, foscarnet, and acyclovir to try to prevent CMV reactivation. Ganciclovir, and less commonly acyclovir, can suppress bone marrow growth and damage the kidneys. Foscarnet can also damage the kidneys but usually doesn't affect blood counts. Your blood counts and blood tests of kidney function will be watched for these side effects. Also, frequent blood tests will be done to look for CMV reactivation. If there is evidence of reactivation, additional treatment will be given to you. Ganciclovir and/or foscarnet will be given. If CMV reactivation progresses to disease, it may be fatal.  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 12 of 22 2. Adenovirus **infection:** A relatively common complication in BMT patients is adenovirus infection. Adenovirus is a common infection in people in general that causes a cold or stomach flu. During the transplant period, adenovirus that is already in the body can become reactivated (referred to as infection) and result in disease of the lungs (pneumonia), liver, and/or intestines (vomiting, diarrhea). The risk of having adenovirus reactivation (having the infection again) is 50%. Frequent blood tests will be done to look for adenovirus reactivation. You will be given an anti-viral drug named cidofovir if adenovirus reactivation occurs. This usually prevents adenovirus disease. If adenovirus reactivation progresses to disease, it may be fatal. Cidofovir can suppress bone marrow growth and damage the kidneys. Your blood counts and blood tests of kidney function will be watched for these side effects and the cidofovir dose will be adjusted if necessary.  
3. **Prolonged immunodeficiency:** Under normal circumstances, when using a matched related donor it usually takes about 3 months for the immune system to start functioning.  
With a CD34+selected, T-cell depleted PBSC transplant, this may be delayed to 6-12 months. During the time that you are unable to fight infection, there will be an increased risk of infections that could be fatal. You will likely receive gammaglobulin (antibodies purified from donor blood that help to protect the body against bacterial and viral infections) infusion after transplant. It will be given to decrease the risk of infection until your immune system can make antibodies. It is possible that you will require monthly infusions of gammaglobulin for a long time after transplant (more than 6 months to 1 year). There is a small chance that you could require IV gammaglobulin for the rest of your life.  
1. **Graft failure:** There is a chance that the donor PBSC will not grow after transplant or will be rejected by your immune system. The graft failure or rejection rate is approximately 10% but could be as high as 20%. If graft failure occurs, it is possible that there will be not be enough platelets, white blood cells and red blood cells to prevent bleeding and infection and if uncorrected this could be fatal. If graft failure occurs, then re-transplantation using the same or another donor would be necessary for survival, which would require further giving of chemotherapy.  
2. **Graft versus Host Disease (GVHD):** Graft-versus-host disease (GVHD) is a reaction in which the donor T cells attack the recipient's body. It ranges from a mild skin disorder to severe involvement of skin, liver, and/or gut and it may be fatal for some patients. Many  
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(20-60%) transplant recipients who receive bone marrow or PBSC that have not had T cell removed experience acute and/or chronic GVHD. About 20-25% of patients will have severe GVHD, which can be fatal. The removal of T cells used in this study significantly reduces the chances of developing GVHD. The chance of acute and chronic GVHD occurring is about 20-25% for each. There is a small chance (less than 5%) of severe, possibly fatal, GVHD. Signs of GVHD include: A. Acute GVHD generally occurs within 1 - 4 weeks of receiving donor T cells, but it may occur after a longer period of time. Acute GVHD can lead to:
Skin damage - sunburn-like rash, peeling, burn Intestinal damage - diarrhea, nausea, vomiting, stomach pain, bleeding Liver damage - yellow skin, decreased liver function Severe acute GVHD can also uncommonly affect the lungs. B. Chronic GVHD usually occurs more than 100 days after receiving donor T cells, but may occur earlier. Chronic GVHD can be life-threatening. It can also result in you not feeling well and being able to do normal activities, sometimes for a long time. Chronic GVHD can affect many parts of the body. The most commonly affected areas are the skin, mouth, liver, and eyes. Chronic GVHD can cause:
