Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation

St. Jude Children's Research Hospital

Status and phase: Completed; Phase 1

Conditions: Osteogenesis Imperfecta

Treatments: Drug: Cyclosporin; Procedure: Mesenchymal Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Busulfan; Other: Bone Marrow Cell Transplantation; Radiation: Irradiation, Total Body

Study type: Interventional

Funder types: Other

Identifiers

NCT00705120

TOIT

Details and patient eligibility

About

This protocol was a prospective, Phase I study of allogeneic bone marrow transplantation (BMT) as the primary therapy for Osteogenesis Imperfecta Types II and III. Compatible sibling donors and unrelated donors were stratified and analyzed according to the type of donor. All patients with a sibling donor will received a chemotherapy conditioning regimen; a non-T cell depleted allogeneic marrow, and GVHD prophylaxis. All patients with an unrelated donor will receive a chemoradiotherapy conditioning regimen, a T-cell depleted allogeneic marrow, and GVHD prophylaxis. The primary objective of this study was to investigate the safety and toxicity of these BMT procedures in this particular population.

Full description

The secondary objective of the protocol assessed the engraftment of donor mesenchymal cells and their ability to increase the synthesis of normal type I procollagen relative to the synthesis of mutated type I procollagen and to assess whether BMT improves the bone structure and the clinical condition of these patients with OI.

Enrollment: 9 patients

Sex: All

Ages: 3+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patient has diagnosis of OI Type II or III. Because there are no specific, defined clinical criteria consistently used to make this diagnosis, we provide the following clinical guidelines to assist in diagnosis. Any appropriate combinations of the following clinical findings will be acceptable.

Diagnosis of OI Type II

• Antenatal ultrasonography (if performed for other indications) by established obstetric impressions including short femurs, a small thoracic cage and poorly mineralized bones. Analysis of collagen synthesized from cultured cells obtained from chorionic villus sampling (CVS) may establish the diagnosis; however, no CVS will be performed specifically for enrollment into this study.
• Clinical examination including prematurity, low birth weight, characteristic facies (blue sclera, beaked nose, extremely soft calvarium), "frog-leg" hips, small thoracic cavity, fractures at birth or shortly thereafter, loose skin or lax joints that cannot be readily explained by other factors.
• Radiographic evaluation demonstrating various aspects of the characteristic picture of telescoped femur, bowed tibias, beaded ribs, flattened vertebral bodies and virtual absence of calvarial mineralization.

Diagnosis of OI Type III

• Antenatal ultrasonography (performed for other indications) by established obstetric impressions for this more moderate form of OI. Chorionic villus sampling will be accepted as above.
• Clinical examination including short stature, bony deformities, many fractures at birth or shortly thereafter. Blue scleras and dental abnormalities are also common.
• Radiographic abnormalities including thin, osteopenic bones of the limbs with evidence of fractures, growth plate abnormalities, and an undermineralized calvarium.
• Diagnosis of other diseases with possibly similar presentation to OI (e.g. hypophosphatasia and rickets) should be excluded by obtaining a serum calcium, phosphate and alkaline phosphatase. These parameters can be expected to be within normal limits (alkaline phosphatase may be somewhat elevated) in patients with OI.
• Age less than 3 years at time of transplant.
• Parents or legal guardians must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects, including treatment related mortality. Patients or their guardians will be given a copy of the consent form.
• Identification of a suitable bone marrow donor.
• Any donor must be of sufficient size so that adequate bone marrow may be harvested.
• HLA mismatched sibling or unrelated donor. DNA typing will be per- formed on unrelated donors. Donors must be a 6/6 match or a 5/6 match (with serologic mismatch at a single Class I allele or mismatch at a single DR1 allele).

Exclusion criteria

• Patients who are ventilatory dependent due to primary lung parenchymal disease prior to BMT.
• Patients with evidence of basilar invagination/compression.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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9 participants in 2 patient groups

1

Other group

Treatment:

Other: Bone Marrow Cell Transplantation

Drug: Cyclosporin

Procedure: Mesenchymal Stem Cell Transplantation

Drug: Busulfan

Drug: Cyclophosphamide

2

Other group

Treatment:

Radiation: Irradiation, Total Body

Other: Bone Marrow Cell Transplantation

Procedure: Mesenchymal Stem Cell Transplantation

Drug: Busulfan

Drug: Cyclophosphamide