Osteopetrosis
Conditions
Keywords
Osteopetrosis, Autosomal recessive bone disease, Haploidentical stem cell transplantation, Allogeneic stem cell transplantation, T-cell depletion methodology, Miltenyi Biotec CliniMACS stem cell selection device
Brief summary
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.
Detailed description
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
Interventions
PROCEDUREStem Cell Transplantation
An infusion of HLA partially matched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.
Stem cell selection device
Haploidentical stem cell transplant recipients will receive a reduced intensity conditioning regimen consisting of OKT-3, Fludarabine, Thiotepa , and Melphalan followed by an infusion of a T-cell depleted donor stem cell product. Rituximab will be administered within 24 hours of the infusion in an effort to prevent post transplantation lymphoproliferative disorders (PTLPD). In addition to T-cell depletion of the donor product, cyclosporine will be provided as prophylaxis for (GVHD)Graft versus Host Disease Recipients of a matched sibling donor product will receive a myeloablative conditioning regimen consisting of busulfan and cyclophosphamide. Cyclosporine will be administered for GVHD prophylaxis.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment | 100 days post-transplant | To determine the need for blood or platelet transfusions and the presence of donor cells being present in the transplant recipient's bone marrow or peripheral blood by 100 day after transplantation for children with malignant infantile osteopetrosis who have received a haploidentical stem cell graft. |
Countries
United States
Participant flow
Recruitment details
OPBMT2 was activated, July 2004. From September, 2004 through February, 2008, six transplant participants, five donors, and four genetic testing participants were recruited and enrolled on the study.
Pre-assignment details
Of the fifteen enrollments, the donors and genetic-testing participants did not receive transplants. Of the six transplant participants, five where eligible for and received a haploidentical hematopoietic stem cell transplant (HSCT) and one received a sibling donor HSCT.
Participants by arm
| Arm | Count |
|---|---|
| Haplo Patients to receive a haploidentical hematopoietic stem cell transplantation (HSCT). | 5 |
| Sibling Genetic testing | 1 |
| Total | 6 |
Baseline characteristics
| Characteristic | Haplo | Sibling | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 1 Participants | 6 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 1 / 1 |
| serious Total, serious adverse events | 5 / 5 | 1 / 1 |
Outcome results
Primary
Engraftment
To determine the need for blood or platelet transfusions and the presence of donor cells being present in the transplant recipient's bone marrow or peripheral blood by 100 day after transplantation for children with malignant infantile osteopetrosis who have received a haploidentical stem cell graft.
Time frame: 100 days post-transplant
Population: From September 2004 to March 2009, 5 consecutive MIOP patients were treated using mismatched family member donors. Favorable engraftment refers to the transplant patient not requiring blood or platelet transfusions and the presence of donor cells being present in the transplant recipient's bone marrow or peripheral blood.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haplo | Engraftment | Favorable engraftment | 5 Participants |
| Haplo | Engraftment | Un-favorable engraftment | 0 Participants |
| Sibling | Engraftment | Favorable engraftment | 1 Participants |
| Sibling | Engraftment | Un-favorable engraftment | 0 Participants |