Skin rash, skin thickening, dark color of skin, loss of color of the skin, loss of hair, thin hair, and gray hair Dry mouth and eyes, mouth sores Joint pain and stiffening, inability to move joints Nausea, vomiting, diarrhea, abdominal cramps, weight loss, decreased appetite, inability to absorb medications or food, difficulty swallowing Liver inflammation Lung damage, cough, shortness of breath, wheezing Breakdown of red blood cells and platelets 3. **HHV-6 infection:** Human Herpes Virus 6 (HHV-6) is a common infection in the first several years of life. Like CMV, it remains in a quiet state in the body. During the transplant period, HHV-6 can become reactivated and cause GVHD or graft rejection. To prevent this, you will be given an anti-viral drug called foscarnet from the time of transplant until discharge. Foscarnet can decrease kidney function and cause loss of salts from your blood. These effects are usually temporary and go away when the drug is stopped.  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 14 of 22 4. **Epstein-Barr virus (EBV) infection:** EBV is a common infection in the first several years of life. About half of all people have been infected and EBV remains in a quiet state in the body. When the immune system is very weak, EBV can reactivate and cause B cells (a type of white blood cell) to multiply. This process, known as post-transplant lymphoproliferative disease (PTLD), can cause fevers, swollen lymph nodes (organ that has white blood cells) and tonsils (part of the lymph system), and difficulty breathing. It can also become lymphoma, or a cancer of lymph nodes. If treated early, patients often do well. However, PTLD can progress and be fatal. We will monitor your blood for EBV reactivation and treat you for reactivation or early PTLD. The treatment is typically a drug called Rituximab. Rituximab can cause fever and chills. It will also slow the ability of your immune system to make antibodies.  
5. **Relapse of leukemia:** In patients with leukemia who receive a matched related donor transplant, the chances of leukemia recurring (returning) after transplant varies from 1050% depending upon the type and stage of leukemia. With T-cell depleted transplants, the relapse (cancer coming back) rate may be higher, especially for patients who lack certain immune system mismatches with the donor.  
6. **Inadequate number of donor PBSC:** There is a chance that not enough PBSC will be collected from your donor. The chance of not having enough PBSC is very small if a mismatched related donor is used. If this happens, PBSC will be collected from another donor. If an unrelated donor is going to be used, your transplant doctor will decide if you can receive the transplant without removing the T cells if not enough PBSC are collected to remove the T cells. If this is the case, you will get PBSC with the T cells that were collected if not enough PBSC are collected. If your transplant doctor decides that the T cells must be removed, then you will only be eligible to be on study if your weight is:
37 kg (about 81 lbs) if your donor's PBSC are collected in 1 day 26 kg (about 57 lbs) if your donor's PBSC are collected in 2 days The difference in weight is because more PBSC are collected with a 1 day collection. The choice of 1 or 2 days of collection is up to the donor and PBSC collection center. We will always request a 1 day collection. If not enough PBSC are collected and you need to have the T cell removed, then PBSC will be collected from another donor.  
7. **Thrombotic microangiopathy (TMA):** Uncommonly, patients may develop very small blood clots. The clots usually occur in the kidneys but might occur elsewhere. TMA can occur in any type of transplant. TMA usually occurs in patients with viral or fungal  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 15 of 22 infections and therefore may be more common when T cells are removed. TMA can result in decreased kidney function, high blood pressure, and lower red blood cell and platelet counts. There are treatments for this problem but it can be life-threatening.  
1. **Contamination of stem cells:** It is possible that an infection might be introduced into your body by the infusion of the processed stem cells. The stem cells will be tested before giving them to you in order to greatly lessen the chance of this happening.  
2. Reaction to the chemicals in the stem cell **infusion:** There is a risk of a reaction to small amounts of the antibody-iron dextran chemical that remains in the preparation of stem cells that is injected into you. Antibodies made in mice have been used to treat cancer and organ rejection for many years. While these typically cause flu-like symptoms, the amount of antibody that will be infused into you is less than 1% (1/100) of that used for cancer treatment. The iron dextran mixture is also used to treat anemia in much higher doses (1000 times higher) than the dose you will receive with the stem cell infusion. For these reasons it is believed that the likelihood of a reaction is extremely small (less than 1%).

