Stem Cell Transplant for Bone Marrow Failure Syndromes

Study Overview
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Brief Summary
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The researchers hypothesize that it will be possible to perform unrelated bone marrow or cord blood transplants in a safer manner by using less intensive therapy yet still achieve an acceptable level of donor cell engraftment for non-malignant congenital bone marrow failure disorders.

Detailed Description
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Prior to transplantation, subjects will receive the drugs busulfan (orally or through the catheter), as well as fludarabine and anti-thymocyte globulin (ATG) via the catheter. Busulfan, fludarabine and ATG will be given with Total Lymphoid Irradiation (TLI) to help the new donor bone marrow take and grow after transplantation. Those patients receiving donor marrow will have the T cells (a type of white blood cell in the donor marrow) removed to lower the risk that the new marrow will react to their body, a condition called Graft-Versus-Host-Disease (GVHD). After bone marrow transplantation, subjects will receive drugs to help prevent GVHD, including cyclosporin and mycophenolate mofetil (MMF). Blood samples are taken at day 28, day 60, day 100, 1 year and as required by medical status yearly for five years after transplant to evaluate how well the new marrow is growing. A bone marrow biopsy is required at day 21, at day 100 and 1 year.

Official Title
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Bone Marrow Transplantation for Non-Malignant Congenital Bone Marrow Failure Disorders

Conditions
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Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome

Intervention / Treatment
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* Procedure: Stem cell transplant
* Drug: Fludarabine monophosphate
* Procedure: Total lymphoid irradiation
* Drug: Busulfan
* Biological: anti-thymocyte globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for transplantation under this protocol will be <35 years of age, and will be diagnosed with: a bone marrow failure syndrome unresponsive to available therapy, including but not limited to Diamond-Blackfan anemia, Shwachman Diamond syndrome or Kostmann's neutropenia but exclusive of aplastic anemia. Diamond Blackfan Anemia: Patients must show evidence of steroid resistance requiring equivalent of >6 transfusions yearly despite steroid therapy. Evidence of developing aplasia or myelodysplasia will also be criteria for transplantation. Kostmann's Neutropenia, Shwachman-Diamond syndrome: Patients must have been previously diagnosed as having a clinical picture characteristic of Shwachman-Diamond syndrome (exocrine pancreatic insufficiency, growth retardation, metaphyseal dysostosis, neutropenia), or must have a bone marrow aspirate consistent with Kostmann's neutropenia, with no evidence of acute leukemia. Patients must have failed therapy with granulocyte-colony stimulating factor (G-CSF), as determined by an inability to maintain an absolute neutrophil count (ANC) >750 cells/ml(3), or manifesting recurrent infections despite G-CSF administration resulting in life threatening infections or repeated hospitalizations (<4 /year). Exclusion Criteria: Patients >35 years of age Karnofsky score <70% Hepatic dysfunction as determined by bilirubin >3.0, ALT >150, or active hepatitis Pulmonary function tests with forced volume vital capacity (FVC) and forced expiratory volume (FEV) <70%; O2 saturation <94% Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted. Cardiac compromise, with left ejection fraction <45%. Severe, stable neurologic impairment. Human immunodeficiency virus (HIV) positivity. Pregnant or lactating females

Ages Eligible for Study
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Maximum Age: 35 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: Bone Marrow Failure Disorders<br>Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome | Procedure: Stem cell transplant<br>* Stem cell transplant on Day 0 - healthy marrow from an unrelated individual. A minimum of 1.0 x 10^9/kg nucleated cells/kg ideal body weight will be collected with a goal of 2.0 x 10^9/kg.<br>* Other names: BMT;Drug: Fludarabine monophosphate<br>* fludarabine 175 mg/m^2 (total) on Days -6 through -3.<br>* Other names: Fludara;Procedure: Total lymphoid irradiation<br>* Dose 500 cGy radiation therapy to specific areas of the body<br>* Other names: TLI;Drug: Busulfan<br>* Busulfan 8 mg/kg (total) on Days - 8 and -7 (orally or through the catheter),<br>* Other names: Busulfex;Biological: anti-thymocyte globulin<br>* anti-thymocyte globulin (ATG) 15 mg/kg on days -2 and -1 via catheter<br>* Other names: ATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Alive (Survival) at 2 Years | Calculated from day 1 of transplant to last contact. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Alive at Three Years (Survival) | Number of subjects who survived 3 years post-transplant. | 3 years | 
| Number of Patients With Succcessful Engraftment After Transplantation | Number of patients who received non-genotypic identical marrow or cord blood cells using a non-myeloablative preparative regimen and exhibited engraftment at Day 42. | 42 Days | 
| Number of Patients With Grade 2-4 Acute Graft Versus Host Disease | Number of patients with Grade 2, 3 and 4 Acute (normally observed within the first 100 days) Graft Versus Host Disease. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. | 100 Days | 
| Number of Patients With Chronic Graft Versus Host Disease | Number of patients who exhibited chronic (normally occurs after 100 days) Graft Versus Host Disease at 2 years post transplant. Chronic graft-versus-host-disease, over its long-term course, can also cause damage to the connective tissue and exocrine glands. | 2 years | 
| Number of Patients With Disease Recurrence | Number of patients who exhibited disease recurrence at 2 years. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem cell transplant, T-cell depletion, TLI, bone marrow failure disorders