Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (HaploHCT) Following Reduced Intensity Conditioning (RIC) for Selected High Risk Non-Malignant Diseases

Study Overview
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Brief Summary
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This is a Phase II study for the use of T-cell replete reduced intensity conditioning (RIC) haploidentical donor allogeneic hematopoietic cell transplantation (HaploHCT) for individuals with high-risk non-malignant diseases who lack a suitable HLA-matched sibling donor.

Official Title
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Haploidentical Donor T-cell Replete Allogeneic Hematopoietic Cell Transplant Following Reducing Intensity Conditioning for Patients With Selected High Risk Non-Malignant Disease

Conditions
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Sickle Cell Disease, Thalassemia, High Risk Hematologic Disorders, Cerebral Adrenoleukodystrophy, Inherited Metabolic Disorders

Intervention / Treatment
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* Procedure: Blood and Marrow Transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sickle Cell Disease (SCD) * If diagnosis of SCD must meet one or more of the following disease characteristics: Stroke, CNS hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism, Impaired neuropsychological function and abnormal cerebral MRI scan Stage I or II sickle lung disease, Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate [GFR] 30-50% of the predicted normal value) Bilateral proliferative retinopathy and major visual impairment in at least one eye Osteonecrosis of multiple joints with documented destructive changes Requirement for chronic transfusions RBC alloimmunization Transfusion Dependent Alpha- or Beta-Thalassemia Other Non-Malignant Hematologic Disorders: Transfusion dependent or involve other potential life-threatening cytopenias, including but not limited to Paroxysmal Nocturnal Hemoglobinuria, Glanzmann's Thrombasthenia, Severe Congenital Neutropenia and Shwachman-Diamond Syndrome cALD Diagnosis of ALD by abnormal plasma very long chain fatty acid (VLCFA) profile or ABCD1 gene mutation Cerebral disease on MRI Absence of a Major Functional Disability (cortical blindness, loss of communication, wheelchair dependence) on the ALD Neurologic Function Scale Other inherited metabolic disorders: Any other inherited metabolic disorder for which alloHCT is indicated and for whom, in the opinion of the treating physician, the patient's best treatment option is with a haploidentical donor following non-myeloablatve conditioning. Age, Performance Status, Consent Age: 0-55 years Performance Status: Karnofsky ≥ 70%, Lansky play score ≥ 70 Consent: voluntary written consent (adult or parental/guardian) Adequate Organ Function Renal: Creatinine <2.0 mg/dl for adults or glomerular filtration rate > 50 ml/min for children Hepatic: Bilirubin and ALT <3 times the upper limit of institutional normal Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 40%. Exclusion Criteria: Availability of a suitable HLA-matched related donor Uncontrolled infection Pregnant or breastfeeding HIV positive

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rATG, FLU/CY/TBI, & Thiotepa<br>Anti-Thymocyte Globulin - Rabbit (rATG), Fludarabine (Fludara), Cyclophosphamide (Cytoxan, Neosar), Total Body Irradiation (TBI), & Thiotepa | Procedure: Blood and Marrow Transplant<br>* Reduced intensity conditioning (RIC) with rabbit ATG, fludarabine, cyclophosphamide, thiotepa and low dose (2 Gy) total body irradiation followed by T-cell replete, unmanipulated, haploidentical related donor stem cell transplant (HaploHCT) and post-transplant cyclophosphamide (PTCy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Recovery | Incidence of neutrophil recovery by day +42 | Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Incidence of overall survival at 1 year | 1 year | 
| Primary Graft Failure (neutropenic and non-neutropenic) | Incidence of primary graft failure (neutropenic and non-neutropenic) by day +42 | Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCD, cALD