The skin will darken after getting thiotepa and this can take months to return to normal. A
skin rash and breakdown of the skin may occur in areas where the skin rubs together, that is, the neck, arm pits and in the groin. These may be painful and can become infected. With preventive measures, these are usually prevented.  
Damage to the liver and lungs  
Sleepiness, forgetfulness, confusion, hallucinations (seeing things that aren't there), and seizures (usually just in patients that have had radiation to the brain before transplant)

Fevers and shaking chills during or soon after it is given and, in 25% of patients, an allergic type rash. These signs and symptoms go away after the rATG has been given.  
Delay in immune system recovery (ability to fight infections)  
There is a slight (less than 1%) chance of a severe allergic reaction (anaphylaxis) to rATG
that could result in severe symptoms involving difficulty breathing and heart failure. Usually, these symptoms can be treated, and they go away with stopping the drug, but, in their most severe form, these reactions can be fatal.  
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Water retention Hiccups Nasal congestion, runny nose, sneezing Liver damage  
Damage to the lining of the bladder leading to blood in the urine (rare when a drug to protect the bladder is given with the cyclophosphamide)
Damage to the lungs and heart Irregular heart beat Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 10 of 22

Fever Chills Nausea Weakness Headache Low blood pressure Itching Rash Bronchospasm (an abnormal narrowing of the windpipe which can be associated with coughing and wheezing)
Abdominal pain Vomiting Anemia Achy joints and muscles Dizziness Congestion Low blood counts.  
Suppression of certain parts of your immune system resulting in a greater risk of infections  
Angioedema (a condition characterized by an itchy rash and swelling of areas of the skin and mucous membranes [the lining of some of the organs], much like an allergic reaction)
Severe reactivation of hepatitis B infection and liver failure Progressive multifocal encephalopathy (Most people, as children, have been infected with a virus called JC virus. In most cases this virus does not cause any problems, but in very rare cases of patients who receive rituximab, this virus can become active again, leading to severe damage to the brain tissue.  
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The chance of a child dying from a T cell-depleted transplant-related complication is approximately 10-30%. This is similar to the risk with an unrelated donor transplant (bone marrow, PBSC, or cord blood) that has not been T cell-depleted. The chance of dying depends upon a number of factors including the transplant patient's past history, the disease for which the transplant is being performed, and the patient's state of health at the time of transplant. Risks that are more or less common with T cell-depleted transplants are:

Increased risk of infection from viruses and other germs  
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Inflammation of the liver  
Damage to the nerves causing tingling or pain and/or weakness At higher doses than used in this study, has been associated with brain damage, causing blindness, confusion and coma (unconsciousness)
Disorders of the immune system causing damage to red cell or platelets

