Reduced Intensity AlloTransplant For Osteopetrosis

Study Overview
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Brief Summary
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We believe that hematopoietic stem cell transplantation (HSCT) will help subjects with Osteopetrosis generate functioning osteoclasts, and by so doing assist in the resolution of the abnormal bone architecture, and the anemia and bone marrow failure that is also characteristic of this disease. However, we have found in past studies that approximately 30% of Osteopetrosis patients do not engraft. Therefore, in this study, we plan to use a different combination of pre-transplant drugs to try to make transplants safer for this disease, as well as to provide a second infusion of stem cells in patients with matched related or unrelated donors. The purpose of this research is to find a safer and more effective means of performing stem cell transplantation in patients with Osteopetrosis, using chemotherapy and radiation designed to bring about engraftment and lessen transplant mortality.

Detailed Description
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This transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include microarray analysis, Campath levels just prior to the administration of the graft, and establishment of mesenchymal stem cell lines. In older patients, studies to evaluation osteoclast differentiation and function will also be offered.

Official Title
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Reduced Intensity Allogeneic Transplantation For Severe Osteopetrosis Incorporating A Second Cd34 Selected Graft

Conditions
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Osteopetrosis

Intervention / Treatment
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* Procedure: Stem Cell or Umbilical Cord Blood Transplantation
* Drug: Campath, Busulfan, Clofarabine
* Procedure: Total Lymphoid Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for transplantation under this protocol will be <45 years of age, and will be diagnosed with severe osteopetrosis. This will be defined as having the following manifestations of the disease. Bones that are uniformly markedly dense based on skeletal survey No history that would suggest autosomal dominant inheritance Evidence of hematologic changes that are attributed to the underlying disease, including the need for ongoing transfusions, OR the presence of progressive anemia or thrombocytopenia, OR a white blood cell differential with a predominance of immature forms and evidence of extramedullary hematopoiesis, OR persistence of serious infectious complications that are thought to be due to the abnormal architecture of the bone that are resistant to surgical and medical interventions. Exclusion Criteria: Patients >45 years of age Evidence of hepatic failure pulmonary dysfunction sufficient to substantially increase the risk of transplant Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted. Cardiac compromise sufficient to substantially increase the risk of transplantation Severe, stable neurologic impairment. Human immunodeficiency virus (HIV) positivity. Pregnant or lactating females

Ages Eligible for Study
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Maximum Age: 45 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intent-To-Treat<br>Patients enrolled and received study treatment. | Procedure: Stem Cell or Umbilical Cord Blood Transplantation<br>* Stem Cell (unrelated or matched related donor grafts (both peripheral blood and marrow) infusion on Day 0 and 42; Umbilical Cord Blood on Day 0 and 42<br>* Other names: Bone Marrow Transplant;Drug: Campath, Busulfan, Clofarabine<br>* 12 Campath-1H 0.3 mg/kg intravenously (IV) over 2 hours 11 Campath-1H 0.3 mg/kg intravenously over 2 hours 10 Campath-1H 0.3 mg/kg intravenously over 2 hours 9 Busulfan <12 kg: 2.2 mg/kg/dose IV every 12 hours >12 kg: 1.6 mg/kg/dose IV every 12 hours 8 Busulfan <12 kg: 2.2 mg/kg/dose IV every 12 hours >12 kg: 1.6 mg/kg/dose IV every 12 hours 7 Rest 6 Clofarabine 40 mg/m2 intravenously over 2 hours 5 Clofarabine 40 mg/m2 intravenously over 2 hours 4 Clofarabine 40 mg/m2 intravenously over 2 hours 3 Clofarabine 40 mg/m2 intravenously over 2 hours 2 Clofarabine 40 mg/m2 intravenously over 2 hours<br>* Other names: Busulfex, Clolar,Alemtuzumab;Procedure: Total Lymphoid Irradiation<br>* Dose 500 cGy via anteroposterior (AP) and posteroanterior (PA) fields (250 cGy AP and 250 cGy PA).<br>* Other names: Therapuetic radation, radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Donor Cell Engraftment | Number of patients with persistent presence of donor-derived cells at Day 100 | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Transplant Related Death | Number of participants died during study by Day 100 and reason for death was related to transplant. | Day 100 | 
| Number of Patients With Transplant Related Toxicity | Number of patients experiencing adverse effects due to transplant categorized by body system using Common Terminology Criteria for Adverse Events coding from the National Cancer Institute, Version 3.0. | Day 100 | 
| Differential Imaging and Biologic Evaluations | These outcome measures were not assessed due to early study termination. | Day 100, 6 months, 1, 2 and 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteopetrosis