Bone Marrow Transplantation, Hemoglobinopathies, SCALLOP
Bone Marrow Transplantation, Hemoglobinopathies, SCALLOP
Patients are being asked to participate in this study because they have severe sickle cell
 anemia (SCD) with or without the beta thalassemia trait. Sickle cell anemia is an illness
 where the red blood cells change shape and can clog up blood vessels. This keeps the body
 from getting the oxygen it needs. Thalassemia is when the body does not make enough
 hemoglobin, something that helps the oxygen get to the places it needs to go in the body. The
 patient may or may not need to get regular blood transfusions (getting more blood) to improve
 their quality of life (feel better) and prevent organ damage (problems with the brain, heart,
 lung, kidney, and gonad, for example.). The transfusions can also cause problems, including
 iron overload (too much iron in the blood), which can be fatal (patients can die) without
 regular deferoxamine shots. Even with the best usual treatments, people with thalassemia or
 SCD die sooner. There is no proven cure.

 We would like to treat patients using bone marrow transplantation, a treatment that has been
 used for people with SCD. The transplant uses healthy "matched" bone marrow. This comes from
 a brother or sister who does not have sickle cell disease or severe thalassemia. If the
 treatment works, the sickle cell disease or thalassemia may be cured. This treatment has been
 used to treat patients with sickle cell disease or thalassemia. It has worked in most cases.
 We hope, but cannot promise, that the transplanted marrow will make healthy cells, and
 patients will not have sickle cell disease or severe thalassemia anymore.

 We do not know what effect this treatment will have on the damage that has already been done
 by the disease. Finding that out is the main reason for this study. Currently, very little
 has been reported about organ function after bone marrow transplants in patients with sickle
 cell anemia.
Prior to any bone marrow transplant, we will need patients to:

 -  Answer questions about their medical history;

 -  Undergo 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 the patient has 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 (GVHD);
 methylprednisolone will be given after the bone marrow infusion if the patient develops GVHD.
 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 200 mL (about 13 tablespoons) of blood will be collected from the
 patient during the entire study.

 After 4 months, if the patient's 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/1.73
 M^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.