1. **Cytomegalovirus (CMV) infection:** A relatively common complication in BMT patients is CMV infection. CMV is a common infection in the first several years of life. About half of all people have been infected and CMV remains in a quiet state in the body. CMV can be also be passed in blood and bone marrow infusions. The chance of passing CMV
is decreased by the CD34+selection process. During the transplant period, CMV that is already in the body can become reactivated (referred to as infection) and result in disease of the lungs (pneumonia), eyes, brain, liver, and/or intestines. In recipients of T cell depleted transplants who have previously been infected, the risk of having CMV reactivation (having the infection again) is 50-60%. You will be given anti-viral drugs that may include ganciclovir, foscarnet, and acyclovir to try to prevent CMV reactivation. Ganciclovir, and less commonly acyclovir, can suppress bone marrow growth and damage the kidneys. Foscarnet can also damage the kidneys but usually doesn't affect blood counts. Your blood counts and blood tests of kidney function will be watched for these side effects. Also, frequent blood tests will be done to look for CMV reactivation. If there is evidence of reactivation, additional treatment will be given to you. Ganciclovir and/or foscarnet will be given. If CMV reactivation progresses to disease, it may be fatal.  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 12 of 22 2. Adenovirus **infection:** A relatively common complication in BMT patients is adenovirus infection. Adenovirus is a common infection in people in general that causes a cold or stomach flu. During the transplant period, adenovirus that is already in the body can become reactivated (referred to as infection) and result in disease of the lungs (pneumonia), liver, and/or intestines (vomiting, diarrhea). The risk of having adenovirus reactivation (having the infection again) is 50%. Frequent blood tests will be done to look for adenovirus reactivation. You will be given an anti-viral drug named cidofovir if adenovirus reactivation occurs. This usually prevents adenovirus disease. If adenovirus reactivation progresses to disease, it may be fatal. Cidofovir can suppress bone marrow growth and damage the kidneys. Your blood counts and blood tests of kidney function will be watched for these side effects and the cidofovir dose will be adjusted if necessary.  
3. **Prolonged immunodeficiency:** Under normal circumstances, when using a matched related donor it usually takes about 3 months for the immune system to start functioning.  
With a CD34+selected, T-cell depleted PBSC transplant, this may be delayed to 6-12 months. During the time that you are unable to fight infection, there will be an increased risk of infections that could be fatal. You will likely receive gammaglobulin (antibodies purified from donor blood that help to protect the body against bacterial and viral infections) infusion after transplant. It will be given to decrease the risk of infection until your immune system can make antibodies. It is possible that you will require monthly infusions of gammaglobulin for a long time after transplant (more than 6 months to 1 year). There is a small chance that you could require IV gammaglobulin for the rest of your life.  
1. **Graft failure:** There is a chance that the donor PBSC will not grow after transplant or will be rejected by your immune system. The graft failure or rejection rate is approximately 10% but could be as high as 20%. If graft failure occurs, it is possible that there will be not be enough platelets, white blood cells and red blood cells to prevent bleeding and infection and if uncorrected this could be fatal. If graft failure occurs, then re-transplantation using the same or another donor would be necessary for survival, which would require further giving of chemotherapy.  
2. **Graft versus Host Disease (GVHD):** Graft-versus-host disease (GVHD) is a reaction in which the donor T cells attack the recipient's body. It ranges from a mild skin disorder to severe involvement of skin, liver, and/or gut and it may be fatal for some patients. Many  
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(20-60%) transplant recipients who receive bone marrow or PBSC that have not had T cell removed experience acute and/or chronic GVHD. About 20-25% of patients will have severe GVHD, which can be fatal. The removal of T cells used in this study significantly reduces the chances of developing GVHD. The chance of acute and chronic GVHD occurring is about 20-25% for each. There is a small chance (less than 5%) of severe, possibly fatal, GVHD. Signs of GVHD include: A. Acute GVHD generally occurs within 1 - 4 weeks of receiving donor T cells, but it may occur after a longer period of time. Acute GVHD can lead to:
Skin damage - sunburn-like rash, peeling, burn Intestinal damage - diarrhea, nausea, vomiting, stomach pain, bleeding Liver damage - yellow skin, decreased liver function Severe acute GVHD can also uncommonly affect the lungs. B. Chronic GVHD usually occurs more than 100 days after receiving donor T cells, but may occur earlier. Chronic GVHD can be life-threatening. It can also result in you not feeling well and being able to do normal activities, sometimes for a long time. Chronic GVHD can affect many parts of the body. The most commonly affected areas are the skin, mouth, liver, and eyes. Chronic GVHD can cause:
