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

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• 作者：Tayfun G眉ng枚r ; Pierre Teira ; Mary Slatter ; Georg Stussi ; Polina Stepensky ; Despina Moshous ; Clementien Vermont ; Imran Ahmad ; Peter J Shaw ; Jos茅 Marcos Telles da Cunha ; Paul G Schlegel ; Rachel Hough ; Anders Fasth ; Karim Kentouche ; Bernd Gruhn ; Juliana F Fern ; es ; Silvy Lachance ; Robbert Bredius ; Igor B Resnick ; Bernd H Belohradsky ; Andrew Gennery ; et al.
• 刊名：The Lancet
• 出版年：1-7 February, 2014
• 年：2014
• 卷：383
• 期：9915
• 页码：436-448
• 全文大小：427 K

文摘

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Summary

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/m² [infants <9 kg 1路2 mg/kg]; one dose per day on days 鈭? to 鈭?), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days 鈭? to 鈭?; or thymoglobuline 2路5 mg/kg, one dose per day on days 鈭? to 鈭?]; or low-dose alemtuzumab [<1 mg/kg on days 鈭? to 鈭?]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L鈥埫椻€坔). Busulfan was administered mainly intravenously and exceptionally orally from days 鈭? to 鈭?. 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路7 years; IQR 6路8-17路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路46-99路09) and of EFS was 91% (79路78-96路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 (鈮?0%) 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.