Non Malignant Disorders, Immunodeficiencies, Congenital Marrow Failures, Hemoglobinopathies, Inborn Errors of Metabolism, Sickle Cell, Thalassemia, Lysosomal Storage Disease
Conditions
Keywords
Immunodeficiencies, Congenital Marrow Failures, Hemoglobinopathies, Inborn Errors of Metabolism, SCIDS, Wiskott Aldrich, FEL, HLH, IPEX, LAD, Sickle Cell, Thalassemia, Omenn's Syndrome, Hurler's Syndrome, MLD, ALD, Sanfilippo, Krabbe, Hunter's syndrome, TaySachs, Diamond Blackfan Anemia, transplant, MPS, Gaucher
Brief summary
The primary objective is to determine the feasibility of attaining acceptable rates of donor cell engraftment (\>25% donor chimerism at 180 days) following reduced intensity conditioning (RIC) regimens in pediatric patients \< 21 years receiving cord blood transplantation for non-malignant disorders.
Detailed description
Myeloablative doses of chemotherapy and/or radiation therapy are employed with the primary purpose of eradicating malignant cells. Additionally, these regimens exert varying degree of immunosuppression/immunoablation that aids in reducing the likelihood of rejection by host hematopoietic cells. However, myeloablative /immunoablative regimens have also been associated with significant regimen related toxicity (RRT) and regimen related mortality (RRM) that may cause death in up to 20% of patients and significantly higher rate of severe organ dysfunction or failure. While most of these RRT occur typically in the first 100 days \[ e.g. VOD (veno occlusive disease), pulmonary or intracranial hemorrhage, multiorgan failure (MOF)\], there are significant long term toxicities of TBI and/or chemotherapy including growth impairment, gonadal dysfunction/failure, hypothyroidism, cataracts, neurocognitive impairment, and second malignancies. The primary objective is to determine the feasibility of attaining acceptable rates of donor cell engraftment (\>25% donor chimerism at 180 days) following reduced intensity conditioning (RIC) regimens in pediatric patients \< 21 years receiving cord blood transplantation for non-malignant disorders. The secondary objectives are: * To describe the pace of neutrophil and platelet recovery * To evaluate the pace of immune reconstitution. * To determine the treatment related mortality, overall survival and disease free survival by days 100 and 180 post-transplant * To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) and chronic extensive GVHD * To describe the incidence of grade 3-4 organ toxicity * To evaluate long-term complications, such as sterility, endocrinopathy, and growth failure * To evaluate the incidence of late graft failures at 2 years post-transplant
Interventions
BIOLOGICALUnrelated Umbilical Cord Blood Transplant
Reduced Intensity Conditioning for unrelated umbilical cord blood transplant
Sponsors
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* 0-21 years of age with a diagnosis of a immunodeficiency, congenital marrow failure syndrome, inborn error of metabolism, or hereditary anemia * Appropriately matched related or unrelated umbilical cord blood unit with a cell dose ≥ 3 x 10e7cells/kg * Performance score (lansky or karnofsky) greater than or equal to 70 * Adequate organ function (Creatinine ≤ 2.0 mg/dl and creatinine clearance ≥ 50 ml/min/1.73 m2; Hepatic transaminases (ALT/AST) ≤ 4 x normal; Shortening fraction \>26% or ejection fraction \>40% or \> 80% of normal value for age; Pulmonary function tests demonstrating CVC or FEV1/FVC of \>60% of predicted for age.) * Informed consent * Not pregnant or breast feeding * Minimum life expectancy of at least 6 months * HIV negative * No uncontrolled infections at the time of cytoreduction * Disease specific inclusion criteria
Exclusion criteria
* Patients with hemoglobinopathies \> 3 years of age * UCB unit with a total nucleated cell count \< 3 x 10e7/kg or \> 2 antigen mismatching * Available HLA-matched related living donor able to donate without previous UCB donation * Allogeneic hematopoietic stem cell transplant within the previous 6 months * Any active malignancy, MDS, or any history of malignancy * Severe acquired aplastic anemia * DLCO \< 60% of normal value for age; requirement for supplemental oxygen * Uncontrolled bacterial, viral or fungal infection (currently taking medication and progression of clinical symptoms) * Pregnancy or nursing mother * HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR * Any condition that precludes serial follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Feasibility of Attaining Acceptable Rates of Donor Cell Engraftment (>25% Donor Cells at 180 Days) Following RIC Regimens in Children < 21 Years Receiving UCBT for Non-malignant Disorders. | 180 days post transplant | Determine the feasibility of attaining acceptable rates of donor cell engraftment (\>25% donor cells at 180 days) following reduced intensity conditioning regimens in children \< 21 years receiving cord blood transplant for non-malignant disorders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Pace of Immune Reconstitution. | 1 year post transplant | Immune reconstitution after RIC in UCBT was described. CD4 count is a standard measure of immune reconstitution and is described here. Additional data is available upon request. |