Skin rash, skin thickening, dark color of skin, loss of color of the skin, loss of hair, thin hair, and gray hair Dry mouth and eyes, mouth sores Joint pain and stiffening, inability to move joints Nausea, vomiting, diarrhea, abdominal cramps, weight loss, decreased appetite, inability to absorb medications or food, difficulty swallowing Liver inflammation Lung damage, cough, shortness of breath, wheezing Breakdown of red blood cells and platelets 3. **HHV-6 infection:** Human Herpes Virus 6 (HHV-6) is a common infection in the first several years of life. Like CMV, it remains in a quiet state in the body. During the transplant period, HHV-6 can become reactivated and cause GVHD or graft rejection. To prevent this, you will be given an anti-viral drug called foscarnet from the time of transplant until discharge. Foscarnet can decrease kidney function and cause loss of salts from your blood. These effects are usually temporary and go away when the drug is stopped.  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 14 of 22 4. **Epstein-Barr virus (EBV) infection:** EBV is a common infection in the first several years of life. About half of all people have been infected and EBV remains in a quiet state in the body. When the immune system is very weak, EBV can reactivate and cause B cells (a type of white blood cell) to multiply. This process, known as post-transplant lymphoproliferative disease (PTLD), can cause fevers, swollen lymph nodes (organ that has white blood cells) and tonsils (part of the lymph system), and difficulty breathing. It can also become lymphoma, or a cancer of lymph nodes. If treated early, patients often do well. However, PTLD can progress and be fatal. We will monitor your blood for EBV reactivation and treat you for reactivation or early PTLD. The treatment is typically a drug called Rituximab. Rituximab can cause fever and chills. It will also slow the ability of your immune system to make antibodies.  
5. **Relapse of leukemia:** In patients with leukemia who receive a matched related donor transplant, the chances of leukemia recurring (returning) after transplant varies from 1050% depending upon the type and stage of leukemia. With T-cell depleted transplants, the relapse (cancer coming back) rate may be higher, especially for patients who lack certain immune system mismatches with the donor.  
6. **Inadequate number of donor PBSC:** There is a chance that not enough PBSC will be collected from your donor. The chance of not having enough PBSC is very small if a mismatched related donor is used. If this happens, PBSC will be collected from another donor. If an unrelated donor is going to be used, your transplant doctor will decide if you can receive the transplant without removing the T cells if not enough PBSC are collected to remove the T cells. If this is the case, you will get PBSC with the T cells that were collected if not enough PBSC are collected. If your transplant doctor decides that the T cells must be removed, then you will only be eligible to be on study if your weight is:
37 kg (about 81 lbs) if your donor's PBSC are collected in 1 day 26 kg (about 57 lbs) if your donor's PBSC are collected in 2 days The difference in weight is because more PBSC are collected with a 1 day collection. The choice of 1 or 2 days of collection is up to the donor and PBSC collection center. We will always request a 1 day collection. If not enough PBSC are collected and you need to have the T cell removed, then PBSC will be collected from another donor.  
7. **Thrombotic microangiopathy (TMA):** Uncommonly, patients may develop very small blood clots. The clots usually occur in the kidneys but might occur elsewhere. TMA can occur in any type of transplant. TMA usually occurs in patients with viral or fungal  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 15 of 22 infections and therefore may be more common when T cells are removed. TMA can result in decreased kidney function, high blood pressure, and lower red blood cell and platelet counts. There are treatments for this problem but it can be life-threatening.  
1. **Contamination of stem cells:** It is possible that an infection might be introduced into your body by the infusion of the processed stem cells. The stem cells will be tested before giving them to you in order to greatly lessen the chance of this happening.  
2. Reaction to the chemicals in the stem cell **infusion:** There is a risk of a reaction to small amounts of the antibody-iron dextran chemical that remains in the preparation of stem cells that is injected into you. Antibodies made in mice have been used to treat cancer and organ rejection for many years. While these typically cause flu-like symptoms, the amount of antibody that will be infused into you is less than 1% (1/100) of that used for cancer treatment. The iron dextran mixture is also used to treat anemia in much higher doses (1000 times higher) than the dose you will receive with the stem cell infusion. For these reasons it is believed that the likelihood of a reaction is extremely small (less than 1%).

