Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601)

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 bone marrow 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 bone marrow 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 bone marrow 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 bone marrow transplant. After the transplant, participants will receive immunosuppression medications for at least 6 months to prevent graft-versus-host disease (GVHD), which may occur if the immune cells from the donated bone marrow attacks 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.

Eligibility Criteria:
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. Patients must have symptomatic SCD (genotype Hb SS, Hb SC, Sß° thalassemia or Sß+ thalassemia), AND have 1 or more of the following clinical complications:(i) Clinically significant neurologic event (stroke) or any neurologic deficit lasting more than 24 hours that is accompanied by an infarct on cerebral MRI; OR (ii) patients who have a Transcranial Doppler (TCD) velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement greater than 185 cm/sec by the imaging technique) measured at a minimum of 2 separate occasions one month or more apart; OR,
  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 3 or more severe pain events per year in the 2 years before study entry
* Lansky/Karnofsky performance score greater than or equal to 40
* Patients must have an unrelated adult bone marrow donor who is Human Leukocyte Antigen (HLA)-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
* Patients with adequate physical function: a)Cardiac: Left ventricular ejection fraction (LVEF) greater than 40%, or LV shortening fraction greater than 26%; b) Pulmonary: Pulse oxymetry with a baseline O2 saturation of greater than or equal to 85% is required for all patients, Carbon Monoxide Diffusing Capacity (DLCO) greater than 40% (corrected for hemoglobin) for patients in whom pulmonary function testing can be performed; c) Renal: Serum creatinine less than or equal to 1.5 x upper limit of normal for age and glomerular filtration rate (GFR) greater than 100 mL/min/1.73 m. For patients older than or equal to 16 years of age, GFR should be greater than 70 mL/min/1.73 m\^2; d) Hepatic: Serum conjugated (direct) bilirubin less than 2x upper limit of normal for age as per local laboratory; alanine transaminase (ALT) and aspartate transaminase (AST) less than 5 times upper limit of normal as per local laboratory.
* If the patient has been receiving chronic transfusion therapy for more than or equal to 1 year AND has clinical evidence of iron overload (serum ferritin level of greater than 1000 ng/ml), a liver biopsy shall be obtained within 90 days of starting conditioning therapy (alemtuzumab). Histologic exam of the liver must document absence of bridging fibrosis or cirrhosis of the liver. In other cases, a liver biopsy is optional.
* Hemoglobin S (Hb S) level less than or equal to 45%, seven days prior to initiation of alemtuzumab

Exclusion Criteria:

* Evidence of uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen
* Pregnant or breastfeeding
* Patients with 8/8 HLA-matched family donors able to donate
* Seropositivity for HIV
* Prior allogeneic marrow or stem cell transplant
* Iron chelation must be discontinued more than or equal to 48 hours before initiating the conditioning regimen
* Hydroxyurea (if receiving this therapy) must be discontinued more than or equal to 48 hours before initiating the conditioning regimen