Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) for Patients With Severe Sickle Cell Disease

Not Applicable

Terminated

Brief Summary: The purpose of this study is to develop a safe and curative stem cell transplant approach to treating sickle cell disease by assessing the safety of haploidentical hematopoietic stem cell transplantation using αβ+ T-cell depletion for children and adolescents with severe sickle cell disease (SCD).

Recruitment & Eligibility

Inclusion Criteria

Hemoglobin SS, SC, S-β0 Thalassemia, or SO-Arab Sickle Cell Disease
Between the ages of 2 and 25 years (Stage 1: 10-25 years; Stage II: 2-25 years)
Lack a fully matched family donor or fully matched unrelated donor register in the National Marrow Donor Program
Partially-matched family member with hemoglobin AA (normal) or hemoglobin AS (sickle trait) phenotype
SCD with Severe Phenotype, defined by the following criteria: Neurologic manifestations of sickle disease including cerebral vascular accident (CVA), transient ischemic event (TIA) or abnormal MRI findings suggestive of silent infarct; Two or more episodes of acute chest syndrome (ACS) requiring admission for transfusional or respiratory support including supplemental oxygen within [two years] of enrollment in study despite hydroxyurea therapy. Patients who cannot tolerate hydroxyurea and who experience multiple episodes of ACS will also be eligible; History of severe vaso-occlusive (VOC) disease requiring hospitalization and intravenous narcotics on 3 or more occasions per year over the two years prior to enrollment despite hydroxyurea therapy. Patients who cannot tolerate hydroxyurea and who experience multiple episodes of VOC will also be eligible; Other severe phenotype as evidenced by end organ dysfunction related to sickle cell disease.

Exclusion Criteria

Karnofsky or Lansky score < 60%
Acute hepatitis or evidence of moderate or severe portal fibrosis on biopsy. (Biopsy will be obtained if patient has been on chronic transfusion therapy > 6 months or has a ferritin > 1000 ng/ml) or AST or ALT >5 times the upper limit of normal
Severe renal impairment (as evidenced by creatinine clearance of <50ml/minute glomerular filtration rate (GFR) < 50% predicted normal)
Cardiac function that demonstrates shortening fraction less than 26% by cardiac echocardiogram or pulmonary hypertension.
Pregnant Female.
Lactating female.
Pulmonary function with baseline O2 saturation <85% or Diffusing Capacity for Carbon Monoxide (DLCO) on pulmonary function testing (PFT) with a DLCO <40%.

Arm && Interventions

Group	Intervention	Description
Stage I	αβ+ T-cell depletion with Miltenyi CliniMACS system	Stage I will include eligible subjects between the ages of 10-25 years.
Stage II	αβ+ T-cell depletion with Miltenyi CliniMACS system	Stage II will include eligible subjects between the ages of 2-25 years.

Primary Outcome Measures

Name	Time	Method
Safety, as Measured by Incidence of Graft Failure, Grade III/IV Irreversible End Organ Toxicity, Grade III/IV aGvHD, or Death Within 100 Days Post-Hap-HSCT	100 days post-Hap-HSCT	Graft Function: efficacy is defined as stable donor engraftment (\>5% total nucleated cell DNA) and donor erythropoiesis that corrects the SCD hematologic phenotype (\<50% HbS in the peripheral blood). Organ Toxicity: grade III/IV irreversible end organ toxicity based on NCI grading Graft Versus Host disease: grade III/IV aGvHD or death within 100 days post- Hap-HSCT

Secondary Outcome Measures

Name	Time	Method
Estimate 1-year Overall and Event-free Survival After Hap-HSCT	1 year post transplant	Proportion of patients at 1 year who have not died or had graft failure
Observe the Incidence of Grades I Through IV Acute GvHD	100 days post transplant	Proportion of subjects with grades I through IV acute GvHD
Observe Incidence of Severe Acute GvHD as Defined by Grades III Through IV	100 days post transplant	Proportion of subjects with grades III through IV acute GvHD
Observe the Incidence of Grades I Through IV Chronic GvHD	1 year post transplant	Proportion of subjects with grades I through IV chronic GvHD
Observe Incidence of Severe Chronic GvHD as Defined by Grades III and IV	1 year post transplant	Proportion of subjects with grades III through IV chronic GvHD