Bone Marrow Transplantation, Hemoglobinopathies, SCALLOP

Prior to any bone marrow transplant, we will need the patients to:

- answer questions about their medical history

- have a physical examination

- have tests done to see how well the lungs are working

- have a chest x-ray

- have an EKG to look at the heart

- have an MRI & MRA (Magnetic Resonance Angiography, which looks at the blood vessels and
the blood flowing through them). These 2 tests will look to see if patients have had
any strokes.

- have a PET scan to look at the head and body

- have a liver biopsy to determine if the liver has been damaged (which can happen from
iron overload that happens after many transfusions). Too much liver damage would mean a
transplant cannot be done.

For the liver biopsy, the skin is numbed with medicine, and a special needle goes into the
liver. The needle removes a very small piece of the liver (tissue). The tissue is taken and
examined.

Also, about 30 cc (2 tablespoons) of blood will be drawn to test the blood for viruses,
including HIV (the virus that causes AIDS). If the HIV test is positive, a transplant will
not be done because it would be too dangerous for the patient.

At least 2 weeks before the bone marrow infusion, the patient will be immunized with Prevnar
7. Prevnar 7 is a vaccine that is used in children to protect against some types of bacteria
called Streptococcus pneumoniae, which can cause the lung infection called pneumonia. People
with Sickle Cell anemia are at a higher risk of dying from an infection from this type of
bacteria. Although children are regularly given the Prevnar 7 vaccine, it is not common to
test a child's immune response to the vaccine. In this study, we will check the immune
system's response to the vaccine by drawing an extra 3 ml (less than 1 teaspoon) of blood 3
weeks after the patient gets the Prevnar 7 vaccine.

Just before the bone marrow transplant, we must kill the cells in the bone marrow that make
the abnormal red blood cells found in patients with severe thalassemia or sickle cell
disease. We will do this by using 3 drugs: busulfan, cyclophosphamide, and CAMPATH-1H.
CAMPATH-1H is used to prevent the body from rejecting or refusing to let the donor blood
cells grow in the body. MESNA is given with the cyclophosphamide to prevent kidney damage.
Methotrexate and cyclosporin are also given to prevent Graft Versus Host Disease;
methylprednisolone will be given after the bone marrow infusion if the patient develops
Graft Versus Host Disease. A drug will also be given to prevent seizures (either dilantin or
lorazepam).

Graft Versus Host Disease (GVHD) is a possible side effect of the transplant. In GVHD, some
cells in the donor marrow attack cells in the patient's body. This causes skin, liver, and
bowel problems and may damage other parts of the body. Often, these problems are fairly
mild, but they can be severe or even cause death. Severe GVHD is likely to occur in about
10% of patients.

After the patient gets the drug treatment, they will be given bone marrow from a brother or
sister who has healthy bone marrow that matches the patients. The healthy bone marrow will
be put into a vein (given IV) in the same way that blood transfusions are given. The marrow
cells then travel to the right places in the body, where they should grow and make new
normal blood cells.

This is the treatment schedule:

Protocol day & Treatment 14 or more days before the bone marrow infusion -- Prevnar 7
vaccine

10 days before the bone marrow infusion -- Begin Dilantin or Lorazepam (to prevent seizures)

9 days before the bone marrow infusion -- Busulfan

8 days before the bone marrow infusion -- Busulfan

7 days before the bone marrow infusion -- Busulfan

6 days before the bone marrow infusion -- Busulfan

5 days before the bone marrow infusion -- Campath 1H, Cyclophosphamide, and MESNA

4 days before the bone marrow infusion -- Campath 1H, Cyclophosphamide, and MESNA

3 days before the bone marrow infusion -- Campath 1H, Cyclophosphamide, and MESNA

2 days before the bone marrow infusion -- Campath 1H, Cyclophosphamide, MESNA, and
cyclosporin

1 day before the bone marrow infusion -- DAY OF REST

Day "0" -- bone marrow infusion given

1 day after the bone marrow infusion -- Methotrexate

3 days after the bone marrow infusion -- Methotrexate

6 days after the bone marrow infusion -- Methotrexate

11 days after the bone marrow infusion -- Methotrexate

After transplant, Filgrastrim, a growth hormone for the bone marrow, may be given
intravenously (through a vein), if medically necessary.

