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

Study Overview
=================
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).

Official Title
-----------------
Hematopoietic Stem Cell Transplantation for Patients With Severe Sickle Cell Disease Using Myeloablative Conditioning and αβ+ T-cell Depleted Hematopoietic Stem Cells From Partially Matched Familial Donors

Conditions
-----------------
Sickle Cell Disease

Intervention / Treatment
-----------------
* Device: αβ+ T-cell depletion with Miltenyi CliniMACS system


Participation Criteria
=================
Eligibility Criteria
-----------------
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%.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage I<br>Stage I will include eligible subjects between the ages of 10-25 years. | Device: αβ+ T-cell depletion with Miltenyi CliniMACS system<br>* Haploidentical CD34+ megadose hematopoietic stem cell transplant in which cells are purified using the Miltenyi CliniMACS system designed for αβ+ T-cell receptor selection using immunomagnetic beads.<br>|
| Experimental: Stage II<br>Stage II will include eligible subjects between the ages of 2-25 years. | Device: αβ+ T-cell depletion with Miltenyi CliniMACS system<br>* Haploidentical CD34+ megadose hematopoietic stem cell transplant in which cells are purified using the Miltenyi CliniMACS system designed for αβ+ T-cell receptor selection using immunomagnetic beads.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 100 days post-Hap-HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate 1-year overall and event-free survival after Hap-HSCT | Proportion of patients at 1 year who have not died or had graft failure | 1 year post transplant | 
| Observe the incidence of grades I through IV acute GvHD | Proportion of subjects with grades I through IV acute GvHD | 100 days post transplant | 
| Observe incidence of severe acute GvHD as defined by grades III through IV | Proportion of subjects with grades III through IV acute GvHD | 100 days post transplant | 
| Observe the incidence of grades I through IV chronic GvHD | Proportion of subjects with grades I through IV chronic GvHD | 1 year post transplant | 
| Observe incidence of severe chronic GvHD as defined by grades III and IV | Proportion of subjects with grades III through IV chronic GvHD | 1 year post transplant |