title: Unrelated donor hematopoietic stem cell transplantation for the treatment of non-malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection.
abstract: Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUD), offers potentially curative therapy for patients with non-malignant genetic diseases. In this pilot study conducted from 2006 to 2014, we report the outcomes of 15 patients with non-malignant genetic diseases who received a myeloablative regimen with a reduced cyclophosphamide dose, adjunctive serotherapy and MUD HSCT [intravenous alemtuzumab (52 mg/m(2) ), busulfan (16 mg/kg), fludarabine (140mg/m(2) ), and cyclophosphamide (105 mg/kg)]. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus/cyclosporine and methylprednisolone. Median (range) time to neutrophil engraftment (>500 cells/µL) and platelet engraftment (>20,000/mm(3) ) were 15 (12-28) and 25 (17-30) days, respectively. At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61-0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44-0.89). Among this small sample, earlier alemtuzumab clearance was significantly associated with graft rejection (P = 0.047), earlier PHA response (P = 0.009) and a trend toward earlier recovery of recent thymic emigrants (RTE) (P = 0.06). This regimen was associated with durable donor engraftment and relatively low rates of regimen related toxicity (RRT); future alemtuzumab pharmacokinetic studies may improve outcomes, by allowing targeted alemtuzumab clearance to reduce graft rejection and promote more rapid immune reconstitution.
authors.affiliation: Division of Hematology, Oncology and Blood and 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: Department of Pediatrics, Pediatric Blood and Marrow Transplantation Program, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Kris Michael
authors.initials: KM
authors.lastname: Mahadeo
authors.affiliation: Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Sajad
authors.initials: S
authors.lastname: Khazal
authors.affiliation: Division of Hematology/Oncology, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, California.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
authors.affiliation: Division of Hematology/Oncology, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, California.
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: Division of Hematology/Oncology, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, California.
authors.forename: Ami J
authors.initials: AJ
authors.lastname: Shah
authors.affiliation: Division of Hematology, Oncology and Blood and 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; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002066:Busulfan / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D030342:Genetic Diseases, Inborn / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006084:Graft Rejection / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006680:HLA Antigens / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D010865:Pilot Projects; D016019:Survival Analysis; D016559:Tacrolimus / Q000627:therapeutic use; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D000074323:Alemtuzumab; D016572:Cyclosporine; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D016559:Tacrolimus; D008775:Methylprednisolone