1. **Transfusion complications:** All blood products (platelets and red blood cell transfusions and gammagobulin) are handled as carefully as possible and are screened for compatibility with you as well as for infection with the hepatitis viruses and HIV, the virus that causes AIDS. However, there remains a very small chance that a reaction could occur or that infection(s) could be passed on to you.

The risk of anesthesia for the placement of a central line (catheter) includes an unforeseen reaction to a medication that may be minor or result in death. The risk of dying from anesthesia in a healthy individual is less than 1 in 20,000. Minor symptoms following anesthesia include sore throat, nausea and vomiting.

Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 16 of 22 The treatment on this study can affect an unborn child. You should not become pregnant or breastfeed your baby while being treated on this study. If you are sexually active and are able to become pregnant or father a child, you and your partner must use birth control or you must not have sex. The study doctor will talk to you about good methods to avoid pregnancy while you are being treated on this study. Your doctor will talk to you about the length of time you need to avoid pregnancy or not have sex. If you have questions about this, please ask your doctor. If you or your partner becomes pregnant during the research study, please tell the study doctor and your doctor immediately.
Clinical trial: NCT00968864
Section: Procedures
Subsections: How The Study Works

During the course of this study, the following will occur:  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 3 of 22 1. You will have several blood tests (requiring approximately 20 ml [4 teaspoons] of blood) to check kidney and liver function as well as past exposure to certain viruses including cytomegalovirus (CMV), hepatitis, and human immunodeficiency virus (HIV). In addition, you will have pulmonary (lungs) function tests and an electrocardiogram (EKG) and echocardiogram (to check the heart). You will also have a dental (teeth) exam. Some of these tests may be done locally by your referring doctor or at CMC/LCH. As part of this study, you will be tested for HIV. You will be notified of the results of this testing and counseled as to the meaning of the results, whether they are positive or negative. If the test indicates that you are infected with HIV, you will receive additional counseling about the significance of your care and possible risks to other people. We are required to report all positive results to the North Carolina State Board of Health. The test results will be kept confidential to the extent permissible under the law. If you do not want to be tested for HIV, then you should not agree to participate in this study. 2. Approximately 2 ounces of blood will be drawn from you, your parents, and your brothers and sisters to determine tissue types. This typing will help choose the best donor for you. 3. If you don't already have one, a central intravenous (through a vein, IV) catheter (small tube) that contains two lumens (openings) will be inserted into a large vein in your chest under sedation or general anesthesia. This catheter is essential for giving drugs, blood products and fluids, drawing blood and providing nutritional support. 4. The donor peripheral blood stem cells (PBSC) will be collected from your donor and will be shipped to a Stem Cell Processing laboratory at the University of California-San Francisco to be processed using the CliniMACS® device. After processing, the PBSC will be frozen. The PBSC will be shipped to Levine Children's Hospital when needed. The PBSC will be thawed and infused (given) into you on Day 0 of transplant. 5. Following admission to the BMT unit at LCH, you will receive a patient-specific conditioning regimen that may include total body irradiation (TBI), fludarabine, thiotepa, rabbit antithymocyte globulin (Thymoglobulin®, rATG), melphalan, busulfan, cyclophosphamide, and/or rituximab. These drugs and TBI are given to kill any cancer cells, destroy your own bone marrow cells and to prevent rejection of the donor stem cells. If your conditioning regimen includes TBI, you will meet with the Radiation Therapy specialists to discuss this procedure in detail and they will answer any questions you have. Patients who do not receive TBI and have a  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 4 of 22 history of Epstein-Barr virus (EBV) infection will receive a dose of Rituximab on Day -1 to try to prevent complications due to EBV (see below in RISKS section).  
a. The standard regimen will be Total Body Irradiation (TBI) followed by chemotherapy.  
The schedule of therapy is as follows:
Day -9 TBI Day -8 TBI Day -7 TBI Day -6 Thiotepa and fludarabine Day -5 Fludarabine and rabbit ATG Day -4 Fludarabine and rabbit ATG Day -3 Fludarabine and rabbit ATG Day -2 Fludarabine and rabbit ATG Day -1 Rest Day 0 Transplant The day listed above is the day prior to the stem cell transplant. For example, Day -9 refers to 9 days before the transplant.  
b. For patients who have a contraindication to TBI or a non-malignant disease, a Chemotherapy Alone Regimen may be used. The schedule of therapy is:
Day -7 Melphalan Day -6 Thiotepa and fludarabine Day -5 Fludarabine and rabbit ATG Day -4 Fludarabine and rabbit ATG Day -3 Fludarabine and rabbit ATG Day -2 Fludarabine and rabbit ATG Day -1 Rituximab (if indicated) Day 0 Transplant c. Depending on your disease, the conditioning therapy may be modified to include other chemotherapy drugs (melphalan, busulfan, and/or cyclophosphamide), with or  
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without TBI. If you require an alternate conditioning therapy, you will have the following schedule for your therapy (the drugs given will depend on your disease):  
  
6. It usually takes 2-3 weeks for the donor cells to grow and begin producing enough red cells, white cells and platelets. During that time you will be in protective isolation (steps will be taken to prevent exposure to infection) in your blood and marrow transplantation (BMT) room. Once your neutrophil (a white blood cell that fights infections) count is greater than 500, your transfusion requirements are no more than every other day, and there is no evidence of infection, you will be discharged from the hospital. Depending on how far from LCH you live, you may need to stay locally for the first 100 days after transplant. The average hospital stay for a recipient of this type of transplant is 4-5 weeks. 7. You will be given the option to participate in a companion study to help your immune system recover more quickly if you meet the study eligibility criteria after transplant. You will sign a separate consent for this companion study. 8. Following discharge, you will be seen in the BMT Clinic at LCH at least weekly until 100 days after transplant, at least monthly until 1 year after transplant (but sometimes still weekly to every other week), every three months for the next year, every 6 months for the following year and yearly thereafter until 5 years post transplant. At those visits, blood (2-4 tsp) may be taken to monitor engraftment (presence of donor cells) and recovery of your immune system (ability to fight infection). You will also have routine BMT follow-up including blood tests to check the function of your kidneys and liver and yearly evaluation of the lungs (pulmonary function testing) and heart (ECG and echocardiogram).  
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Clinical trial: NCT00968864
Section: Withdrawal from Study
Subsections: Withdrawal

Your participation in this study is completely voluntary. You should feel under no pressure to be in the study. If you decide not to be in the study, it will not in any way harm your relations with your doctors or with Carolinas HealthCare System. You are free to stop being in the study if you  
Prot. Ver. \#1.9: 1/30/2015 Revised: 1/30/2015 Expires: 03/01/2017 Page 18 of 22 change your mind after entering it. This would not harm your relations with your doctors or Carolinas HealthCare System. However, once intensive chemotherapy and total body irradiation is given to you, infusion of stem cells is absolutely necessary for survival since the drugs and total body irradiation will destroy the marrow cells in your body. The investigators or sponsor also have the right to stop your participation at any time. This could be because you have had an unexpected reaction, have failed to follow instructions, or because the entire study has been stopped. We will tell you about new medical findings that may affect your willingness to continue in the study.