• Survival; neutrophil and platelet recovery; acute graft-versus-host disease (aGVHD); chronic GVHD (cGVHD); hepatic veno-occlusive disease; idiopathic pneumonia syndrome; and central nervous system toxicity [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]
• Neurocognitive dysfunction; cytomegalovirus, adenovirus, and fungal infections; Epstein Barr virus infection; chimerism; immune reconstitution; and quality of life [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]

• Survival; red blood cell, neutrophil, and platelet recovery; aGVHD; cGVHD; hepatic veno-occlusive disease; idiopathic pneumonia syndrome; and central nervous system toxicity [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]
• Neurocognitive dysfunction; cytomegalovirus, adenovirus and fungal infections; Epstein Barr virus post-transplant lymphoproliferative disease; chimerism; immune reconstitution; and quality of life [ Time Frame: Measured at Year 2 ] [ Designated as safety issue: Yes ]

Sickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease that can cause organ damage, stroke, and intense pain episodes. A blood stem cell transplant is a treatment option for someone with a severe form of the disease. Prior to undergoing a transplant, people typically receive a conditioning regimen of high doses of chemotherapy and other medications to prepare the body to accept the transplant. A conditioning regimen that uses lower doses of chemotherapy and medications may be safer for transplant recipients. This study will evaluate the safety and effectiveness of blood stem cell transplants, using either bone marrow or umbilical cord blood from unrelated donors, in children with severe SCD who receive a reduced intensity conditioning regimen prior to the transplant.

SCD is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain, also called "sickle cell crises." SCD is caused by an abnormal type of hemoglobin, which is a protein inside red blood cells that carries oxygen to vital organs, such as the brain, heart, lungs, and kidneys. Defective hemoglobin damages red blood cells. The damaged cells, in turn, can block blood flow in vessels and block oxygen and nutrients from reaching organs. For people with severe forms of SCD, one treatment option is a bone marrow transplant, which may correct the abnormal blood cell production problem. In most cases, bone marrow transplants are performed in people who have a healthy sibling with the same tissue type. If people do not have a sibling with the same tissue type, it is possible for them to receive a blood stem cell transplant from an unrelated donor through either a bone marrow transplant or an umbilical cord blood transplant.

Traditionally, people with SCD who are undergoing a bone marrow transplant receive high doses of chemotherapy and medications before the transplant as part of the conditioning regimen to prepare their immune system to accept the donor cells. Participants will experience fewer side effects with a reduced intensity conditioning regimen than with a more intense conditioning regimen. The purpose of this study is to determine the safety and effectiveness of blood stem cell transplants, using either bone marrow or umbilical cord blood from unrelated donors, in children with severe SCD who receive a reduced intensity conditioning regimen before the transplant. Specifically, researchers will evaluate whether the reduced intensity conditioning regimen is successful in allowing donor cells to settle and grow successfully, in preventing the production of SCD-damaged red blood cells, and in limiting SCD-related organ damage.

This study will enroll children with severe SCD who lack a sibling with the same tissue type who can serve as their donor. Participants will attend a study visit prior to the transplant to undergo a blood collection, neurocognitive testing to measure learning and brain function, and magnetic resonance angiogram (MRA) and magnetic resonance imaging (MRI) scans. Questionnaires to assess quality of life will also be completed. Twenty-two days before the transplant, participants will begin receiving a reduced intensity conditioning regimen of chemotherapy and medications to prepare them for the transplant. Eight days before the transplant, participants will be admitted to the hospital and will continue the conditioning regimen. Participants will then receive the umbilical cord blood or bone marrow transplant. After the transplant, participants will receive immunosuppression medications for at least 6 months to prevent graft-versus-host disease (GVHD), which occurs when the immune cells from the donated bone marrow or umbilical cord blood attack the body of the recipient. One week after the transplant, participants will receive granulocyte-colony-stimulating factor (G-CSF), which is a natural protein that increases the white blood cell count and helps protect the body against infections. Participants will receive G-CSF until their white blood cell level is normal again. Participants will remain in the hospital and be closely monitored for signs of infection or other complications until study researchers feel it is safe for them to return home.

After leaving the hospital, participants will attend study visits weekly during Weeks 1 to 8, at Day 60, weekly during Weeks 9 to 14, at Day 100, at Month 6, and at Years 1 and 2. At all study visits, a blood collection, medical history review, and physical exam will occur. In addition, at Day 100, Month 6, and Years 1 and 2, questionnaires to assess quality of life will be completed. At select visits the following procedures will also occur: lung function testing, heart function testing, MRA and MRI scans, and neurocognitive testing.

Inclusion Criteria:

• SCD (genotype hemoglobin SS disease [Hb SS], genotype hemoglobin SC disease [HbSC],sickle ß°[Sß°] thalassemia, or sickle ß^+[Sß^+]thalassemia) with one or more of the following:

  1. Clinically significant neurologic event (stroke) or any neurologic defect lasting more than 24 hours and accompanied by an infarct on cerebral MRI
  2. Minimum of two episodes of acute chest syndrome in the 2 years before study entry, defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales, or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures
  3. History of three or more severe pain events per year in the 2 years before study entry
• Lansky performance score greater than or equal to 40
• Hemoglobin S (Hb S) level less than or equal to 45%
• An 8 of 8 human leucocyte antigen (HLA)-A, -B, -C, and -DRB1 allele-matched unrelated bone marrow donor OR an unrelated umbilical cord blood (UCB) donor HLA-matched at 5 of 6 HLA-A, -B (low/intermediate resolution) and -DRB1 (high resolution molecular typing) loci
• The UCB unit must contain a pre-cryopreserved total nucleated cell dose (TNC) of at least 3.0 x 10^7 per kilogram.

Exclusion Criteria:

• Cirrhosis of the liver, with uncontrolled bacterial, viral, or fungal infection in the 1 month before study entry
• Seropositivity for HIV
• Patients with HLA-matched family donors
• Has undergone a prior hematopoietic stem cell transplant
• Pregnant or breastfeeding

• Blood and Marrow Transplant Clinical Trials Network
• National Cancer Institute (NCI)
• National Marrow Donor Program
• Sickle Cell Disease Clinical Research Network