Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

The purpose of this study is to learn if it is possible and safe to treat persons with severe
sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA)
half-matched related donors. Preparation before transplant includes the chemotherapy drugs
hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also
includes radiation.

Investigators also seek to understand the side effects of BMT in adolescents and young adults
with SCD and measure how often serious side effects occur including those that are expected
and unexpected. After transplant, investigators will measure the health of the body organs
that ordinarily would have been damaged by having SCD in addition to testing the lungs,
brain, and kidneys.

Inclusion Criteria:

1. Disease severity: Participants with SCD who have 1 or more of the following (i-v).

- Clinically significant neurologic event (stroke) or any neurological deficit
lasting > 24 hours;

- 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);

- 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);

- Administration of regular red blood cell (RBC) transfusion therapy, defined as
receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive
clinical complications (i.e. pain, stroke, and ACS). Patients on chronic
transfusion who have to discontinue transfusion because of allo-sensitization
will be eligible.

- An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥
2.7 m/sec. Patients under the age of 18 years must have cardiac catheterization
proven pulmonary arterial hypertension to qualify on this eligibility criterion.

2. Age: Patients must be 15 - 40 years of age inclusive OR if younger than 15 years must
be pubertal

3. Adequate physical function as measured by:

- Karnofsky/Lansky performance score ≥ 60

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

- Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and
DLCO > 40% (corrected for hemoglobin).

- Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per
local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m2 or
GFR > 70 mL/min/1.73 m2 by radionuclide GFR.

- Hepatic function: Serum conjugated (direct) bilirubin < 2 x upper limit of normal
for age as per local laboratory and ALT and AST < 5 x upper limit of normal as
per local laboratory. Patients with hyperbilirubinemia as a consequence of
hyperhemolysis, or who experience a sudden, profound change in the serum
hemoglobin after a RBC transfusion, are not excluded.

- For participants with a suitable donor who meet eligibility criteria and are
willing to proceed to HCT, if they have received chronic transfusion therapy for
≥ 1 year and have clinical evidence of iron overload by serum ferritin or MRI, an
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

4. Suitable Donor: To undergo transplantation on this study, participants must have an
adult first degree relative who shares at least 1 human leukocyte antigen (HLA)
haplotype with the participant, does not have SCD or other hemoglobinopathy, and is in
good health; if these criteria are met, they will be allowed to serve as donors.
Relatives with sickle cell trait are not excluded as donors. When more than 1 donor is
available, the donor with the fewest HLA allele mismatches will be chosen, unless the
patient had donor anti-HLA antibodies or there was a medical reason to exclude the
donor. If donor anti-HLA antibodies are detected, the next best related match will be
chosen. Umbilical cord blood or peripheral blood stem cell donors will not be
accepted.

Exclusion Criteria:

- Availability of HLA matched sibling or 8 of 8 HLA-A, B, C and DRB1 matched unrelated
donor

- Presence of donor specific antibodies in the patient

- 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). The presence of bridging fibrosis will be an exclusion criterion.

- Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment

- Seropositivity for HIV

- Previous hematopoietic cell transplantation (HCT)

- Participation in a clinical trial in which the patient received an investigational
drug or device or off-label use of a drug or device within 3 months of enrollment

- Demonstrated lack of compliance with prior medical care

- Unwilling to use approved contraception for at least 6 months after transplant

- A history of substance abuse in the last 5 years that interferes with care

- Pregnant or breast feeding females at the time of consideration for HCT

Donor Selection Criteria:

Preference will be given to related marrow donors who are 2-4 (out of 8) HLA antigen
mismatched and towards whom the recipient does not have donor specific antibodies. Donors
will sign an informed consent disclosing that the marrow donation will be used by a patient
participating in this study. The donor must be matched with the recipient for at least 4 of
8 HLA alleles (HLA -A, -B, -C and -DRB1 by allele-level DNA methodology). The target total
nucleated cell count (TNC) is 3.5-8.0 x 108/kg of recipient weight. Marrow will be
collected without mobilization. Mobilized peripheral blood stem cell (HPC-A) collections
will not be permitted. Donors must undergo hemoglobinopathy screening by electrophoresis;
donors who have a hemoglobinopathy will be excluded but trait condition is acceptable.