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

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.

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