Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Conditions
Keywords
Stem cell transplant, T-cell depletion, TLI, bone marrow failure disorders
Brief summary
The researchers hypothesize that it will be possible to perform unrelated bone marrow or cord blood transplants in a safer manner by using less intensive therapy yet still achieve an acceptable level of donor cell engraftment for non-malignant congenital bone marrow failure disorders.
Detailed description
Prior to transplantation, subjects will receive the drugs busulfan (orally or through the catheter), as well as fludarabine and anti-thymocyte globulin (ATG) via the catheter. Busulfan, fludarabine and ATG will be given with Total Lymphoid Irradiation (TLI) to help the new donor bone marrow take and grow after transplantation. Those patients receiving donor marrow will have the T cells (a type of white blood cell in the donor marrow) removed to lower the risk that the new marrow will react to their body, a condition called Graft-Versus-Host-Disease (GVHD). After bone marrow transplantation, subjects will receive drugs to help prevent GVHD, including cyclosporin and mycophenolate mofetil (MMF). Blood samples are taken at day 28, day 60, day 100, 1 year and as required by medical status yearly for five years after transplant to evaluate how well the new marrow is growing. A bone marrow biopsy is required at day 21, at day 100 and 1 year.
Interventions
PROCEDUREStem cell transplant
Stem cell transplant on Day 0 - healthy marrow from an unrelated individual. A minimum of 1.0 x 10\^9/kg nucleated cells/kg ideal body weight will be collected with a goal of 2.0 x 10\^9/kg.
fludarabine 175 mg/m\^2 (total) on Days -6 through -3.
PROCEDURETotal lymphoid irradiation
Dose 500 cGy radiation therapy to specific areas of the body
DRUGBusulfan
Busulfan 8 mg/kg (total) on Days - 8 and -7 (orally or through the catheter),
BIOLOGICALanti-thymocyte globulin
anti-thymocyte globulin (ATG) 15 mg/kg on days -2 and -1 via catheter
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
No minimum to 35 Years
Healthy volunteers
No
Inclusion criteria
* Patients eligible for transplantation under this protocol will be \<35 years of age, and will be diagnosed with: * a bone marrow failure syndrome unresponsive to available therapy, including but not limited to Diamond-Blackfan anemia, Shwachman Diamond syndrome or Kostmann's neutropenia but exclusive of aplastic anemia. * Diamond Blackfan Anemia: * Patients must show evidence of steroid resistance requiring equivalent of \>6 transfusions yearly despite steroid therapy. * Evidence of developing aplasia or myelodysplasia will also be criteria for transplantation. * Kostmann's Neutropenia, Shwachman-Diamond syndrome: * Patients must have been previously diagnosed as having a clinical picture characteristic of Shwachman-Diamond syndrome (exocrine pancreatic insufficiency, growth retardation, metaphyseal dysostosis, neutropenia), or must have a bone marrow aspirate consistent with Kostmann's neutropenia, with no evidence of acute leukemia. * Patients must have failed therapy with granulocyte-colony stimulating factor (G-CSF), as determined by an inability to maintain an absolute neutrophil count (ANC) \>750 cells/ml(3), or manifesting recurrent infections despite G-CSF administration resulting in life threatening infections or repeated hospitalizations (\<4 /year).
Exclusion criteria
* Patients \>35 years of age * Karnofsky score \<70% * Hepatic dysfunction as determined by bilirubin \>3.0, ALT \>150, or active hepatitis * Pulmonary function tests with forced volume vital capacity (FVC) and forced expiratory volume (FEV) \<70%; O2 saturation \<94% * Renal dysfunction with glomerular filtration rate (GFR) \<30% of predicted. * Cardiac compromise, with left ejection fraction \<45%. * Severe, stable neurologic impairment. * Human immunodeficiency virus (HIV) positivity. * Pregnant or lactating females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Alive (Survival) at 2 Years | 2 years | Calculated from day 1 of transplant to last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Alive at Three Years (Survival) | 3 years | Number of subjects who survived 3 years post-transplant. |
| Number of Patients With Succcessful Engraftment After Transplantation | 42 Days | Number of patients who received non-genotypic identical marrow or cord blood cells using a non-myeloablative preparative regimen and exhibited engraftment at Day 42. |
| Number of Patients With Grade 2-4 Acute Graft Versus Host Disease | 100 Days | Number of patients with Grade 2, 3 and 4 Acute (normally observed within the first 100 days) Graft Versus Host Disease. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening. |
| Number of Patients With Chronic Graft Versus Host Disease | 2 years | Number of patients who exhibited chronic (normally occurs after 100 days) Graft Versus Host Disease at 2 years post transplant. Chronic graft-versus-host-disease, over its long-term course, can also cause damage to the connective tissue and exocrine glands. |
| Number of Patients With Disease Recurrence | 2 years | Number of patients who exhibited disease recurrence at 2 years. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bone Marrow Failure Patients All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Bone Marrow Failure Patients |
|---|---|
| Age, Categorical <=18 years | 10 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.8 years STANDARD_DEVIATION 7.6 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 5 / 10 |
Outcome results
Primary
Number of Patients Alive (Survival) at 2 Years
Calculated from day 1 of transplant to last contact.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients Alive (Survival) at 2 Years | 6 Participants |
Secondary
Number of Patients Alive at Three Years (Survival)
Number of subjects who survived 3 years post-transplant.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients Alive at Three Years (Survival) | 6 Participants |
Secondary
Number of Patients With Chronic Graft Versus Host Disease
Number of patients who exhibited chronic (normally occurs after 100 days) Graft Versus Host Disease at 2 years post transplant. Chronic graft-versus-host-disease, over its long-term course, can also cause damage to the connective tissue and exocrine glands.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients With Chronic Graft Versus Host Disease | 3 Participants |
Secondary
Number of Patients With Disease Recurrence
Number of patients who exhibited disease recurrence at 2 years.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients With Disease Recurrence | 0 Participants |
Secondary
Number of Patients With Grade 2-4 Acute Graft Versus Host Disease
Number of patients with Grade 2, 3 and 4 Acute (normally observed within the first 100 days) Graft Versus Host Disease. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening.
Time frame: 100 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients With Grade 2-4 Acute Graft Versus Host Disease | 5 Participants |
Secondary
Number of Patients With Succcessful Engraftment After Transplantation
Number of patients who received non-genotypic identical marrow or cord blood cells using a non-myeloablative preparative regimen and exhibited engraftment at Day 42.
Time frame: 42 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bone Marrow Failure Patients | Number of Patients With Succcessful Engraftment After Transplantation | 10 Participants |