title: Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation.
abstract: Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non-malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo-immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine-based non-myeloablative conditioning regimen in patients with transfusion-dependent non-malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty-six patients with transfusion dependent/anti-thymocyte globulin (ATG)-refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)-compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion-independence. Twenty-four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II-IV, 54% grades III-IV) and chronic GVHD (56%) was observed, only one patient died from transplant-related causes (cumulative incidence 7%). These data show that HCT following fludarabine-based non-myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Colleen
authors.initials: C
authors.lastname: Dorrance
authors.forename: Takehito
authors.initials: T
authors.lastname: Igarashi
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.forename: Nancy
authors.initials: N
authors.lastname: Geller
authors.forename: Richard W
authors.initials: RW
authors.lastname: Childs
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000628:therapy; D001855:Bone Marrow Diseases / Q000628:therapy*; D002648:Child; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006457:Hemoglobinuria, Paroxysmal / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D014740:Vidarabine; C024352:fludarabine