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Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment., Case: A 9-year old boy initially presented aged 5 years with a restrictive joint disease. He subsequently developed dysgammaglobulinemia, episodic severe pneumonitis, aplastic anaemia, gastritis and cerebral vasculitis. A diagnosis of XLP was made, based on flow cytometric analysis and the identification of a novel mutation in SH2D1A, c.96G>C. No peripheral blood lymphocyte clonal proliferation was identified and he was EBV negative, although human herpes virus-7 (HHV7) was detected repeatedly in his cerebrospinal fluid. He underwent a reduced intensity unrelated umbilical cord blood transplant, but failed to engraft. A second 5/6 matched cord gave 100 % donor engraftment. Complications included BK virus-associated haemorrhagic cystitis, a possible NK-cell mediated immune reconstitution syndrome and post-transplant anti-glomerular basement membrane disease, the latter treated with cyclophosphamide and rituximab. At +450 days post-transplant he is in remission from his vasculitis and anti-glomerular basement membrane disease, and HHV-7 has remained undetectable., Conclusion: This is the second published description of joint disease in XLP, and only the fourth case of non-EBV associated cerebral vasculitis in XLP, as well as being the first to be successfully treated for this manifestation. This case raises specific questions about vasculitis in XLP, in particular the potential relevance of HHV-7 to the pathogenesis.

HLA matching is a critical determinant of outcomes for patients who have undergone umbilical cord blood transplantation (UCBT). Data have been published on the importance of donor/recipient HLA mismatch direction on UCBT outcomes. HLA mismatch in the graft-versus-host (GVH) direction is defined as a donor homozygous at an HLA locus, while the recipient shares one HLA Ag with the donor. HLA mismatch in the host-versus-graft (HVG) direction is defined as a recipient homozygous with the donor sharing one HLA Ag. In our study we focused on confirming, using an independent population, whether transplantation outcomes would be different when HLA mismatch direction was considered. We analyzed 1565 patients who received a single-unit UCBT for malignant disease. Median age was 15 years and 72% of patients were transplanted for leukemia. In multivariate analysis, using the 5/6 HLA-matched population as reference, one or two HLA mismatches in the GVH or HVG direction were not associated with non-relapse related mortality and survival. On the basis of our results, there is no evidence to support a change in the current practice for cord blood unit selection.

We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 × 10(7)/kg (range, 1.7-27.6 × 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted.

The efficient use of haematopoietic stem cells (HSC) for transplantation is often limited by the relatively low numbers of HSC collected. The ex vivo expansion of HSC for clinical use is a potentially valuable and safe approach to increase HSC numbers thereby increasing engraftment and reducing the risk of morbidity from infection. Here we describe a protocol for the robust ex vivo expansion of human CD34(+) HSC isolated from umbilical cord blood. The protocol described can efficiently generate large numbers of HSC. We also describe a flow cytometry-based method using high resolution division tracking to characterise the kinetics of HSC growth and differentiation. Utilising the guidelines discussed, it is possible for investigators to use this protocol as presented or to modify it for their specific needs.

Unrelated umbilical cord blood (UCB) is an alternative stem cell source for paediatric patients lacking a matched related or unrelated marrow donor. We report the results of all paediatric unrelated UCB transplants performed in Australia and New Zealand over a 10-year period. A total of 135 patients were transplanted, 100 for malignant disease (74%) and 35 for non-malignant disorders. The majority (88%) of patients received an HLA-mismatched graft. The median infused total nucleated cell dose was 4.7 x 10(7)/kg and CD34+ count 1.9 x 10(5)/kg. Neutrophil engraftment occurred in 83% of patients by day 42 (median 23 days) and platelet engraftment in 55% by day 60 (median 56 days). Grades II-IV and III-IV acute GVHD occurred in 41 and 18% of patients, respectively. TRM and overall survival 1-year post transplant were 32 and 61%, respectively. A higher probability of neutrophil recovery (P=0.004) and faster time to recovery (median 18 days vs 26 days, P=0.008) were observed in recipients of a cord unit with a CD34 cell dose >or=1.7 x 10(5)/kg. Our results support selection of cord units with CD34 cell doses >or=1.7 x 10(5)/kg to promote faster engraftment, improve survival and lower TRM.

Haematopoietic stem cell transplantation (HSCT) is an accepted curative therapy for many malignant and non-malignant conditions affecting children and adults. Where possible, stem cells for HSCT are provided by human leukocyte antigen (HLA)-matched, related donors. Only 30% of patients have a suitable matched donor; for other patients, donors are sought from bone marrow registries or public umbilical cord blood (UCB) banks. While public UCB banks have been established to support transplant programs in Australia and internationally, parents also have the option of storing their child's UCB in a private commercial UCB bank for personal or family use. In contrast with public UCB banks, there is little social or medical justification for private UCB banking, as it provides no benefit to the community and little benefit to parents (other than reassurance and amelioration of regret), due to the very low likelihood of requiring autologous UCB later in life. Should UCB prove to be beneficial for tissue repair or replacement in the management of degenerative disorders, such as diabetes and Parkinson's disease, then a stronger case may be made in support of commercial banking of UCB for personal use. This may have a major impact on public UCB programs.

Haematopoietic stem cell transplantation is an accepted curative therapy for many cancers and inherited non-malignant diseases, including bone marrow failure syndromes, haemoglobinopathies, and inborn errors of metabolism. Stem cells can be used from the bone marrow or blood of matched siblings or appropriately matched unrelated volunteers, but many patients do not have a suitably matched donor. Umbilical cord blood (UCB) has been successfully used as an alternative stem cell source. It has the advantage of tolerance for a degree of human leukocyte antigen (HLA) incompatibility not possible with adult bone marrow, resulting in greater likelihood of finding an appropriate match. UCB is also stored fully tested and cryopreserved, leading to rapid availability. Greatest clinical experience in UCB transplants has been in treating paediatric leukaemia. Results using well matched UCB grafts are equivalent or better than with unrelated bone marrow transplant. Cell dose and the degree of HLA matching are critical determinants in the success of UCB transplant. The use of UCB in older children and adult patients has been limited by the fixed, low cell dose available in a UCB unit, relative to recipient weight. This can be overcome by strategies such as using two or more UCB units. Early animal studies suggest that UCB may have the potential to differentiate into other cell types, including nervous tissue, and may in future play a role in the treatment of disorders such as Alzheimer disease and Parkinson disease.