Diamond-Blackfan Anemia, Severe Congenital Neutropenia, Shwachman-Diamond Syndrome, Sickle Cell Disease, Thalassemia
Conditions
Keywords
high risk hemoglobinopathy, stem cell transplant, donor lymphocyte infusion, transfusion dependent, stem cell donor, cord blood, marrow, transfusion dependent non-malignant hematologic disorders
Brief summary
This study tests the clinical outcomes of one of two preparative regimens (determined by available donor source) in patients with non-malignant hemoglobinopathies. The researchers hypothesize that these regimens will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease. Regimen A2 has replaced Regimen A in this study. Two patients were treated on Regimen A but did not have evidence of initial engraftment thus triggering the stopping rule for that arm of this study.
Detailed description
Prior to transplantation, subjects will receive either: Cyclophosphamide, Fludarabine, Campath, Total body irradiation (TBI) Or Busulfan, Cyclophosphamide, antithymocyte globulin (ATG), granulocyte colony-stimulating factor (GSCF) These drugs (and the radiation) are being given to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter. After stem cell transplantation, subjects will be given cyclosporine-A and mycophenolate (MMF)/or Methylprednisone/or Methotrexate to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.
Interventions
DRUGBusulfan, Fludarabine, ATG, TLI
Busulfan 0.8 mg/kg/dose intravenous (IV) Days -8 and -7 Fludarabine 35 mg/m2 IV Days -6 through -2 Antithymocyte globulin (ATG) 30 mg/kg IV Days -2 and -1 Total lymphoid radiation 300 cGy
DRUGBusulfan, Cyclophosphamide, ATG, GCSF
Busulfan 0.8 mg/kg/dose intravenous (IV) Days -9 through -6 Cyclophosphamide 50 mg/kg IV Days -5 through -2 ATG 30 mg/kg IV Day -1 GCSF 5 mcg/kg/day IV until ANC \>2500 x 2 days.
DRUGCampath, Fludarabine, Cyclophosphamide
Receives Campath-1H 0.2 mg/kg Days -10 through -6, Fludarabine 35 mg/m2 intravenous (IV) Days -6 through -2, total body irradiation (TBI) 300 cGy Day -1.
RADIATIONTotal Body Irradiation
300 cGY Day -1
PROCEDUREStem cell infusion
Given Day 0
Sponsors
National Marrow Donor Program
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 50 Years
Healthy volunteers
No
Inclusion criteria
* Patients with Sickle Cell Disease/Thalassemia (SCD/THAL) 0-50 years of age with an acceptable stem cell donor and disease characteristic defined by the following: * Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral magnetic resonance imaging (MRI) or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing * Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions * Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism, * Impaired neuropsychological function and abnormal cerebral MRI scan * Stage I or II sickle lung disease, * Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate \[GFR\] 30-50% of the predicted normal value) * Bilateral proliferative retinopathy and major visual impairment in at least one eye * Osteonecrosis of multiple joints with documented destructive changes * Requirement for chronic transfusions but with red blood cell (RBC) alloimmunization \>2 antibodies during long term transfusion therapy * Patients with transfusion dependent alpha- or beta-thalassemia 0-35 years of age with an acceptable stem cell donor as defined in the criteria in section above. * Patients with other non-malignant hematologic disorders that are transfusion-dependent or involve other potentially life-threatening cytopenias (including but not limited to Severe Congenital Neutropenia, Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome) who are 0-35 years of age with an acceptable stem cell donor * Second Transplants * Patients with sickle cell disease or thalassemia who have failed to engraft or have autologous recovery after a myeloablative SCT regimen or non-myeloablative regimen are eligible for this protocol. * Regimen A2 will be utilized for patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or for any patient who has pre-existing organ dysfunction making them ineligible for a myeloablative preparative regimen. * Regimen B will be utilized for patients with sickle cell disease or thalassemia who have an HLA-identical sibling donor. * Patients must meet above criteria. * If the patient has received prior radiation therapy, eligibility to receive additional radiation therapy must be determined by Dr. Dusenbery * If first transplant was a non-myeloablative regimen, the second transplant can occur at any time * If the first transplant was a myeloablative regimen, then the second transplant must be \> 6 months from the first transplant
Exclusion criteria
