Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders

Study Overview
=================
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

Official Title
-----------------
A Pilot Study of Reduced Intensity Conditioning in Pediatric Patients <21 Years of Age With Non-Malignant Disorders Undergoing Umbilical Cord Blood Transplantation

Conditions
-----------------
Non Malignant Disorders, Immunodeficiencies, Congenital Marrow Failures, Hemoglobinopathies, Inborn Errors of Metabolism, Sickle Cell, Thalassemia, Lysosomal Storage Disease

Intervention / Treatment
-----------------
* Biological: Unrelated Umbilical Cord Blood Transplant
* Drug: Reduced Intensity Conditioning


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RIC Cord Blood Transplant<br>Reduced Intensity Conditioning for Umbilical Cord Blood Transplant | Biological: Unrelated Umbilical Cord Blood Transplant<br>* Reduced Intensity Conditioning for unrelated umbilical cord blood transplant<br>Drug: Reduced Intensity Conditioning<br> <br> * Other names: Thiotepa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 180 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 42 days post transplant | 
| 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. | 1 year post transplant | 
| To Determine the Overall Survival at day180 Post-transplant | To determine the overall survival at day180 post-transplant: determined by Kaplan Meier survival analysis | 180 days | 
| 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 | 100 days post transplant | 
| To Describe the Incidence of Grade 3-4 Organ Toxicity |  | 2 years post transplant | 
| 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 | Platelet engraftment was defined as the first day of platelet counts more than 50,000/uL for 7 consecutive days without transfusions | 180 days post transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IPEX, SCIDS, Immunodeficiencies, Congenital Marrow Failures, Hemoglobinopathies, Inborn Errors of Metabolism, Wiskott Aldrich, FEL, HLH, LAD, Sickle Cell, Thalassemia, Omenn's Syndrome, Hurler's Syndrome, MLD, ALD, Sanfilippo, Krabbe, Hunter's syndrome, TaySachs, Diamond Blackfan Anemia, transplant, MPS, Gaucher