title: Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.
abstract: BACKGROUND
  In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients.
  
  
  METHODS
  This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up.
  
  
  RESULTS
  56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients.
  
  
  CONCLUSIONS
  This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease.
  
  
  BACKGROUND
  None.
authors.affiliation: University Children's Hospital, Division of Blood and Marrow Transplantation, Zurich, Switzerland. Electronic address: tayfun.guengoer@kispi.uzh.ch.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngör
authors.affiliation: Centre de Recherche du CHU Sainte-Justine, Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Teira
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Slatter
authors.affiliation: University Hospital, Division of Hematology and Blood and Marrow Transplantation, Zürich, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Stussi
authors.affiliation: Hadassah Hebrew University Medical Center, Department of Blood and Marrow Transplantation, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: AP-HP, Hôpital Necker Enfants Malades, Paediatric Immunology, Sorbonne Paris Cité, Université Paris Descartes, Imagine Institute, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Leiden University Medical Center, Department of Paediatrics, Leiden, Netherlands.
authors.forename: Clementien
authors.initials: C
authors.lastname: Vermont
authors.affiliation: Blood and Marrow Transplantation Program, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Children's Hospital, Division of Blood and Marrow Transplantation, Westmead, Sydney, NSW, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Hospital Albert Einstein, Haematology and Hematopoietic stem cell transplantation Unit, Sao Paulo, Brazil.
authors.forename: José Marcos
authors.initials: JM
authors.lastname: Telles da Cunha
authors.affiliation: University Children's Hospital, Division of Blood and Marrow Transplantation, Würzburg, Germany.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Schlegel
authors.affiliation: University College London Hospitals NHS Foundation Trust, London, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hough
authors.affiliation: Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Fasth
authors.affiliation: Department of Paediatrics, Jena University Hospital, Jena, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.affiliation: Department of Paediatrics, Jena University Hospital, Jena, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.affiliation: Instituto da Criança, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Fernandes
authors.affiliation: Blood and Marrow Transplantation Program, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada.
authors.forename: Silvy
authors.initials: S
authors.lastname: Lachance
authors.affiliation: Leiden University Medical Center, Department of Paediatrics, Leiden, Netherlands.
authors.forename: Robbert
authors.initials: R
authors.lastname: Bredius
authors.affiliation: Hadassah Hebrew University Medical Center, Department of Blood and Marrow Transplantation, Jerusalem, Israel.
authors.forename: Igor B
authors.initials: IB
authors.lastname: Resnick
authors.affiliation: Dr von Hauner University Children's Hospital, Munich, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.affiliation: AP-HP, Hôpital Necker Enfants Malades, Paediatric Immunology, Sorbonne Paris Cité, Université Paris Descartes, Imagine Institute, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Great Ormond Street Children's Hospital, Division of Blood and Marrow Transplantation, London, UK; Molecular Immunology Unit; UCL Institute of Child Health, London, UK.
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.affiliation: University Hospital, Division of Hematology and Blood and Marrow Transplantation, Zürich, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Schanz
authors.affiliation: University Children's Hospital, Division of Blood and Marrow Transplantation, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seger
authors.affiliation: University Hospital, Divison of Clinical Chemistry, KFC, Novum, Laboratory Medicine, Karolinska University Hospital-Huddinge Stockholm, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rentsch
authors.affiliation: Great Ormond Street Children's Hospital, Division of Blood and Marrow Transplantation, London, UK; Molecular Immunology Unit; UCL Institute of Child Health, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
authors.affiliation: Centre de Recherche du CHU Sainte-Justine, Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
authors.affiliation: Dr von Hauner University Children's Hospital, Munich, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Division of Experimental Cancer Medicine, KFC, Novum, Laboratory Medicine, Karolinska University Hospital-Huddinge Stockholm, Sweden; Karolinska Institute, Stockholm, Sweden.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D002066:Busulfan / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007223:Infant; D011446:Prospective Studies; D018183:Transplantation Chimera / Q000502:physiology; D019172:Transplantation Conditioning / Q000379:methods*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; C512542:thymoglobulin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine