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

Sponsor

Columbia University (Other)

Overall Status

Unknown status

CT.gov ID

NCT01019876

Collaborator

(none)

Enrollment

Location

Arms

131

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bone Marrow Failure Osteopetrosis Fanconi Anemia Severe Combined Immunodeficiency	Drug: Fludarabine Drug: Cyclophosphamide Drug: Cyclophosphamide 40 Drug: Cyclophosphamide 30	Phase 2/Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2002

Anticipated Primary Completion Date :

May 1, 2012

Anticipated Study Completion Date :

May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabine	Drug: Fludarabine Fludarabine/Busulfan/Alemtuzumab
Experimental: Cyclohosphamide 200	Drug: Cyclophosphamide Cyclophosphamide/Fludarabine/TMG
Experimental: Cyclophosphamide 40	Drug: Cyclophosphamide 40 Cyclophosphamide/Fludarabine/ATG/TBI Other Names: Cyclophosphamide
Experimental: Cyclophosphamide 30	Drug: Cyclophosphamide 30 Cyclophosphamide /Fludarabine/TMG Other Names: Cyclophosphamide

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.