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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemoglobinopathies; Thalassemia; Lysosomal Storage Disease; Immunodeficiencies; Inborn Errors of Metabolism; Sickle Cell; Non Malignant Disorders; Congenital Marrow Failures
• Intervention / Treatment: Biological: Unrelated Umbilical Cord Blood Transplant; Drug: Reduced Intensity Conditioning

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

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center Pediatric Blood and Marrow Transplant Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: RIC Cord Blood Transplant; Reduced Intensity Conditioning for Umbilical Cord Blood Transplant	Biological: Unrelated Umbilical Cord Blood Transplant; Reduced Intensity Conditioning for unrelated umbilical cord blood transplant; Drug: Reduced Intensity Conditioning; Other Names: Campath; Fludarabine; Melphalan; Thiotepa; Hydroxyurea

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

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Suhag Parikh, MD, Duke Pediatric Blood and Marrow Transplant

Publications and helpful links

General Publications

• Parikh SH, Mendizabal A, Benjamin CL, Komanduri KV, Antony J, Petrovic A, Hale G, Driscoll TA, Martin PL, Page KM, Flickinger K, Moffet J, Niedzwiecki D, Kurtzberg J, Szabolcs P. A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases. Biol Blood Marrow Transplant. 2014 Mar;20(3):326-36. doi: 10.1016/j.bbmt.2013.11.021. Epub 2013 Dec 1.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): April 1, 2014

Study Registration Dates

• First Submitted: August 28, 2008
• First Submitted That Met QC Criteria: August 29, 2008
• First Posted (ESTIMATE): September 1, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): August 13, 2014
• Last Update Submitted That Met QC Criteria: July 23, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: transplant; MPS; Thalassemia; Sickle Cell; Diamond Blackfan Anemia; MLD; Gaucher; Inborn Errors of Metabolism; IPEX; ALD; Hemoglobinopathies; Krabbe; LAD; HLH; Hurler's Syndrome; Sanfilippo; Immunodeficiencies; Congenital Marrow Failures; SCIDS; Wiskott Aldrich; FEL; Omenn's Syndrome; Hunter's syndrome; TaySachs
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Immunologic Deficiency Syndromes; Thalassemia; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Hemoglobinopathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antisickling Agents; Melphalan; Fludarabine; Hydroxyurea; Thiotepa
• Other Study ID Numbers: Pro00008753