Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases

Study Overview
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Brief Summary
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Reduced intensity conditioning followed by allogeneic stem cell transplantation will result in mixed/complete donor chimerism and potentially alter the natural history and outcome of patients with non-malignant diseases.

Detailed Description
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This study is to determine the toxicity of administering a fludarabine/cyclophosphamide (Flu/CY) or busulfan (Bu)/Flu based conditioning regimen followed by allogeneic stem cell transplant (AlloSCT) in patients with non-malignant diseases.

Official Title
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Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Selected Non-Malignant Diseases

Conditions
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Bone Marrow Failure, Osteopetrosis, Fanconi Anemia, Severe Combined Immunodeficiency

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Cyclophosphamide 40
* Drug: Cyclophosphamide 30


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must meet the eligibility criteria for organ function regardless of diagnosis: Age < 30 or = 30 years of age Adequate renal function defined as serum creatinine < or = 1.5 x normal, or creatinine clearance or radioisotope GFR > or =40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range Adequate liver function defined as SGOT (AST) or SGPT (ALT) < 5.0 x normal Adequate cardiac function defined as shortening fraction of > or = 28% by echocardiogram, or ejection fraction of > or = 48% by radionuclide angiogram or echocardiogram Adequate pulmonary function defined as asymptomatic or, if symptomatic, DLCO >45% of predicted (corrected for hemoglobin level). If unable to obtain pulmonary function test, O2 saturation >85% in room air. Bone Marrow Failure Syndromes Patients with the following diagnoses are eligible: Severe Aplastic Anemia: Hypocellular bone marrow biopsy (<25% cellularity) and 2/3 of the following (at diagnosis or nadir): Absolute Neutrophil Count (ANC) <200/mm3, Platelets <20,000/mm3 Reticulocyte count <60,000/mm3 Fanconi Anemia: Abnormal clastogenic studies (all patients) Severe Congenital Neutropenia (Kostmann's Syndrome) Amegakaryocytic Thrombocytopenia Severe thrombocytopenia (< or =20,000/mm3) at diagnosis Severe depletion of megakaryocytes on bone marrow aspirate (< or =25% normal) Diamond-Blackfan Anemia: Corticosteroid dependent for > 6 months OR Transfusion dependent OR refractory acquired pure red cell aplasia. Infantile Osteopetrosis Schwachman-Diamond Syndrome Dyskeratosis Congenita Other bone marrow failure syndromes at discretion of co-principal investigators Immunodeficiencies SCIDS, all subtypes Combined Immunodeficiency Syndrome Wiskott-Aldrich Syndrome Chronic Granulomatous Disease Chediak-Higashi Syndrome Leukocyte Adhesion Deficiency Other immunodeficiencies at discretion of co-principal investigators Inborn Errors of Metabolism (IEOM) Transplant is recommended for the following disorders: Hurler syndrome (alpha-L-iduronidase deficiency, MPS-I), preferably before age 24 months Maroteaux-Lamy syndrome (galactosamine-4-sulfatase deficiency,MPSVI) Sly syndrome (beta-glucuronidase deficiency, MPS-VII) Globoid cell leukodystrophy (galactocerebrosidase deficiency), with careful attention to neurologic status in the infantile form Metachromatic leukodystrophy (arylsulfatase A deficiency),juvenile or adult onset form; late infantile MLD only if pre-symptomatic Childhood-onset X-linked adrenoleukodystrophy (X-ALD), at initial signs of neuropsychological deterioration, with dietary modification prior to transplant Fucosidosis (fucosidase deficiency) Mannosidosis Aspartylglucosaminuria Niemann-Pick Disease Type B (acid sphingomyelinase deficiency) Other diagnoses may be considered at the discretion of the co-principal investigators For X-ALD patients greater than 5 years of age, IQ >80 is required. For other patients greater than 5 years of age, IQ > 70 is required. For Gaucher disease (glucocerebrosidase deficiency) Type I (non-neuropathic), the primary therapy is enzyme replacement, but allogeneic stem cell transplant has been used effectively. Histiocytoses Hemophagocytic Lymphohistiocytosis (HLH) Familial Erythrophagocytic Lymphohistiocytosis Langerhans Cell Histiocytosis Patients with multi-system disease whose initial disease is stable or progressive after minimum 6 weeks of appropriate therapy, OR Patients with recurrent multi-system disease. Malignant Histiocytosis Other non-malignant diseases not listed above may be eligible if deemed appropriate by the co-principal investigators.

Ages Eligible for Study
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Maximum Age: 30 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine<br> | Drug: Fludarabine<br>* Fludarabine/Busulfan/Alemtuzumab<br>|
| Experimental: Cyclohosphamide 200<br> | Drug: Cyclophosphamide<br>* Cyclophosphamide/Fludarabine/TMG<br>|
| Experimental: Cyclophosphamide 40<br> | Drug: Cyclophosphamide 40<br>* Cyclophosphamide/Fludarabine/ATG/TBI<br>* Other names: Cyclophosphamide;|
| Experimental: Cyclophosphamide 30<br> | Drug: Cyclophosphamide 30<br>* Cyclophosphamide /Fludarabine/TMG<br>* Other names: Cyclophosphamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| This study is to determine the toxicity of administering a fludarabine/cyclophosphamide (Flu/CY) or busulfan (Bu)/Flu based conditioning regimen followed by allogeneic stem cell transplant. |  | Day 30, Day 60, Day 100, 1 year, 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the risk of disease progression (including neuropsychological deterioration in patients with metabolic non-malignant diseases) following a Flu/CY or Bu/Flu based conditioning regimen. |  | Day 30, Day 60, Day 100, 1 year | 
| To measure immune reconstitution following a Flu/CY or Bu/Flu based conditioning regimen and AlloSCT in patients with selected non-malignant diseases. |  | Day 30, Day 60, Day 100, 1 year | 
| To estimate the incidence and severity of GVHD following a Flu/Cy or Bu/Flu based conditioning regimen |  | Day 30, Day 60, Day 100, 1 year | 
| To determine metabolic/immune (gene/protein) reconstitution by standard biochemical/PCR assays in patients |  | Day 30, Day 60, Day 100, 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone marrow Failure, Fanconi, SCID