Nonmyeloablative Conditioning for Mismatched Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Disease

Recipient Inclusion Criteria:

- Age greater than or equal to 19 years.

- Diagnosis of sickle cell disease (HB SS, SC, or SBeta-thal(0)); confirmed by
hemoglobin electrophoresis, high-performance liquid chromatography, DNA testing when
necessary or both.

- At high risk for disease-related morbidity or mortality, defined by having at least
one of the following manifestations (A-E):

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

- B: 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
including hydroxyurea.

- C: Three or more pain crises per year in the 2-year period preceding referral
(required intravenous pain management in the outpatient or inpatient hospital
setting) despite the institution of supportive care measures including
hydroxyurea.

- D: Administration of regular 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, acute chest syndrome, and priapism).

- E: Pulmonary hypertension (defined as tricuspid regurgitant jet velocity (TRV)
≥2.5 m/s at baseline (without vaso-occlusive crisis)

- Any one of the below complications not ameliorated by hydroxyurea at the maximum
tolerated dose for at least 6 months:

- Vaso-occlusive crises with more than 1 hospital admission per year while on
maximal tolerated dose of hydroxyurea

- Acute chest syndrome occurring while on hydrox*Eyurea

- Age greater than or equal to 19 years.

- Availability of one antigen mismatched unrelated or haploidentical related donor

- Cerebral MRI/MRA within 30 days prior to initiation of transplant conditioning. If
there is clinical or radiologic evidence of a recent neurologic event (such as stroke
or transient ischemic attack) subjects will be deferred for at least 6 months with
repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to
proceeding to transplantation.

- Ability to comprehend and willing to sign an informed consent

Recipient Exclusion Criteria:

- Detectable antibody to ABO, Rh, or other red blood cell antigen of their donors

- Presence of donor specific antibodies detected by donor specific antibody screen (if
using product from a haploidentical donor).

- Karnofsky/Lansky performance score < 60

- Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
medication and progression of clinical symptoms) within one month prior to starting
the conditioning regimen. Patients with fever or suspected minor infection should
await resolution of symptoms before starting the conditioning regimen.

- Poor cardiac function defined as left ventricular ejection fraction < 40%.

- Poor pulmonary function defined as FEV1 and FVC < 40% predicted or diffusing capacity
of the lung for carbon monoxide (DLCO) < 40% (corrected for hemoglobin)

- Poor liver function defined as direct bilirubin > 2x upper limit of normal for age and
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5 times upper
limit of normal.

- Poor kidney function defined by creatinine clearance < 70mL/min.

- HIV-positive.

- Unwillingness to use approved contraception method from time of biologic assignment
until discontinuation of all immunosuppressive medications.

- Demonstrated lack of compliance with prior medical care (determined by referring
physician).

- Pregnant or breastfeeding.

- Diagnosis of any debilitating medical or psychiatric illness that would preclude
giving informed consent or receiving optimal treatment and follow-up.

Donor Selection:

- Must be one antigen mismatched unrelated donor or first-degree relative who shares at
least one HLA haplotype with the recipient.

- Must not have SCD or another hemoglobinopathy.

- In good health based on institutional standards.

- Weight ≥ 20kg.

- If donor is < 18 years old must have ability to give informed assent based on
institutional standards for pediatric donors.

- Able to undergo peripheral blood stem cell mobilization with G-CSF

- Hemoglobin S ≤ 50%.

- HIV-1&2 antibody, HTLV-I&II antibody, HBV and HCV sero-negative.

- Note: When more than one donor is available, the donor with the lowest number of
HLA allele mismatches will be chosen, unless there is HLA cross-match
incompatibility or a medical reason to select otherwise, in which case donor
selection is the responsibility of the PI, in consultation with the
immunogenetics laboratory. In cases where there is more than one donor with the
least degree of mismatch, donors will be selected based on the most favorable
combination of (i) HLA compatibility in cross-match testing, (ii) ABO
compatibility, (iii) CMV status and (iv) non-inherited maternal antigens (NIMAs)
mismatching.

- HLA crossmatching (in order of priority)

- Mutually compatible (no cross-matching antibodies)

- Recipient non-cross-reactive with donor, donor cross-reactive with recipient

- Mutually cross-reactive

- ABO compatibility (in order of priority)

- Compatible

- Major incompatibility

- Minor incompatibility

- Major and minor incompatibility

- CMV negative donor is preferred

- NIMA mismatched donor is preferred