| To Determine the Overall Survival at day180 Post-transplant | 180 days | To determine the overall survival at day180 post-transplant: determined by Kaplan Meier survival analysis |
| To Describe Incidence of Acute Graft Versus Host Disease (GVHD) (II - IV) | 100 days post transplant | To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) : measured by cumulative incidence analysis |
| To Describe the Pace of Neutrophil Recovery | 42 days post transplant | Neutrophil recovery was defined as the first day of an absolute neutrophil count (ANC) more than 500/uL for 3 consecutive days not secondary to granulocyte infusions |
| To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure | at least 2 years post transplant | — |
| To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant | 2 years post transplant | — |
| To Describe the Pace of Platelet Recovery | 180 days post transplant | Platelet engraftment was defined as the first day of platelet counts more than 50,000/uL for 7 consecutive days without transfusions |
| To Describe the Incidence of Grade 3-4 Organ Toxicity | 2 years post transplant | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RIC Cord Blood Transplant Reduced Intensity Conditioning for Umbilical Cord Blood Transplant
Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant
Reduced Intensity Conditioning | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | RIC Cord Blood Transplant |
|---|---|
| Age, Categorical <=18 years | 22 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 2.83 years |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 22 |
| serious Total, serious adverse events | 18 / 22 |
Outcome results
Primary
Determine the Feasibility of Attaining Acceptable Rates of Donor Cell Engraftment (>25% Donor Cells at 180 Days) Following RIC Regimens in Children < 21 Years Receiving UCBT for Non-malignant Disorders.
Determine the feasibility of attaining acceptable rates of donor cell engraftment (\>25% donor cells at 180 days) following reduced intensity conditioning regimens in children \< 21 years receiving cord blood transplant for non-malignant disorders.
Time frame: 180 days post transplant
Population: Of the 22 patients enrolled, 18 patients were alive at 180 days, the time-point for primary end point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | Determine the Feasibility of Attaining Acceptable Rates of Donor Cell Engraftment (>25% Donor Cells at 180 Days) Following RIC Regimens in Children < 21 Years Receiving UCBT for Non-malignant Disorders. | 88 % of participants |
Secondary
To Describe Incidence of Acute Graft Versus Host Disease (GVHD) (II - IV)
To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) : measured by cumulative incidence analysis
Time frame: 100 days post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | To Describe Incidence of Acute Graft Versus Host Disease (GVHD) (II - IV) | 22.7 percentage of participants |
Secondary
To Describe the Incidence of Grade 3-4 Organ Toxicity
Time frame: 2 years post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | To Describe the Incidence of Grade 3-4 Organ Toxicity | 0 participants |
Secondary
To Describe the Pace of Neutrophil Recovery
Neutrophil recovery was defined as the first day of an absolute neutrophil count (ANC) more than 500/uL for 3 consecutive days not secondary to granulocyte infusions
Time frame: 42 days post transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Cord Blood Transplant | To Describe the Pace of Neutrophil Recovery | 20 days |
Secondary
To Describe the Pace of Platelet Recovery
Platelet engraftment was defined as the first day of platelet counts more than 50,000/uL for 7 consecutive days without transfusions
Time frame: 180 days post transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Cord Blood Transplant | To Describe the Pace of Platelet Recovery | 48 days |
Secondary
To Determine the Overall Survival at day180 Post-transplant
To determine the overall survival at day180 post-transplant: determined by Kaplan Meier survival analysis
Time frame: 180 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | To Determine the Overall Survival at day180 Post-transplant | 81.8 percentage of participants |
Secondary
To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure
Time frame: at least 2 years post transplant
Population: Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of this 2 year late effects endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure | 0 percentage of patients |
Secondary
To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant
Time frame: 2 years post transplant
Population: Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of this 2 year late graft failure endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIC Cord Blood Transplant | To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant | 0 participants |
Secondary
To Evaluate the Pace of Immune Reconstitution.
Immune reconstitution after RIC in UCBT was described. CD4 count is a standard measure of immune reconstitution and is described here. Additional data is available upon request.
Time frame: 1 year post transplant
Population: Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of Immune reconstitution endpoint. CD4 count is reported here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RIC Cord Blood Transplant | To Evaluate the Pace of Immune Reconstitution. | 805 cells/uL |