T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
The purpose of this study is to evaluate what effect, if any, mismatched unrelated volunteer
 donor and/or haploidentical related donor stem cell transplant may have on severe sickle cell
 disease and other transfusion dependent anemias. By using mismatched unrelated volunteer
 donor and/or haploidentical related donor stem cells, this study will increase the number of
 patients who can undergo a stem cell transplant for their specified disease. Additionally,
 using a T-cell depleted approach should reduce the incidence of graft-versus-host disease
 which would otherwise be increased in a mismatched transplant setting.
CD3/CD19 depletion of mismatched donor grafts in the setting of reduced intensity,
 immune-ablative conditioning for patients with sickle cell disease and other
 transfusion-dependent anemias should sufficiently achieve engraftment while decreasing the
 incidence of treatment-related toxicities and achieving an acceptable incidence of graft
 versus host disease. Utilizing mismatched unrelated volunteer donors and haploidentical
 related donors will increase the number of patients able to undergo hematopoietic stem cell
 transplant (HSCT) for these diseases. Additionally, the institutional availability of
 virus-specific, donor-derived cytotoxic T lymphocytes should address complicated viral
 infections refractory to standard anti-viral therapy.

 The purpose is to:

 -  To provide alternate donor transplantation from cryopreserved stem cell grafts that are
 fully characterized for safety and potency to patients with severe sickle cell disease,
 beta-thalassemia major, or Diamond-Blackfan anemia who do not have matched sibling
 donor, matched unrelated donor or cord blood donor options.

 -  To utilize a reduced-intensity conditioning regimen to achieve minimal treatment-related
 morbidity and mortality while attaining sustained donor engraftment and donor chimerism
 >20% in order to rescue disease phenotype, specifically in SCD patients.

 -  To utilize ex-vivo T-cell depletion methods to prevent graft-versus-host disease in the
 setting of mismatched donor transplantation.

 -  To utilize additional donor cell products to ensure sufficient immune reconstitution in
 the immediate post-transplant period, to improve mixed chimerism or provide non-specific
 anti-viral activity in patients with virus reactivation in the post-transplant period.

 -  To utilize calcineurin inhibitor-free regimen in an effort to minimize/prevent central
 nervous system toxicity
Inclusion Criteria

 1. Patient, parent, or legal guardian must have given written informed consent and/or
 assent according to FDA guidelines.

 2. Ages 5 years to 40 years, at time of consent.

 3. Diagnosis of Sickle Cell Disease (Hemoglobin SS, Sβ0-thalassemia) complicated by any
 of the following:

 -  Recurrent acute painful episodes (also known as vaso-occlusive crises; VOC)
 despite supportive care, minimum of 2 new pain events per year requiring
 hospitalization for parenteral pain management in the previous 2 years.

 -  Recurrent acute chest syndrome (ACS) despite supportive care, minimum of 2
 episodes in preceding 2-year period.

 -  Stroke or neurologic event lasting > 24 hours with an accompanying infarct on MRI
 in any patient for all ages; Brain MRI with silent infarct without clinical event
 in patients ≤ 16 years.

 -  Chronic transfusion therapy defined as > 8 packed red blood cell transfusions per
 year in the year prior to enrollment and/or evidence of red blood cell
 alloimmunization.

 -  Elevated transcranial Doppler velocities - > 200 cm/s, via the non-imaging
 technique or > 185 cm/s by the imaging technique measured on 2 separate occasions
 ≥ 1-month apart

 -  Elevated TRV > 2.6m/s in patients ≥ 16 years old.

 -  Sickle-related renal insufficiency and/or sickle hepatopathy and/or any
 irreversible end-organ damage in patients ≥ 16 years old.

 OR Diagnosis of beta-thalassemia or Diamond-Blackfan anemia complicated by transfusion
 dependence with evidence of iron overload.

 4. A minimum donor match of 4/8 via high resolution HLA typing at HLA-A, -B, -C, -DRB1
 loci in the related setting or minimum donor match of 6/8 via high resolution HLA
 typing at HLA-A, -B, -C, -DRB1 loci (with the DRB1 locus as a full match requirement).
 An unrelated donor and cord blood search must have been completed without an eligible
 8/8 matched unrelated donor or 6/8 cord blood unit available. Patients who may have
 acceptable cord blood donor options (4/6 or better) but are limited by cell dose of a
 single cord will also be eligible for the proposed study.

 5. Adequate function of other organ systems as measured by:

 -  Creatinine clearance or GFR ≥ 45 ml/min/1.73m.

 -  Hepatic transaminases (ALT/AST) ≤ 3 x upper limit of normal.

 -  Liver MR imaging for iron content should be performed in all patients with
 Ferritin > 500 ng/mL. If hepatic iron content > 10mg Fe/g liver should have
 hepatology consultation and liver biopsy to confirm absence of cirrhosis,
 fibrosis or hepatitis.

 -  Adequate cardiac function as measure by echocardiogram (shortening fraction > 26%
 or ejection fraction > 40% or >80% of age-specific normal).

 -  Pulmonary evaluation testing demonstrating FEV1/FVC ≥ 60% of predicted for age
 and/or resting pulse oximeter ≥ 92% on room air.

 -  Cardiology clearance to proceed with conditioning regimen and HSCT.

 -  Pulmonology clearance to proceed with conditioning regimen and HSCT.

 6. Subjects must be human immunodeficiency virus (HIV) negative by PCR.

 7. Negative pregnancy test for females ≥10 years old or who have reached menarche, unless
 surgically sterilized.

 8. All females of childbearing potential and sexually active males must agree to use an
 FDA approved method of birth control for up to 24 months after BMT or for as long as
 they are taking any medication that may harm a pregnancy, an unborn child or may cause
 a birth defect.

 9. Subject and/or parent guardian will also be counseled regarding the potential risks of
 infertility following BMT and advised to discuss sperm banking or oocyte harvesting
 (Refer to section,

 10. Hydroxyurea must have been trialed and failed in patients with sickle cell disease.

 Patient Exclusion Criteria

 1. Patients with alternate, superior donor options (matched sibling donor or matched
 unrelated donor).

 2. Patients who have undergone stem cell transplantation in the 6 months prior to
 anticipated conditioning.

 3. Patients with history of a central nervous system (CNS) event within six months prior
 to start of conditioning (patient will be delayed until eligible).

 4. Patients who are pregnant or lactating

 5. Patients with uncontrolled bacterial, viral or fungal infection

 6. Past or current medical problems or findings from physical examination or laboratory
 testing that are not listed above, which, in the opinion of the investigator, may pose
 additional risks from participation in the study, may interfere with the participant's
 ability to comply with study requirements or that may impact the quality or
 interpretation of the data obtained from the study.