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Lancet. 2014 Feb 1;383(9915):436-48. doi: 10.1016/S0140-6736(13)62069-3. Epub 2013 Oct 23.

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

Author information

  • 1University Children's Hospital, Division of Blood and Marrow Transplantation, Zurich, Switzerland. Electronic address: tayfun.guengoer@kispi.uzh.ch.
  • 2Centre de Recherche du CHU Sainte-Justine, Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
  • 3Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 4University Hospital, Division of Hematology and Blood and Marrow Transplantation, Zürich, Switzerland.
  • 5Hadassah Hebrew University Medical Center, Department of Blood and Marrow Transplantation, Jerusalem, Israel.
  • 6AP-HP, Hôpital Necker Enfants Malades, Paediatric Immunology, Sorbonne Paris Cité, Université Paris Descartes, Imagine Institute, Paris, France.
  • 7Leiden University Medical Center, Department of Paediatrics, Leiden, Netherlands.
  • 8Blood and Marrow Transplantation Program, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC, Canada.
  • 9Children's Hospital, Division of Blood and Marrow Transplantation, Westmead, Sydney, NSW, Australia.
  • 10Hospital Albert Einstein, Haematology and Hematopoietic stem cell transplantation Unit, Sao Paulo, Brazil.
  • 11University Children's Hospital, Division of Blood and Marrow Transplantation, Würzburg, Germany.
  • 12University College London Hospitals NHS Foundation Trust, London, UK.
  • 13Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden.
  • 14Department of Paediatrics, Jena University Hospital, Jena, Germany.
  • 15Instituto da Criança, Universidade de São Paulo, São Paulo, Brazil.
  • 16Dr von Hauner University Children's Hospital, Munich, Germany.
  • 17Great Ormond Street Children's Hospital, Division of Blood and Marrow Transplantation, London, UK; Molecular Immunology Unit; UCL Institute of Child Health, London, UK.
  • 18University Children's Hospital, Division of Blood and Marrow Transplantation, Zurich, Switzerland.
  • 19University Hospital, Divison of Clinical Chemistry, KFC, Novum, Laboratory Medicine, Karolinska University Hospital-Huddinge Stockholm, Sweden.
  • 20Division of Experimental Cancer Medicine, KFC, Novum, Laboratory Medicine, Karolinska University Hospital-Huddinge Stockholm, Sweden; Karolinska Institute, Stockholm, Sweden.

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.

FINDINGS:

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.

INTERPRETATION:

This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease.

FUNDING:

None.

Copyright © 2014 Elsevier Ltd. All rights reserved.

PMID:
24161820
[PubMed - indexed for MEDLINE]
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