Sometimes, the donor's bone marrow does not grow. Then, the patient would be without working
bone marrow cells. So that we will be ready to treat this problem if it happens, we will
take bone marrow from the hip bone before the patient gets the drug treatment. The patient
will be asleep (sedated) when the marrow is taken, and they will be given medicine for any
pain they have afterwards. This bone marrow will be frozen and stored or preserved. If the
donor bone marrow does not grow, we will thaw the stored marrow and put it back into the
body. This stored bone marrow should grow and produce working blood cells. If the stored
bone marrow must be given back, the disease will not be cured.

To tell whether the transplant has worked or "engrafted", we will take samples of bone
marrow (bone marrow aspirate). We will do this 3 weeks after the transplant to make sure the
new cells are beginning to grow. We will take another marrow sample at 3 months after the
transplant. We want to make sure the new cells are still growing. This test will take about
30 to 45 minutes. Because this test is painful, the patient will be given pain medicine
before, during, and after the test.

The patient will need to be in the hospital for at least 3 weeks after the transplant to
make sure the transplant has engrafted. We will do several tests (of the lung, kidney, and
liver) before and after the bone marrow transplant. We want to find out how much the
treatment has helped the patient and how much it might help other patients. Most tests will
be done every week for 4 months and at each visit to the hospital. Also, we will be looking
at the immune function. To do this, we will take about 8 ml (less than 2 teaspoonful) at 6
months, 1 year, and 2 years after the transplant. When possible, we will take the blood from
an IV line that the patient already has. However, at times we will have to draw the blood
with another needle stick. A total amount of 200ml (about 13 tablespoons) of blood will be
collected from the patient during the entire study.

After 4 months--if the patients health is good--they will not need to come to the hospital
so often. The visits to the doctor should be more like they were before the bone marrow
transplant. Since problems may happen months after the transplant and this is a new way to
treat sickle cell disease and thalassemia the patient will need to have exams and blood
tests done every few months during the first and second years after their transplant. After
that, if all is well, the patient will need to be examined and have blood tests 4 times a
year.

Inclusion Criteria:

1. Patients with a related HLA genotype identical donor and hemoglobin SS, hemoglobin SC,
or hemoglobin Sb0/+ and at least one of the following conditions:

1. previous central nervous system vaso-occlusive episode with or without residual
neurologic findings, or has an abnormal transcranial doppler exam without neurologic
findings, or abnormal MRI/MRA of the brain with or without neurologic findings;

2. frequent painful vaso-occlusive episodes which significantly interfere with normal
life activities and which necessitate chronic transfusion therapy;

3. recurrent SCD chest syndrome events, which necessitate chronic transfusion therapy;

4. severe anemia which prevents acceptable quality of life and necessitates chronic
transfusion therapy;

5. any of the above symptoms in which the patient is not undergoing chronic transfusion
therapy;

6. The patient is undergoing chronic transfusion therapy for symptoms other than those
listed and which significantly interferes with normal life activities;

7. Failed hydroxyurea therapy;

8. Indication of pulmonary hypertension on 2 separate echocardiogram examinations;

9. Patients who plan to return to resource poor areas/countries.

2. Between the ages of birth and 40 years.

3. Women of childbearing potential must have a negative pregnancy test.

EXCLUSION CRITERIA:

1. Patient with biopsy proven chronic active hepatitis or fibrosis with portal
bridging.

2. Patient with SCD chronic lung disease > stage 3 (see Appendix 1). 3. Patient
with severe renal dysfunction defined as creatinine clearance < 40
ml/min/1.73M^2.

4. Patient with severe cardiac dysfunction defined as echocardiogram shortening
fraction < 25% or NYHA class III or IV.

5. Patient with HIV infection.

6. Patient with unspecified chronic toxicity serious enough to detrimentally affect
the patient's capacity to tolerate bone marrow transplantation.

7. Patient or patient's guardian(s) unable to understand the nature and risks
inherent in the BMT process.

8 Pregnant/lactating women and those unwilling to use acceptable contraception will
be excluded.

9. Patient or patient's guardian who have not signed an informed consent.

NOTE: Patients who would be excluded from the protocol strictly for laboratory
abnormalities can be included at the investigator's discretion after approval by the
CAGT Protocol Review Committee and the FDA reviewer.