Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study - PubMed (original) (raw)

Clinical Trial

. 2014 Feb 1;383(9915):436-48.

doi: 10.1016/S0140-6736(13)62069-3. Epub 2013 Oct 23.

Pierre Teira 2, Mary Slatter 3, Georg Stussi 4, Polina Stepensky 5, Despina Moshous 6, Clementien Vermont 7, Imran Ahmad 8, Peter J Shaw 9, José Marcos Telles da Cunha 10, Paul G Schlegel 11, Rachel Hough 12, Anders Fasth 13, Karim Kentouche 14, Bernd Gruhn 14, Juliana F Fernandes 15, Silvy Lachance 8, Robbert Bredius 7, Igor B Resnick 5, Bernd H Belohradsky 16, Andrew Gennery 3, Alain Fischer 6, H Bobby Gaspar 17, Urs Schanz 4, Reinhard Seger 18, Katharina Rentsch 19, Paul Veys 17, Elie Haddad 2, Michael H Albert 16, Moustapha Hassan 20; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation

Collaborators, Affiliations

Clinical Trial

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

Tayfun Güngör et al. Lancet. 2014.

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.

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