Myeloablative Conditioning, Prophylactic Defibrotide and Haplo AlloSCT for Patients With Sickle Cell Disease

Inclusion Criteria:

- Patients must demonstrate one or more of the following Sickle Cell Disease
Complications (or patients in Cohort 2 can meet other high risk criteria instead)

- Clinically significant neurologic event (stroke) or any neurologic deficit lasting >24
hours that is accompanied by an infarct on cerebral MRI

- Minimum of two episodes of acute chest syndrome (defined as new pulmonary alveolar
consolidation involving at least one complete lung segment associated with acute
symptoms including fever >38.5, chest pain, tachypnea, intercostal retractions, nasal
flaring, use of accessory muscles of respiration, wheezing, rales, or cough not
attributable to asthma or bronchiolitis) in the preceding two year period prior to
enrollment that have failed, been non-compliant or declined hydroxyurea treatment, or
prior to chronic RBC transfusion therapy, exchange transfusion or erythrocyte
pheresis. The acute chest syndrome event occured despite adequate supportive care
measures (i.e. despite the use of supportive care and interventions including asthma
therapy and/or hydroxyurea; patients who decline hydroxyurea or non-compliant with
this therapy are eligible if they meet the other pulmonary criteria defined above for
inclusion).

- Recurrent painful events (at least 3 in the 2 years prior to enrollment or prior to
chronic chronic RBC transfusion therapy, exchange transfusion or erythrocyte
pheresis). Pain occurred in typical sites associated with vaso-occlusive painful
events and cannot be explained by causes other than sickle cell disease. Pain lasted
at least 2-4 hours and required parenteral narcotic treatment, or an equianalgesic
dose of oral narcotics or parenteral nonsteroidal anti-inflammatory drugs. These
painful events may have been treated in any setting; however, the events, including
events that were managed at home, will be considered for eligibility only if there is
documentation of the event in a clinical record that may be reviewed by the
investigator.

- Abnormal TCD study requiring starting on chronic transfusion therapy and/or exchange
transfusions.

- At least one silent infarct lesion on a MRI scan of the head. An infarct-like lesion
is defined as an MRI signal abnormality that is at least 3 mm in one dimension and
that is visible in two planes on fluid-attenuated inversion recovery (FLAIR)
T2-weighted images, as determined by a neuroradiologist.

= OR for Cohort #2 ONLY: Patient must be between 18 and 34.99 years of age, patients
must demonstrate at least two of the following:

- WBC > 13,500 cells/microliter at baseline when not acutely ill (on two separate
occasions) > 2 weeks from a VOC event or hospitalization.

- Tricuspid Regurgitant Jet Velocity (TRV) > 3.0 m/s

- Requiring Chronic Monthly Transfusions ( > 12 transfusions in the 12 months)

- History of sepsis

- N-terminal pro-brain natriuretic peptide (NT-proBNP) > 160 ng/L at clinical baseline
when not acutely ill or hospitalized.

- all patients must meet disease, age, organ function and donor criteria;

Exclusion Criteria:

- Females who are pregnant or breast-feeding are not eligible

- SCD Patients with documented uncontrolled infection at the time of study entry are not
eligible.

- SCD patients who have an unaffected HLA matched family donor willing to proceed to
donation will not be eligible for this study.

- Karnofsky or Lansky (age appropriate) Performance Score <50% (hemiplegia alone
secondary to a previous stroke is not an exclusion)

- Demonstrated lack of compliance with medical care.

- Patients with clinically significant fibrosis or cirrhosis of the liver will not be
eligible.

- Patients who have previously received a HSCT will not be eligible.

- Patients with contraindications to the use of defibrotide