Treatment of Sickle Cell Anemia With Stem Cell Transplant

Hemoglobinopathies, such as sickle cell disease and thalassemia major, constitute a group of
genetic diseases associated with significant morbidity and premature death. In the 1970s,
the mean survival of patients with sickle cell disease was 14.3 years. With improvements in
medical practice, this has improved such that estimates are now into the third decade of
life.

In patients with sickle cell disease, a single amino acid substitution in beta-hemoglobin
causes erythrocytes to sickle in response to oxidative stress. The sequelae of this defect
are vaso-occlusive crises, resulting in episodes of bony pain and infarction, acute chest
syndrome, and strokes. Life long need for transfusion leads to complications including
alloimmunization and iron overload. The latter condition is frequently associated with
significant end-organ damage.

In recent years, new strategies in supportive care, such as the use of hydroxyurea to
stimulate fetal hemoglobin production in patients with sickle cell anemia, have resulted in
the amelioration of some of the devastating manifestations of this disease. However, this
therapy does not benefit all patients, and there have been concerns about the possible risk
of latent transformation to leukemia with prolonged use of this drug. Clearly, better
treatment strategies are needed for this devastating group of diseases.

Patients with sickle cell anemia will be offered enrollment on a clinical trial of reduced
intensity stem cell transplant. The transplant donors will be either HLA matched siblings
or family members who are 50% matched for HLA. Patients will receive therapy in 2 steps.

For patients who are allo-immunized against the donor (patients who have made an immune
response already against the donor's HLA type), there will be a desensitization process.
This will be outpatient therapy and will include therapy with bortezomib on the 1st, 4th,
8th and 11th day of a 21 day cycle. This will be repeated for a second cycle, for a total
of 8 doses of bortezomib over a 6 week period. In addition, they will receive rituximab on
the 1st and 8th day of each cycle. These therapies are designed to decrease the subject's
chance of rejecting the transplant, as it is known that patients with sickle cell anemia are
likely to be heavily immunized against donors. For patients who have high levels of
antibodies against the donors, a plasmapheresis procedure will be performed prior to
admission as well. All patients will undergo red cell exchange prior to admission.

During the transplant admission, subjects will receive a "Two Step" chemotherapy and
transplant regimen. The chemotherapy "first step" will be with fludarabine and cytarabine
and a low dose of total body irradiation. This will be followed by the "first step" of the
transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two
doses of cyclophosphamide. This will then be followed by the "second step" of the
transplant graft - the stem cells.

Inclusion Criteria:

Patient Selection:

i) Patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C
disease, or sickle cell-β0-thalassemia) confirmed by hemoglobin electrophoresis.

ii) Patients should have one or more of the following:

1. History of acute chest syndrome requiring recurrent hospitalization or exchange
transfusion (Acute chest syndrome is defined as pulmonary infiltrate involving at
least one complete lung segment, consistent with alveolar consolidation but not
atelectasis, accompanied by chest pain, fever, cough, tachypnea or wheezing)

2. History of nonhemorrhagic stroke or central nervous system event lasting longer than
24 hours

3. Recurrent vaso-occlusive pain (≥5 episodes during the past two years) or recurrent
priapism requiring hospitalization or visits to the emergency room or sickle cell day
unit

4. Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate
30-50% of normal predicted value) with progression on ACE inhibitor therapy iii)
Patient must have failed therapy with hydroxyurea, as HU as evidenced by at least 6
months of maximum HU dosage for sickle cell disease, i.e. dose escalation to a level
which caused some minimal hematologic toxicity in terms of CBC values. Failure to
respond must also be documented by no significant increase in subjects HbF levels at
this maximally tolerated dosage.AND development/ persistence of items listed in (ii)
Patients who are deemed not eligible for hydroxyurea by the primary hematologist will
be considered eligible without having failed hydroxyurea. Non-eligibility for
hydroxyurea therapy is based on:

(1) the diagnoses of SC disease and sickle cell-β0-thalassemia in which no clear evidence
supports the use of hydroxyurea therapy and thus treatment with hydroxyurea is not
considered the standard of care in these entities (2) the presence of high hemoglobin F
levels in patients with sickle cell anemia and documented Hereditary Persistence of Fetal
Hemoglobin (HPFH) in which hydroxyurea is not considered the standard of care (3) severe
adverse reactions to hydroxyurea in patients with sickle cell anemia based on, but not
limited to, count suppression, GI intolerance, and dermatomyositis Patient unwillingness
to be compliant with hydroxyurea therapy is not an acceptable reason for non-eligibility
iv) Patients must have an acceptable related donor

1. who is matched at the HLA-A;B; C; DR loci (8 of 8 match) or mismatched for at most
one locus (7 of 8 match) (well matched related donor

2. who is mismatched at 2-4 alleles (haplo-identical) v) Patient age greater than 18 -
45 years vi) ECOG performance status 0-2/ Karnofsky 70-100% vii) Written informed
consent obtained from the patient. viii) Transaminases <3X ULN; patients with
transaminases greater than the ULN but less than 3XULN will be evaluated by the
hepatology service and will undergo further imaging and biopsy as deemed necessary by
hepatology. They will not be considered eligible unless cleared by hepatology.

Exclusion Criteria:

Patient Selection:

i) Pregnancy/ unwillingness to use adequate contraception during study period ii) Liver
disease including

1. Acute hepatitis (transaminases >3x normal value)

2. Chronic hepatitis C

3. Chronic hepatitis B or history of exposure to hepatitis B iii) Cardiac ejection
fraction < 50% iv) Pulmonary hypertension - as evidenced by findings on resting
echocardiogram of pulmonary artery systolic pressure ≥ 40 mmHg or any evidence of
right ventricular dysfunction (hypokinesis or RV dilation) v) Severe renal impairment
(GFR <30% of predicted normal value) vi) Severe residual functional neurologic
impairment (other than hemiplegia alone) vii) DLCO ≤50 viii) Any evidence of
infection by the human immunodeficiency virus ix) Psychiatric disorder that would
preclude patients from signing an informed consent x) Severe neuro-cognitive or
executive function making informed consent possible