* Patients with one or more of the following: * Karnofsky or Lansky performance score \<70 * Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy * Stage III-IV lung disease * GFR\<30% predicted * Pregnant or lactating females * Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or ARC or HIV seropositivity * Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance * Patients not able to receive total lymphocytic irradiation (TLI) due to prior radiation therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity | 1 year | In general, grade 3 equates to moderate, grade 4 to severe and grade 5 to death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Chimerism at 6 Months | 6 months | The number of patients whose blood and/or bone marrow contains \> 10% donor cells. |
| The Incidence of Chimerism at 1 Year | 1 year | The number of patients whose blood and/or bone marrow contains \> 10% donor cells. |
| The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) | 100 days | The number of patients who experienced grades 2-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Grades 2-4 equate to mild to severe disease. Symptoms typically appear within weeks after transplant. |
| The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) | 100 days | The number of patients who experienced grades 3-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. IGrades 3-4 equate to moderate to severe disease. Symptoms typically appear within weeks after transplant. |
| The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 6 months | The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant. |
| The Incidence of Chimerism at 100 Days | 100 days | The number of patients whose blood and/or bone marrow contains \> 10% donor cells. |
| Determine Physical Characteristics and Biologic Effects of Mixed Populations of Donor and Host Red Blood Cells | During study | — |
| Determine the Concentration of Campath in the Serum | Day 0 | — |
| Overall Survival | 100 days | Number of patients alive 100 days after transplant. |
| Disease Free Survival | 100 days | Number of patients alive without disease 100 days after transplant. |
| Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | pre-transplant | The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Full Conditioning (Discontinued / A) Full Preparative Regimen for subjects with matched donors using Busulfan on Day -8 and -7, Fludarabine on Day -6 through -2, antithymocyte globulin (ATG) on Day -2 through -1, total lymphoid radiation (TLI) on Day -1, stem cell infusion on Day 0.
Busulfan, Fludarabine, ATG, TLI: Busulfan 0.8 mg/kg/dose intravenous (IV) Days -8 and -7 Fludarabine 35 mg/m2 IV Days -6 through -2 Antithymocyte globulin (ATG) 30 mg/kg IV Days -2 and -1 Total lymphoid radiation 300 cGy | 3 |
| Busulfan Conditioning (B) Myeloablative Preparative Regimen for subjects with HLA identical sibling donors consists of Busulfan on day -9 through -6, Cyclophosphamide on day -5 through -2, ATG on day -3 through -1, stem cell infusion on Day 0 and Granulocyte Colony Stimulating Factor on day -3 until ANC \>2500 x 2 days.
Busulfan, Cyclophosphamide, ATG, GCSF: Busulfan 0.8 mg/kg/dose intravenous (IV) Days -9 through -6 Cyclophosphamide 50 mg/kg IV Days -5 through -2 ATG 30 mg/kg IV Day -1 GCSF 5 mcg/kg/day IV until ANC \>2500 x 2 days.
Total Body Irradiation: 300 cGY Day -1
Stem cell infusion: Given Day 0 | 5 |
| Campath and TBI Conditioning (A2) Patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or who has pre-existing organ dysfunction making myeloablative condition ineligible will receive Campath on day -10 through -6, Cyclophosphamide on day -7, Fludarabine on day -6 through -2, total body irradiation (TBI) on day -1, stem cell infusion on Day 0.
Campath, Fludarabine, Cyclophosphamide: Receives Campath-1H 0.2 mg/kg Days -10 through -6, Fludarabine 35 mg/m2 intravenous (IV) Days -6 through -2, total body irradiation (TBI) 300 cGy Day -1.
Total Body Irradiation: 300 cGY Day -1
Stem cell infusion: Given Day 0 | 14 |
| Total | 22 |
Baseline characteristics
| Characteristic | Full Conditioning (Discontinued / A) | Busulfan Conditioning (B) | Campath and TBI Conditioning (A2) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 5 Participants | 12 Participants | 20 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 13 / 14 |
| serious Total, serious adverse events | 2 / 3 | 0 / 5 | 0 / 14 |
Outcome results
Primary
Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity
In general, grade 3 equates to moderate, grade 4 to severe and grade 5 to death.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity | 0 Participants |
| MA Bu/Cy (B) | Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity | 0 Participants |
| RIC Cy/Flu/TBI (A2) | Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity | 2 Participants |
Secondary
Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death.
