Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease

This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy
and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell
disease (SCD) who have high risk features.

The primary goal of this multi-center Phase II study is to determine the safety and
feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/
anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will
be used for this study. The first component will be restricted to patients who have an
HLA-identical sibling donor. Five patients will be transplanted during the first component of
the study. If no more than 2 of the first 5 patients experience unacceptable toxicity,
including death, within the first six months after transplantation, then the safety of the
regimen will be considered promising in adult SCD patients.

The second component will include patients who have a related or an unrelated human leukocyte
antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this
component of the study which will evaluate the safety and feasibility of unrelated donor
hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints
for 1 year after transplantation will be collected; however, participating centers will be
encouraged to conduct long-term follow-up evaluations of patients according to standard
institutional guidelines. The purpose of this pilot safety trial is to see if this approach
is feasible and meets accrual goals lending support to the development of a subsequent full
scale investigation of HCT and comparing outcomes in a transplantation cohort to a control
cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive
therapy with a primary endpoint of five years survival for this full scale comparative trial.

The primary objective is to determine event-free survival (EFS) at 1 year after hematopoietic
cell transplantation (HCT) using bone marrow in patients with sickle cell disease. Death,
disease recurrence or graft rejection by 1 year will be considered events for this endpoint.

Secondary objectives include determining the effect of HCT on clinical and laboratory
manifestations of severe sickle cell disease and determining the incidence of other
transplant-related outcomes.

Inclusion Criteria:

- Diagnosis of severe sickle cell disease and have one or more of the following:

1. Clinically significant neurologic event (stroke) or any neurological deficit
lasting > 24 hours

2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year
period preceding enrollment despite the institution of supportive care measures
(i.e. asthma therapy and/or hydroxyurea). Acute Chest Syndrome (ACS) is defined
as new pulmonary alveolar consolidation (or infiltrate) involving at least one
complete lung segment associated with acute symptoms including one or more of the
following: fever ≥ 38.5 Celsius, chest pain, tachypnea per age adjusted normal,
intercostal retractions/nasal flaring/use of accessory muscles of respiration,
wheezing, rales or cough that is not attributed to asthma or bronchiolitis.

3. History of three or more severe pain crises per year in the 2-year period
preceding enrollment despite the institution of supportive care measures (i.e. a
pain management plan and/or treatment with hydroxyurea). Pain Crisis is defined
as new onset of pain that last for at least 2 hours for which there is no other
explanation (i.e. vaso-occlusive, priapism).

4. Administration of regular red blood cell (RBC) transfusion therapy, defined as
receiving 8 or more transfusions per year for greater than or equal to 1 year to
prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest
syndrome)

5. Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet (TRJ)
velocity greater than or equal to 2.7 m/sec.

- Adequate physical function as measured by:

1. Karnofsky performance score greater than or equal to 60

2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV
shortening fraction > 26% by cardiac echocardiogram or by multigated acquisition
(MUGA) scan.

3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than
or equal to 85% and diffusing capacity of the lungs for carbon monoxide (DLCO) >
40% (corrected for hemoglobin)

4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and
24-hour urine creatinine clearance > 70 mL/min/1.73 m2 by radionuclide glomerular
filtration rate (GFR); or GFR > 70 mL/min/1.73 m2 by radionuclide GFR.

5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal
for age as per local laboratory; and alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 5 times upper limit of normal as per local laboratory.
Patients whose hyperbilirubinemia is the result of hyperhemolysis, or a severe
drop in hemoglobin post blood transfusion, are not excluded

6. If the patient has been receiving chronic transfusion therapy for greater than or
equal to 1 year and has clinical evidence of iron overload by serum ferritin
(mean of 3 ferritin levels >1000 and chronic transfusions >20 in a lifetime or
MRI), evaluation by liver biopsy is required. Histological examination of the
liver must document the absence of cirrhosis, bridging fibrosis and active
hepatitis. The absence of bridging fibrosis will be determined using the
histological grading and staging scale as described by Ishak and colleagues
(1995).

- Patients must have a related or unrelated bone marrow donor with HLA-matched at 8 of 8
HLA-A, B, C, and DRB1 loci by allelic testing. Umbilical cord blood or peripheral
blood stem cell donors will not be accepted.

Exclusion Criteria:

- Patients with cirrhosis of the liver, uncontrolled bacterial, viral or fungal
infection in the 6 weeks before enrollment, or seropositivity for HIV

- Patients who have received prior HCT

- Patients who within 3 months of enrollment have participated in another clinical trial
in which the patient received an investigational drug or device or off-label use of a
drug or device

- Patients who demonstrate lack of compliance with prior medical care

- Patients who are unwilling to use approved contraception for at least 6 months after
transplant

- Patients who have a history of substance abuse in the last 5 years that interferes
with their care

- Patients who are pregnant or breast feeding

- Patients unable to provide consent