title: Unrelated donor allogeneic hematopoietic stem cell transplantation for patients with hemoglobinopathies using a reduced-intensity conditioning regimen and third-party mesenchymal stromal cells.
abstract: Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California. Electronic address: ksandhya@stanford.edu.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Division of Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Smith
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Hutchinson
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David H
authors.initials: DH
authors.lastname: McKenna
authors.affiliation: Rocky Mountain Pediatric Hematology Oncology, Rocky Mountain Hospital for Children, Denver, Colorado.
authors.forename: James B
authors.initials: JB
authors.lastname: Ball
authors.affiliation: Departments of Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Lamb
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California.
authors.forename: Rajni
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
authors.affiliation: Division of Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000074323:Alemtuzumab; D000755:Anemia, Sickle Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D006680:HLA Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D045164:Mesenchymal Stem Cell Transplantation; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D017211:Treatment Failure; D061349:Unrelated Donors; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D017086:beta-Thalassemia / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006680:HLA Antigens; D019653:Myeloablative Agonists; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan
keywords: Bone marrow; Engraftment; Graft-versus-host disease; Hematopoietic stem cell transplant; Hemoglobinopathies; Mesenchymal stromal cells; Reduced-intensity conditioning; Sickle cell disease; Thalassemia; Umbilical cord