Unrelated Donor Transplant for Malignant and Non-Malignant Disorders

Study Overview
=================
Brief Summary
-----------------
Unrelated matched donor (cord blood, bone marrow or peripheral blood) allogeneic stem cell transplantation (UDAlloSCT) with either myeloablative or reduced intensity conditioning will be well tolerated and result in a high degree of engraftment in patients with selected malignant and non malignant disorders.

Detailed Description
-----------------
This is a non-randomized study to determine the tolerability and degree of engraftment of unrelated matched donor allogeneic stem cell transplantation with either myeloablative or reduced intensity conditioning in patients with selected malignant and non malignant disorders. Patients will receive one of either full intensity or reduced intensity regimen based on the patient's disease status, organ function and performance and determined by the PI.

Official Title
-----------------
Unrelated Donor Stem Cell Transplant for Patients With Malignant and Non-Malignant Disorders

Conditions
-----------------
Leukemia, Lymphoma, Bone Marrow Failure Syndromes, Immunodeficiencies, Histiocytosis

Intervention / Treatment
-----------------
* Procedure: UDAlloSCT
* Other: Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adequate renal function defined as: serum creatinine 2.0 x normal, or creatinine clearance or radioisotope GFR > 40 ml/min/m2 or > 40 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range. Adequate liver function defined as: total bilirubin < 2.5 x normal; or SGOT (AST) or SGPT (ALT) < 5.0 x normal. Adequate cardiac function defined as: shortening fraction of > 25% by echocardiogram, or ejection fraction of > 40% by radionuclide angiogram or echocardiogram. Adequate pulmonary function defined as: DLCO > 35% by pulmonary function test. For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% in room air. Diseases: CML (CP, AP or BC) AML/MDS/JCML ALL Lymphoma (Hodgkin's and non-Hodgkin's) Non-malignant disorders Bone Marrow Failure Syndromes: Patients with the following diagnoses are eligible: Severe Aplastic Anemia: Fanconi Anemia Severe Congenital Neutropenia (Kostmann's Syndrome) Amegakaryocytic Thrombocytopenia Diamond-Blackfan Anemia Infantile Osteopetrosis Schwachman-Diamond Syndrome Dyskeratosis Congenita Other bone marrow failure syndromes at discretion of Principal Investigator Immunodeficiencies: SCIDS, all subtypes Combined Immunodeficiency Syndrome Wiskott-Aldrich syndrome Chronic Granulomatous Disease Chediak-Higashi Syndrome Leukocyte Adhesion Deficiency Other immunodeficiencies at discretion of Principal Investigator Inborn Errors of Metabolism (IEOM): Transplant is recommended for the following disorders: Hurler syndrome (L-iduronidase deficiency, MPS-I), Maroteaux-Lamy syndrome (galactosamine-4-sulfatase deficiency, MP VI), Sly syndrome (glucuronidase deficiency, MPS-VII), Globoid cell Leukodystrophy (galactocerebrosidasedeficiency), Metachromatic leukodystrophy (arylsulfatase A deficiency), Childhood-onset X-linked adrenoleukodystrophy (X-ALD), Fucosidosis (fucosidase deficiency), Mannosidosis, Aspartylglucosaminuria, Niemann-Pick Disease Type B (acid sphingomyelinase deficiency), Gaucher disease (glucocerebrosidase deficiency) Type I (non neuropathic), Other diagnoses may be considered at the discretion of the Principal Investigator 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 patients less than 5 years of age, the developmental quotient or clinical neurodevelopmental examination should demonstrate potential for stabilization at a level of functioning where continuous life support (e.g. mechanical ventilation) would not be predicted to be required in the year following transplantation. Histiocytosis: Hemophagocytic Lymphohistiocytosis (HLH) Familial Erythrophagocytic Lymphohistiocytosis Langerhans Cell Histiocytosis Malignant Histiocytosis Other Malignant and non-malignant diseases: Other malignant and non-malignant diseases not listed above may be eligible if deemed appropriate by the Principal Investigator. Exclusion Criteria: Women who are pregnant and/or breast feeding are ineligible

Ages Eligible for Study
-----------------
Maximum Age: 55 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UDAlloSCT + Therapy<br>This is a non-randomized study to test the safety and response of unrelated matched donor allogeneic stem cell transplantation (UDAlloSCT) with either myleoablative (full intensity) or reduced intensity conditioning therapy in patients with selected malignant and non-malignant disorders. UDAlloSCT has been performed in both adults and children as an alternative transplant for patients who lack and HLA-matched family donor in both malignant and non-malignant disease with varying degrees of response. | Procedure: UDAlloSCT<br>* unrelated matched donor allogeneic stem cell transplantation (UDAlloSCT)<br>Other: Therapy<br>* Full Intensity Therapy (myeloablative) (TBI + Thiotepa + Cyc) OR Reduced Intensity Therapy (Fludarabine, Busulfan, and Alemutuzumab (FBA))<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity related to myeloablative therapy | To determine the safety and toxicity of myeloablative therapy (TBI + Melphalan) and unrelated donor alloSCT in selected patients with malignant and non-malignant disorders. | Up to 10 years from start of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity related to reduced intensity therapy | To determine the safety and toxicity of reduced intensity therapy (Fludarabine, Busulfan, and Alemtuzumab (FBA) and unrelated donor alloSCT in selected patients with malignant and non malignant disorders | Up to 10 years from start of study | 
| Percentage of donor chimerism | To quantitate the percentage of donor chimerism following both myeloablative and reduced intensity conditioning and unrelated donor alloSCT in selected patients with malignant and non-malignant disorders. | Up to 10 years from start of study | 
| Prevalence of progression free survival | To estimate the progression free survival (PFS), if applicable, event free survival (EFS) and overall survival (OS) following unrelated donor alloSCT in selected patients with malignant and non malignant disorders. | Up to 10 years from start of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Allogeneic Stem Cell Transplant, Unrelated donor, Cord blood donor