Time frame: pre-transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
| MA Bu/Cy (B) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 98 units on a scale |
| RIC Cy/Flu/TBI (A2) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 99 units on a scale |
Secondary
Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death.
Time frame: 2 years
Population: Two of the 14 patients treated on Arm A2 died before 2 years and 2 failed their 2 year clinic appointment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
| MA Bu/Cy (B) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
| RIC Cy/Flu/TBI (A2) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
Secondary
Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death.
Time frame: 1 year
Population: Two of the 14 patients treated on Arm A2 died before 1 year.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 97 units on a scale |
| MA Bu/Cy (B) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
| RIC Cy/Flu/TBI (A2) | Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | 100 units on a scale |
Secondary
Determine Physical Characteristics and Biologic Effects of Mixed Populations of Donor and Host Red Blood Cells
Time frame: During study
Population: data were not collected
Secondary
Determine the Concentration of Campath in the Serum
Time frame: Day 0
Population: The Principal Investigator removed this as a study objective and therefore Campath concentrations were not collected.
Secondary
Disease Free Survival
Number of patients alive without disease 1 year after transplant.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Disease Free Survival | 3 Participants |
| MA Bu/Cy (B) | Disease Free Survival | 5 Participants |
| RIC Cy/Flu/TBI (A2) | Disease Free Survival | 11 Participants |
Secondary
Disease Free Survival
Number of patients alive without disease 100 days after transplant.
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Disease Free Survival | 3 Participants |
| MA Bu/Cy (B) | Disease Free Survival | 5 Participants |
| RIC Cy/Flu/TBI (A2) | Disease Free Survival | 11 Participants |
Secondary
Overall Survival
Number of patients alive 100 days after transplant.
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Overall Survival | 3 Participants |
| MA Bu/Cy (B) | Overall Survival | 5 Participants |
| RIC Cy/Flu/TBI (A2) | Overall Survival | 12 Participants |
Secondary
Overall Survival
Number of patients alive 1 year after transplant.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | Overall Survival | 3 Participants |
| MA Bu/Cy (B) | Overall Survival | 5 Participants |
| RIC Cy/Flu/TBI (A2) | Overall Survival | 12 Participants |
Secondary
The Incidence of Chimerism at 100 Days
The number of patients whose blood and/or bone marrow contains \> 10% donor cells.
Time frame: 100 days
Population: One of the 3 patients treated on Arm A was retreated at Day 40 and was not evaluable. One of the 14 patients on Arm A2 died before 100 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Chimerism at 100 Days | 1 Participants |
| MA Bu/Cy (B) | The Incidence of Chimerism at 100 Days | 5 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Chimerism at 100 Days | 11 Participants |
Secondary
The Incidence of Chimerism at 1 Year
The number of patients whose blood and/or bone marrow contains \> 10% donor cells.
Time frame: 1 year
Population: One of the 3 patients treated on Arm A was retreated at Day 40 and was not evaluable. One of the 14 patients on Arm A2 died before 1 year.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Chimerism at 1 Year | 1 Participants |
| MA Bu/Cy (B) | The Incidence of Chimerism at 1 Year | 5 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Chimerism at 1 Year | 8 Participants |
Secondary
The Incidence of Chimerism at 6 Months
The number of patients whose blood and/or bone marrow contains \> 10% donor cells.
Time frame: 6 months
Population: One of the 3 patients treated on Arm A was retreated at Day 40 and was not evaluable. One of the 14 patients on Arm A2 died before 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Chimerism at 6 Months | 1 Participants |
| MA Bu/Cy (B) | The Incidence of Chimerism at 6 Months | 5 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Chimerism at 6 Months | 8 Participants |
Secondary
The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD)
The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
| MA Bu/Cy (B) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
Secondary
The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD)
The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
| MA Bu/Cy (B) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | 0 Participants |
Secondary
The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD)
The number of patients who experienced grades 2-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Grades 2-4 equate to mild to severe disease. Symptoms typically appear within weeks after transplant.
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |
| MA Bu/Cy (B) | The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |
Secondary
The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD)
The number of patients who experienced grades 3-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. IGrades 3-4 equate to moderate to severe disease. Symptoms typically appear within weeks after transplant.
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIC Bu/Flu (A) (Discontinued) | The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |
| MA Bu/Cy (B) | The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |
| RIC Cy/Flu/TBI (A2) | The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) | 0 Participants |