Reduced Intensity Conditioning (RIC) Regimen for Patients With Non-malignant Disorders

Study Overview
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Brief Summary
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This is a Phase II pilot study to evaluate engraftment and toxicity of patients with non-malignant diseases using a reduced intensity conditioning regimen in the setting of allogeneic transplant for non malignant diseases. Bone Marrow or cord blood will be acceptable as a stem cell source. Recently, reduced intensity conditioning (RIC) regimens have been used for both adult patients with leukemias and pediatric patients with non-malignant diseases. These regimens are better tolerated, resulting in less transplant related morbidity and mortality. Stable mixed chimerism, while insufficient for eradication of leukemias, may be sufficient to cure patients with non-malignant diseases.

Detailed Description
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There are two conditioning regimens in this protocol for children >6 months. Alemtuzumab (Campath), Fludarabine and Melphalan are used. The regimens differ by the timing and dosing of Alemtuzumab (Campath). The two timings are distal and intermediate. Distal campath is initiated 22 days prior to the allogeneic transplant. Intermediate campath is initiated 14 days prior to allogeneic transplant. The conditioning regimen for children with immunodeficiencies <6 months omits melphalan, and substitutes two days of busulfan. This regimen is successfully used in the United Kingdom, and has been successful in a 3 month old infant at the Children's Hospital of Philadelphia (CHOP) who engrafted with a haploidentical donor.

Official Title
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Reduced Intensity Conditioning (RIC) Regimen for Patients With Non-malignant Disorders

Conditions
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Non Malignant Diseases, Immunodeficiencies, Hemoglobinopathies

Intervention / Treatment
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* Drug: RIC: Distal Campath
* Drug: RIC:Intermediate Campath
* Drug: RIC: Mini Busulfan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >6 months- 25 years Diseases eligible for Distal Alemtuzumab: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome Sickle cell disease Thalassemia major Bone marrow failure Diseases eligible for Intermediate Alemtuzumab Hemophagocytic lymphohistiocytosis other macrophage activation syndromes, severe Langerhans histiocytosis Severe combined immune deficiency, adenosine deaminase deficiency, common variable immunodeficiency Wiskott-Aldrich syndrome Organ criteria: Cardiac: Echocardiogram shortening fraction >27% Renal: Serum creatinine less than 1.5 times the upper limit of normal for age Hepatic: liver function tests must be less than 5 times the upper limit of normal No active infections Exclusion criteria 1. Uncontrolled bacterial, fungal or viral infections

Ages Eligible for Study
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Minimum Age: 6 Months
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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RIC: Distal Campath<br>Day Treatment Day - 22 Inpatient: Alemtuzumab (Campath) test dose IV or SQ (subcutaneously) (subcutaneously) over 2 hours Day - 21 to-19 Alemtuzumab IV/ SQ (subcutaneously) Day - 7 to -3 Readmission to hospital Fludarabine IV Day - 2 Melphalan IV Day - 1 Begin cyclosporine infusion Day 0 Transplant: Bone marrow or cord blood infusion | Drug: RIC: Distal Campath<br>* Campath, Fludarabine, Melphalan, Cyclosporine, Cellcept (MMF)<br>* Other names: Reduced Intensity Conditioning Regimen;|
| Experimental: RIC:Intermediate Campath<br>Day Treatment Day - 14 to-10 Inpatient: Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 7 to -3 Fludarabine IV Day - 2 Melphalan 140 mg/m2 IV Day - 1 Cyclosporine infusion starts Day 0 Transplant: Bone marrow or cord blood infusion | Drug: RIC:Intermediate Campath<br>* Campath, Fludarabine, Melphalan, Cyclosporine, Cellcept (MMF)<br>* Other names: Reduced Intensity Conditioning Regimen;|
| Experimental: RIC: Mini Busulfan<br>Day Treatment Day - 8 Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 7 Alemtuzumab (Campath) IV or SQ (subcutaneously) Day - 6 Alemtuzumab (Campath) IV or SQ (subcutaneously) Busulfan IV Fludarabine IV Day - 5 Alemtuzumab (Campath) IV or SQ (subcutaneously) Busulfan IV Fludarabine IV Day - 4 Alemtuzumab (Campath) IV or SQ (subcutaneously) Fludarabine IV Day - 3 Fludarabine IV Day - 2 Fludarabine IV Cyclosporine infusion Day - 1 Rest Day 0 Transplant: Bone marrow or cord blood infusion | Drug: RIC: Mini Busulfan<br>* Campath, Fludarabine, Busulfan, Cyclosporine, Cellcept (MMF)<br>* Other names: Reduced Intensity Conditioning Regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | engraftment of patients with non-malignant disorders will be evaluated using a reduced-intensity conditioning regimen | Post Transplant -100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Event free survival will be evaluated by the time interval to either the primary or late graft failure, disease recurrence or death. | 1 year post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-malignant diseases, Immune deficiencies, Hemoglobinopathies, Reduced Intensity Conditioning(RIC)