Stem Cell Transplantation for Children Affected With Osteopetrosis

Allogeneic Hematopoietic Stem Cell Transplantation for Children Affected With Malignant Osteopetrosis: A Pilot Study

Malignant infantile osteopetrosis (MIOP) is a rare fatal genetic disorder that is characterized by the bone's inability to regulate remodeling. The only curative therapy is hematopoietic stem cell transplantation. Stem cells provided from an HLA identical matched sibling donor is the standard of care, but not feasible for the majority of patients. In addition, due to the potentially rapid progression of this disease, the time to identify a suitable HLA matched unrelated donor is not optimal. Therefore this study is designed to test the hypothesis that children with osteopetrosis can properly engraft hematopoietic stem cells that are donated from a partially matched parental donor, or "haploidentical" stem cell donor that are processed on the investigational device, CliniMACS selection system.

The primary objective of this trial will be answered strictly by those patients enrolled who receive a haploidentical stem cell donor graft.

Patients with a matched sibling donor will be offered participation in this clinical trial and will receive a standard myeloablative conditioning regimen followed by the infusion of an unmanipulated bone marrow graft. However, data from these transplant recipients will be reported in a descriptive manner only.

Secondary Objectives in this trial include the following:

• To describe the outcome of children with MIOP who receive hematopoietic stem cells from a matched sibling donor or a haploidentical donor utilizing a uniform approach one year from transplant
• To estimate the fraction of children with MIOP who have a genetic defect correlating to the osteopetrosis phenotype
• To assess carrier-state of the genetic mutation in parents with an affected child
• To assess carrier-state of the genetic mutation in siblings of affected children
• To estimate the effect of age at the time of hematopoietic stem cell transplantation on the overall outcome of children with MIOP
• To describe the kinetics of select cytokine expression before and after transplantation

Inclusion Criteria:

• Clinical diagnosis of malignant osteopetrosis as documented by bone marrow biopsy and radiographic imaging
• A suitable hematopoietic stem cell donor is available

Exclusion Criteria:

• Participant has the Carbonic Anhydrase II (CAII) deficiency osteopetrosis variant
• Symptomatic cardiac disease or evidence of significant cardiac dysfunction by ECHO (shortening fraction <30%)
• Creatinine clearance ≤ 40ml/min/1.73m^2
• Bilirubin ≥ 3mg/dL
• SGPT ≥ 500 U/L
• Evidence of current severe infection which would preclude ablative chemotherapy or a successful transplantation
• Karnofsky or Lansky score < 70 noting expected abnormalities