title: A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.
abstract: Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina. Electronic address: suhag.parikh@duke.edu.
authors.forename: Suhag H
authors.initials: SH
authors.lastname: Parikh
authors.affiliation: The Emmes Corporation, Rockville, Maryland.
authors.forename: Adam
authors.initials: A
authors.lastname: Mendizabal
authors.affiliation: Adult Stem Cell Transplant Program, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Benjamin
authors.affiliation: Adult Stem Cell Transplant Program, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
authors.affiliation: Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Jeyaraj
authors.initials: J
authors.lastname: Antony
authors.affiliation: Blood and Marrow Transplant Program, All Children's Hospital, St. Petersburg, Florida.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Petrovic
authors.affiliation: Blood and Marrow Transplant Program, All Children's Hospital, St. Petersburg, Florida.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hale
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Driscoll
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Page
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ketti
authors.initials: K
authors.lastname: Flickinger
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jerelyn
authors.initials: J
authors.lastname: Moffet
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Duke University Medical Center, Durham, North Carolina.
authors.forename: Joanne
authors.initials: J
authors.lastname: Kurtzberg
authors.affiliation: Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Paul
authors.initials: P
authors.lastname: Szabolcs
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control; D006680:HLA Antigens / Q000276:immunology; D006453:Hemoglobinopathies / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007223:Infant; D008297:Male; D008659:Metabolic Diseases / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D061349:Unrelated Donors
chemical_list: D000970:Antineoplastic Agents; D006680:HLA Antigens
keywords: Hemophagocytic lymphohistiocytosis (HLH); Nonmalignant diseases; Pediatric disorders; Reduced-intensity conditioning; Thalassemia; Umbilical cord blood transplantation