Severe Osteopetrosis
Conditions
Keywords
osteopetrosis
Brief summary
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
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.
Interventions
PROCEDUREumbilical cord blood transplantation
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.
DRUGCampath-1H
Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.
RADIATIONTotal Lymphoid Irradiation
Dose 500 cGy via anteroposterior (AP) and posteroanterior(PA) fields (250 cGy AP and 250 cGy PA).
DRUGCyclophosphamide
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.
DRUGBusulfan
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.
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.
PROCEDUREmarrow graft transplantation
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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 45 Years
Healthy volunteers
No
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. 1. Bones that are uniformly markedly dense based on skeletal survey 2. No history that would suggest autosomal dominant inheritance 3. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients Who Achieved Donor Cell Engraftment | Day 100 |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Marrow Graft Transplant Conditioning 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.
Campath-1H: Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.
Total Lymphoid Irradiation: Dose 500 cGy via anteroposterior (AP) and posteroanterior(PA) fields (250 cGy AP and 250 cGy PA).
Busulfan: 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.
Fludarabine monophosphate: 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. | 6 |
| Cord Blood Transplant Conditioning 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.
Campath-1H: Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.
Busulfan: 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.
Cyclophosphamide: 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 | 1 |
| Total | 7 |
Baseline characteristics
| Characteristic | Marrow Graft Transplant Conditioning | Cord Blood Transplant Conditioning | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 0 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 1 / 1 |
| serious Total, serious adverse events | 3 / 6 | 0 / 1 |
Outcome results
Primary
Number of Patients Who Achieved Donor Cell Engraftment
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Graft Transplant Conditioning | Number of Patients Who Achieved Donor Cell Engraftment | 5 Participants |
| Cord Blood Transplant Conditioning | Number of Patients Who Achieved Donor Cell Engraftment | 0 Participants |
Secondary
Incidence of Grade II - IV Acute Graft-versus-host Disease
Time frame: by Day 100 after transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Graft Transplant Conditioning | Incidence of Grade II - IV Acute Graft-versus-host Disease | 2 Participants |
| Cord Blood Transplant Conditioning | Incidence of Grade II - IV Acute Graft-versus-host Disease | 0 Participants |
Secondary
Transplant Related Mortality at 100 Days
Time frame: day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Graft Transplant Conditioning | Transplant Related Mortality at 100 Days | 0 Participants |
| Cord Blood Transplant Conditioning | Transplant Related Mortality at 100 Days | 0 Participants |
Secondary
Transplant Related Toxicity
Time frame: Day 100 post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Marrow Graft Transplant Conditioning | Transplant Related Toxicity | 3 Participants |
| Cord Blood Transplant Conditioning | Transplant Related Toxicity | 1 Participants |