title: A reduced-toxicity regimen is associated with durable engraftment and clinical cure of nonmalignant genetic diseases among children undergoing blood and marrow transplantation with an HLA-matched related donor.
abstract: Blood and marrow transplantation (BMT) is a standard curative therapy for patients with nonmalignant genetic diseases. Myeloablative conditioning has been associated with significant regimen-related toxicity (RRT), whereas reduced-intensity conditioning regimens have been associated with graft failure. In this prospective pilot trial conducted at 2 centers between 2006 and 2013, we report the outcome of 22 patients with nonmalignant genetic diseases who were conditioned with a novel reduced-toxicity regimen: i.v. busulfan (16 mg/kg), alemtuzumab (52 mg/m(2)), fludarabine (140 mg/m(2)), and cyclophosphamide (105 mg/kg). The median age of the study population was 3.5 years (range, 5 months to 26 years). No cases of sinusoidal obstruction syndrome, severe or chronic graft-versus-host disease (GVHD), or primary graft failure were reported. Median time to neutrophil engraftment (>500 cells/μL) and platelet engraftment (>20K cells/μL) were 19 (range, 12 to 50) and 23.5 (range, 14 to 134) days, respectively. The median length of follow-up was 3 years (range, .2 to 6.3). The overall survival rates were 95% at 100 days (95% confidence interval, .72 to .99) and 90% at 6 years (95% confidence interval, .68 to .98). RRT and chronic GVHD are significant barriers to BMT for patients with nonmalignant genetic diseases. This alemtuzumab-based reduced-toxicity regimen appears to be promising with durable engraftment, effective cure of clinical disease, low rates of RRT, and no observed chronic GVHD.
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York. Electronic address: kmahadeo@montefiore.org.
authors.forename: Kris Michael
authors.initials: KM
authors.lastname: Mahadeo
authors.affiliation: Pediatric Stem Cell Transplantation, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.affiliation: Pediatric Stem Cell Transplantation, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California.
authors.forename: David B
authors.initials: DB
authors.lastname: Miklos
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Renna
authors.initials: R
authors.lastname: Killen
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Mattel Children's Hospital, University California Los Angeles, Los Angeles, California.
authors.forename: Donald
authors.initials: D
authors.lastname: Kohn
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Mattel Children's Hospital, University California Los Angeles, Los Angeles, California.
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Mattel Children's Hospital, University California Los Angeles, Los Angeles, California.
authors.forename: Ami J
authors.initials: AJ
authors.lastname: Shah
authors.affiliation: Pediatric Stem Cell Transplantation, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Pediatric Stem Cell Transplantation, Lucille Packard Children's Hospital, Stanford University, Palo Alto, California.
authors.forename: Rajni
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Neena
authors.initials: N
authors.lastname: Kapoor
mesh_terms: D000293:Adolescent; D000328:Adult; D064591:Allografts; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D030342:Genetic Diseases, Inborn / Q000401:mortality* / Q000628:therapy*; D006084:Graft Rejection / Q000401:mortality / Q000517:prevention & control; D006085:Graft Survival; D006801:Humans; D007223:Infant; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage*; D010865:Pilot Projects; D015996:Survival Rate; D019172:Transplantation Conditioning
chemical_list: D019653:Myeloablative Agonists
keywords: Nonmalignant diseases; Pediatrics; alemtuzumab; reduced toxicity