Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Multi-center, Open Label, Randomized Trial Comparing Single Versus Double Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia (0501)
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December 2006 – October 2014
November 1, 2019
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To determine whether two partially HLA-matched umbilical cord-blood (UCB) units were better than one at improving one-year survival in pediatric patients with high risk leukemia or myelodysplasia.
Umbilical cord-blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. As compared with stem-cell grafts from adult donors, cord blood has the advantages of more rapid availability, relative absence of donor attrition, and, after transplantation, a reduced risk of graft-versus-host disease (GVHD). However, the limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. For this reason, various strategies have been explored to increase the number of hematopoietic stem cells in a cord-blood graft, including the infusion of two cord-blood units from different partially HLA-matched donors. A pilot study evaluating the safety and efficacy of double-unit cord-blood transplantation was performed, with promising results. As adequate single UCB units can be identified for > 80% of pediatric recipients (in contrast to < 30% for adults), this study was open only to pediatric patients. The population was restricted to patients with high-risk hematologic malignancy, the most common indication of UCB transplantation in children.
Eligible patients were 1 to 21 years of age (i.e., at least 1 and less than 22 years of age) and had high-risk acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome, a performance status of 70 or higher (on the Karnofsky scale for patients 16 to 21 years of age or the Lansky scale for patients younger than 16 years of age, with both scales ranging from 0 to 100 and lower scores indicating greater disability), adequate organ function, and availability of two cord-blood units that had adequate cell doses and were HLA matched both to the patient and each other on at least four of six loci (i.e., a match score of 4/6, 5/6, or 6/6), considering only HLA-A and HLA-B at the antigen level and HLA-DRB1 at the allele level. At cryopreservation, the primary unit had to contain at least 2.5×107 nucleated cells per kilogram of the recipient’s actual body weight, with the second unit containing at least 1.5×107 nucleated cells per kilogram of body weight. A total of 111 patients were randomly assigned to receive a double-unit transplant, with 108 undergoing transplantation (2 did not proceed to the transplantation stage, and 1 left the study); 113 patients were randomly assigned to receive a single-unit transplant, with 112 undergoing transplantation (1 did not proceed to the transplantation stage). One patient randomly assigned to receive a double-unit transplant and 2 patients randomly assigned to receive a single-unit transplant crossed over to the other treatment group.
The study was an open-label, phase 3, multicenter, randomized trial. Randomization was performed in a 1:1 ratio, with the use of random block sizes, and was stratified according to patient age and the expected volume of cord-blood transplantation procedures performed at each center. Patients were treated with 75 mg of fludarabine per square meter of body-surface area, 1320 cGy of total-body irradiation, and 120 mg of cyclophosphamide per kilogram, followed by the infusion of one or two cord-blood units. The median number of infused total nucleated cells per kilogram was 7.2×107 for recipients of double-unit grafts and 3.9×107 for recipients of single-unit grafts. Prophylaxis for GVHD consisted of cyclosporine administered through day 180, with subsequent tapering, and mycophenolate mofetil administered until day 45 (or longer if there was active GVHD). Absolute numbers of CD4+, CD8+, CD19+, and CD16/CD56+ cells were determined on days 100, 180, and 365 after cord-blood transplantation. All patients were followed for at least 1 year or until death; the median follow-up for surviving patients was 26.9 months.
The primary endpoint was 1-year overall survival, as assessed by means of an intention-to-treat analysis. Pre-specified secondary endpoints included incidences of neutrophil and platelet recovery, acute and chronic GVHD, transplantation-related mortality, disease-free survival, infection, and relapse. Other endpoints included an evaluation of immunologic reconstitution.
These results indicate that double-unit cord-blood transplantation does not confer a survival advantage in children and adolescents. Poorer platelet recovery and higher rates of grade III and IV acute and extensive chronic GVHD were observed after double-unit transplantation. The risk of relapse was similar in the two treatment groups.
Wagner JE Jr, Eapen M, Carter S, et al. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. 2014;371(18):1685–1694. doi:10.1056/NEJMoa1405584
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Resources AvailableStudy Datasets Only
- Data Dictionary (PDF - 792.7 KB)
- BMT CTN 0501 Case Report Forms (PDF - 1.1 MB)
- BMT CTN 0501 Documentation for Outcomes Dataset (PDF - 267.2 KB)
- BMT CTN 0501 Protocol (PDF - 1.4 MB)
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