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

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 granulornatous 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 1-2 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 alerntuzurnab [<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 xh). 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 relateddonors 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 chimerisrn, 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 granulornatous 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-rnatched unrelated-donor transplants were done. Median time to engraftrnent 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.