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

Duke University22 enrolled

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMax age: 21 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Secondary Outcomes

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

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

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

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

To Describe the Incidence of Grade 3-4 Organ Toxicity

Time frame: 2 years post transplant

To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure

Time frame: at least 2 years post transplant

To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant

Time frame: 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