UK experience of unrelated cord blood transplantation in paediatric patients

Cord blood is a valuable alternative source of cells for haematopoietic stem cell transplantation when suitable human leucocyte antigen (HLA)-matched sibling or unrelated donors are unavailable. The use of unrelated cord blood transplantation (UCBT) has been widely adopted in North America (Kurtzberg et al, 2008), but uptake in the UK had been slow. Following recommendations for incorporating UCBT into standard transplant practice within the UK (Shaw et al, 2009), the use of UCBT in children has increased significantly. British Society of Blood and Marrow Transplantation and Eurocord data revealed that 335 children (0 1–17 9 years) underwent UCBT in the UK between 1998 and 2012 (Table I). The median follow-up of survivors was 4 4 years (0 4–14 6). Amongst patients with malignant disease (MD) (n = 167), the median age was 6 5 years (0 3–17 7), most had acute leukaemia (n = 128) and the majority were cytomegalovirus (CMV) seronegative (n = 93). Most patients received myeloablative conditioning (n = 138), with a single cord blood unit (CBU) (n = 138) matched for 5/6 HLA antigens (n = 82). The median collected total nucleated cell (TNC) and CD34 cell dose was 6 7 9 10/kg (range 1 4–62 3) and 2 7 9 10/kg (range 0 1–41 7), respectively. Amongst patients with non-malignant diseases (NMD), the median age was younger at 1 year (range 0 1–17 9), and the most frequent diagnosis was primary immune deficiency (PID) (n = 74). In contrast to MD, the majority of patients received reduced intensity conditioning (n = 92), a better HLA-matched CBU (6/6 n = 77; 5/6 n = 65) and higher TNC and CD34 cell doses: 14 4 9 10/kg (2 9–65 1) and 5 3 9 10/kg (0 5–59 7). Engraftment was achieved in 149/167 (89%) patients with MD and 136/162 (84%) with NMD. The median time to neutrophil recovery >0 5 9 10/l was 23 days (7–77) and 19 days (9–80) in patients with MD NMD, respectively. Platelet recovery was also slower in MD patients at a median of 40 days (8–151) versus 33 days (13–152), presumably reflecting the lower TNC and CD34 dose. The cumulative incidence of neutrophil and platelet recovery by day 100 was 90 9% [95% confidence interval (CI): 85 2–94 4] and 75 8% (95% CI: 68 1–82 0) for MD and 84 4% (95% CI: 77 8–89 3) and 72 9% (95% CI: 65 1–79 2) for NMD patients. The cumulative incidence of graft-versus-host disease (GvHD), non-relapse mortality and relapse are given in Appendix S1. Overall survival (OS) at 1 and 4 years was 64 6% (95% CI: 57 6–72 3) and 51 8% (95% CI: 44 4–60 4) for the group of patients with MD (Fig 1a). Univariate analysis (Table I) showed improved OS for patients aged <6 5 years, with the use of myeloablative conditioning, a TNC and CD34 collected cell dose >median (Fig 1b), and CBUs matched for 6/6 HLA antigens (Fig 1c). There was a trend to improved OS with patient CMV-negative serology and a single CBU. There was significantly worse survival in patients with lymphoproliferative disease. Surprisingly, there was no impact of disease status on outcome, so acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) patients were analysed separately. There remained no impact of disease status on outcome for AML patients (P = 0 52), but for ALL there was a trend to improved survival in CR1 (P = 0 07). For the NMD group, OS was 85 2% (95% CI: 79 9–90 8) at 100 days, 75 2% (95% CI: 68 8–82 1) at 1 year and 74 5% (68 1–81 6) at 4 years (Fig 1d). Univariate analysis showed a trend to improved OS with 6/6 HLA-matched CBU (Fig 1f), a significantly poorer outcome with a collected TNC dose in the lowest quartile (Fig 1e), and a trend to poorer outcome in haemophagocytic lymphohistiocytosis (HLH) (Table I). Multivariate analyses are given in Appendix S2. This report provides a comprehensive picture of the use of UCBT in the UK paediatric population from 1998 to 2012, reflecting approximately 16% of all unrelated transplants performed during this time. Although similar numbers MD and NMD patients were transplanted throughout this period, use of UCBT significantly increased after 2009 in both groups. Despite the relative reluctance to use UCBT in the UK, the outcomes have been comparable to UCBT performed elsewhere. Eapen et al (2007) examined the outcomes of 503 children with leukaemia undergoing UCBT in the USA, determining 5-year probabilities of leukaemia-free survival of 60%, 45% and 33% after 6/6, 5/6 and 4/6 HLA-matched CBT, respectively. The equivalent figures from this UK study were similar, at 75%, 48% and 33%, respectively (Table I). Treatment-related mortality (TRM) and relapse rates for leukaemia patients undergoing UCBT were also broadly similar between the two series: 37 8% and 23 5% respectively in the USA; 24% and 26 5%, respectively in the UK. Eurocord examined the outcome of 279 children with NMD undergoing UCBT (Rocha & Gluckman, 2009). There was better engraftment in this UK study compared to the Eurocord study, with a cumulative incidence of neutrophil and platelet recovery of 84% and 73% versus 69% and 50%, reflecting a larger proportion of children with marrow failure, lower cell doses infused and greater HLA-mismatching in the Eurocord cohort. Acute GvHD (II–IV) and chronic GvHD rates were very similar at 32% and 24% for Eurocord and 31% and 17% for the UK cohort. The 49% OS at 100 days in the Eurocord cohort was influenced by cell dose