The purpose of this study is to determine and confirm the role of bone marrow
transplantation in the treatment of disorders of the red cell and hemoglobin including
sickle cell anemia, thalassemia and diamond blackfan anemia.
The trial proposed is a single armed phase II treatment protocol designed to examine the
engraftment,toxicity and graft-versus-host disease following a novel cytoreductive regimen
including cyclophosphamide and Busulfan for the treatment of patients with Severe Sickle
Cell Anemia,Thalassemia, and Diamond Blackfan Anemia using stem cell transplants derived
from HLA-genotypically identical siblings.
Patients will be conditioned for transplantation with cyclophosphamide (50 mg/kg/day x 4
days), and busulfan [(if < 4 years of age 1 mg/kg 4 times per day x 4 days), (if > 4 years
of age 0.8 mg/kg 4 times per day x 4 days)]. Patients will receive Methotrexate &
Cyclosporin-A for prophylaxis against GvHD and GCSF to promote engraftment.
The preferred source of stem cells from related HLA-matched related donors will be
unmodified bone marrow stem cells.
- Patients with severe HOMOZYGOUS SICKLE CELL ANEMIA or SICKLE/BETA THALASSEMIA
- Neurologic event (stroke or hemorrhage).
- Abnormal cerebral MRI scan and cerebral arteriogram or MRI angiographic study (MRA)
and impaired neuropsychologic testing.
- Recurrent acute chest syndrome (> 2 episodes)
- Stage I-II sickle chronic lung disease
- Sickle cell nephropathy (moderate or severe proteinuria or GFR 30-50% of predicted
- Major visual impairment in at least one eye with bilateral proliferative retinopathy.
- Osteonecrosis of multiple bones
- Chronic debilitating pain secondary to vasoocclusive crisis (>= 3 episodes per year
for >= 3 years) Recurrent priapism
- Allo-immunization with the development of antibodies following chronic transfusion
- Patients with HOMOZYGOUS SICKLE CELL ANEMIA or SICKLE/BETA THALASSEMIA with the
following criteria will be considered for accrual on this protocol
- Patients < 2 years with high WBC counts and/or >1 episode of dactylitis and/or a Hgb
< 7 g/dl
- History of death from sickle cell disease in sibship of patient
- Patients with BETA-THALASSEMIA MAJOR with Lucarelli class 1 or 2 risk status i.e with
only 0-2 of the following factors: hepatomegaly, portal fibrosis, or poor chelation
- Patients with DIAMOND-BLACKFAN ANEMIA who have failed conventional therapy.
- Patients must have an HLA-compatible related donor. The donor must be healthy and
able to undergo general anesthesia. Donors with heterozygous sickle cell anemia
(hemoglobin AS) or with heterozygous thalassemia are acceptable donors.
- At the time of referral for transplantation, patients must be in good clinical
condition without any evidence of infections and a Karnofsky or Lansky pediatric
performance scale > 70%
- Each patient and donor must be willing to participate as a research subject and must
sign an informed consent form after having been advised as to the nature and risk of
the study prior to entering the protocol. Parents or legal guardians of patients who
are minor will sign the consent form after being advised of the nature and risks of
- Patients whose life expectancy is less than 8 weeks. Patients with a Karnofsky or
Lansky performance score of < 70%
- Patients with severe major organ dysfunction:
- Patients with severe renal impairment. This will be determined by a creatinine
clearance < 70 ml/min/1.73 m2 (or serum creatinine > 1.5 x Normal) or by a glomerular
filtration rate < 30% of predicted normal for age
- Inadequate cardiac function as determined by fractional shortening < 28% on
echocardiogram, and/or ejection fraction of < 50% on echocardiogram or RNCA.
- Patients with FS of 23-28% who show an increase in FS in response to stress on the
supine bicycle ergometer are eligible
- Major liver dysfunction: SGOT > 3 x upper limit of normal. Hyperbilirubinemia will
not be used as an exclusion criteria because of the hemolytic component of the
bilirubin. Patients with active hepatitis or severe liver fibrosis will also be
- Severe residual functional neurologic impairment
- Stage III-IV sickle chronic lung disease
- Pregnant or lactating women are excluded