Allogeneic Transplantation For Severe Osteopetrosis

Study Overview
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Brief Summary
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The purpose of this research is to explore what we believe may be 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. Prior multi-institutional data in past studies found that approximately 30% of Osteopetrosis patients do not engraft. Therefore, in this study, we utilize a reduced intensity design 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.

Detailed Description
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This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol and a second infusion of stem cells on day 42, 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, and evaluation of blood parameters and genes that may be important in the disease process. In older patients, studies to evaluation osteoclast differentiation and function will also be offered.

Official Title
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Allogeneic Hematopoietic Stem Cell Transplantation For Severe Osteopetrosis

Conditions
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Severe Osteopetrosis

Intervention / Treatment
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* Procedure: umbilical cord blood transplantation
* Drug: Campath-1H
* Radiation: Total Lymphoid Irradiation
* Drug: Cyclophosphamide
* Drug: Busulfan
* Drug: Fludarabine monophosphate
* Procedure: marrow graft transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for transplantation under this protocol will be < or = 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 significantly 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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Minimum Age: 1 Day
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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: marrow graft transplant conditioning<br>Pre-transplant conditioning using Campath-1H, Busulfan, Fludarabine monophosphate, and total lymphoid irradiation followed by unrelated or matched related donor marrow graft transplantation (both peripheral blood and marrow) and a second CD34 cell infusion on Day 42. | Drug: Campath-1H<br>* Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.<br>* Other names: Alemtuzumab;Radiation: Total Lymphoid Irradiation<br>* Dose 500 cGy via anteroposterior (AP) and posteroanterior(PA) fields (250 cGy AP and 250 cGy PA).<br>* Other names: TLI;Drug: Busulfan<br>* patients<12 kg: 1.1 mg/kg/dose IV every 6 hours for 8 doses total; patients >12 kg: 0.8 mg/kg/dose IV every 6 hours for 8 doses. on Day -8 to -7 for donor grafts-receiving patients, and on Day -9 to -6 for cord blood grafts-receiving patients.<br>* Other names: Busulfex;Drug: Fludarabine monophosphate<br>* Fludarabine (35 mg/m2 daily for 5 days, 175 mg/m2 total) will be administered IV over 30 minutes on days -6, -5, -4, -3, and -2 for donor grafts-receiving patients only.<br>* Other names: Fludara;Procedure: marrow graft transplantation<br>* Related donor marrow will be collected, processed and shipped according to existing protocols of the National Marrow Donor Program or other URD registry, with the goal of achieving a cell dose of ≥ 6.0 x 108 nucleated cells/kg. The proportion of cells that are CD34+ will be determined prior to the administration of the graft. This will allow a portion of the graft (2 x 106 CD34+ cells) to be frozen for a subsequent infusion on day +42.<br>* Other names: HSCT;|
| Active Comparator: cord blood transplant conditioning<br>Pre-transplant conditioning using Campath-1H, Busulfan and Cyclophosphamide followed by unrelated umbilical cord blood transplantation and a second smaller portion cord blood graft infusion on Day 42. | Procedure: umbilical cord blood transplantation<br>* Umbilical cord blood will be collected, processed and shipped according to existing protocols. 2 cord blood units will be utilized if available. The choice of units will be based on the HLA typing standards of the University of Minnesota Blood and Marrow Program. If 2 units are not available, a single unit may be used. If a single unit is used, the unit should provide at least 10 x 107 nucleated cells/kg recipient body weight.<br>* Other names: UCBT;Drug: Campath-1H<br>* Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.<br>* Other names: Alemtuzumab;Drug: Cyclophosphamide<br>* Cyclophosphamide (50 mg/kg/dose) will be given IV on day -4, -3, -2 and -1 over 2 hours. The total dose to be given over 4 days is 200 mg/kg for cord blood grafts-receiving patients only.<br>* Other names: Cytoxan;Drug: Busulfan<br>* patients<12 kg: 1.1 mg/kg/dose IV every 6 hours for 8 doses total; patients >12 kg: 0.8 mg/kg/dose IV every 6 hours for 8 doses. on Day -8 to -7 for donor grafts-receiving patients, and on Day -9 to -6 for cord blood grafts-receiving patients.<br>* Other names: Busulfex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Achieved Donor Cell Engraftment |  | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant Related Mortality at 100 Days |  | day 100 | 
| Transplant Related Toxicity |  | Day 100 post transplant | 
| Incidence of Grade II - IV Acute Graft-versus-host Disease |  | by Day 100 after transplant | 

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