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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

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

PMID:
24161820
DOI:
10.1016/S0140-6736(13)62069-3
[Indexed for MEDLINE]

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