Optimizing Unrelated Donor Cord Blood Transplantation

In contrast to the very high transplant-related mortality (TRM) associated with the early experience of cord blood (CB) transplantation (CBT), recent transplant series have been associated with comparable survival to that of human leucocyte antigen (HLA)-matched unrelated donor transplantation in children with similarly promising results in adults. Consequently, the use of CB as an alternative stem cell source and the global inventory of units in public banks are rapidly increasing although challenges remain. This review will address efforts to optimize CBT from 3 different perspectives: that of the transplant center, the CBT registry, and the CB bank

Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on Clinical Outcomes

Cord blood transplantation (CBT) from an unrelated donor is recognized as one of the major treatment modalities in allogeneic stem cell transplantation (SCT) for children with hematologic malignancies. We analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified the risk factors for the transplant outcomes. From 1997 to 2006, 332 children with ALL underwent CBT from unrelated donors, 270 of which had no prior transplant. Their disease statuses at transplant were first complete remission (CR) (n = 120), second CR (n = 71), and more advanced stages (n = 75). As preconditioning for SCT, total body irradiation (TBI) was given to 194 patients and, for the prophylaxis of graft-versus-host disease (GVHD), methotrexate (MTX) was given to 159 patients. The cumulative incidents of neutrophil and platelet recovery (>20 K) were 88.5% and 78.4%, respectively. The incidents of grade II-IV, III-IV acute GVHD (aGVHD), and chronic GVHD (cGVHD) were 45.6%, 20.4%, and 19.2%, respectively, and treatment-related mortality was 22.6%. The 5-year event-free survival (EFS) and overall survival (OS) at CR1, CR2, and advanced status were 47.4%, 45.5%, 15.0%, and 63.7%, 59.7%, and 20.7%, respectively. Multivariate analysis revealed that MTX with calcineurin inhibitor (CNI) was associated with decreased incidence of grade II-IV GVHD (CNI alone: hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.06-2.83, P = .027; CNI + prednisolone (PSL), HR = 1.61, 95% CI = 1.03-2.50, P = .036), III-IV aGVHD (CNI alone: HR = 3.02, 95% CI = 1.55-5.91, P = 0.001; CNI + PSL, HR = 1.89, 95% CI = 0.93-3.83, P = .078), or cGVHD (CNI alone: HR = 1.78, 95% CI = 0.83-3.82, P = .143; CNI + PSL, HR = 2.44, 95% CI = 1.24-4.82, P = .01), compared with CNI alone or CNI + PSL. At an advanced stage of disease, GVHD prophylaxis with MTX + CNI is associated with improved OS compared with CNI alone (CNI alone: HR = 3.20, 95% CI = 1.43-7.15, P = .005; CNI + PSL, HR = 1.47, CI = 0.67-3.20, P = .332). Our retrospective study showed that CBT for children with ALL is feasible and GVHD prophylaxis with MTX + CNI is associated with significant favorable outcomes in prevention of aGVHD and cGVHD as well as survival advantage in advanced cases

Risk Factors and Options to Improve Engraftment in Unrelated Cord Blood Transplantation

Use of umbilical unrelated cord-blood (UCB) cells as an alternative source of hematopoietic cell transplantation has been widely used mainly for patients lacking an HLA-matched donor. UCB present many advantages over bone marrow or mobilized peripheral blood from volunteer donors, such as rapid availability, absence of risk for the donor, and decreased incidence of acute graft-versus-host disease. However, a significant clinical problem is delayed engraftment that is directly correlated with the number of hematopoietic stem cells in a cord-blood unit. The identification of prognostic factors associated with engraftment that can be easily modified (e.g., strategies for donor choice) and the development of new approaches including use of multiple donors, intrabone injection of UCB, ex vivo expansion, and cotransplantation with accessory cells are of crucial importance in order to circumvent the problem of delayed engraftment after UCB transplantation. Those approaches may increase the quality and availability of UCB for transplantation

Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis

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

A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes 2 phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome, however the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. Median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores (2 (23%), 3 (30%), 4 (23%) and 5 (19%)). Most patients received HLA mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. Cumulative incidence of neutrophil recovery at day-60 was 89% and day-100 acute graft-versus-host disease grade II-IV was 38%; use of methotrexate for graft-versus- host disease prophylaxis delayed engraftment (p=0.02), but decreased acute graft-versus-host disease (p=0.03). At 5-year, overall survival and event-free survival were 75% and 70%, respectively. Estimated 5 year- event-free survival was 83%, 73% and 55% for patients with clinical score 2, 4-5 and 3, respectively. In multivariate analysis, age<2years at umbilical cord blood transplantation and clinical phenotype X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be improved after 2007 (p=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor

Hematopoietic Stem Cell Source and Storage

Hematopoietic stem cell transplantation(HSCT), has been accepted as a feasible treatment option that prolongs survival in hematological malignancies. Stem cell choice during hematopoietic stem cell transplantation can differ according to the experience of physicians, mostly treated hematological diseases in the centers or ongoing clinical trials. In this chapter we will discuss the advantages and disadvantages of three stem cell sources peripheral blood, bone marrow and umbilical cord blood

Early and late outcomes after cord blood transplantation for pediatric patients with inherited leukodystrophies

Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; P = .006), well-matched (80 preCBT, 50% remained stable, 20% declined to 60 to 80, and 30% to, 60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes

Hematopoietic Stem Cell Transplantation in Children with Leukemia: A Single Institution Experience with Respect to Donors

Aim of this study was to compare the outcomes of transplantation by donor source and to help select the best alternative donor in children with leukemia. Donor sources included matched related donor (MRD, n = 35), allele-matched unrelated donor (M-UD, n = 10) or -mismatched (MM)-UD (n = 13) or unrelated umbilical cord blood (UCB, n = 11). UCB group had a significantly higher incidence of grade II-IV acute graft versus host disease (MRD, 11.8%; M-UD, 30.0%; MM-UD, 15.4%, UCB, 54.4%, P = 0.004) but there was no difference in incidence of chronic graft versus host disease between 4 groups. The 5-yr leukemia-free survival (LFS) was 76.7%, 60.0%, 69.2%, and 45.5%, respectively (P = 0.128). MRD group showed higher LFS rate than UCB group (P = 0.022). However, LFS of M-UD and MM-UD together (65.2%) was not different from that of MRD group (76.7%, P = 0.325), or from that of UCB (45.5%, P = 0.190). The relapse incidence at 5 yr was 17.1%, 20.0%, 15.4%, and 0%, respectively (P = 0.460). The 100-day treatment-related mortality was 2.9%, 20.0%, 7.7%, and 36.4%, respectively (P = 0.011). Despite the limitations of small number of patients, unrelated donor transplants including even allele-mismatched ones, seem to be as effective in children with leukemia lacking suitable relative donors. Also, UCB transplant may serve as another possible option in urgent transplants

Juvenile Myelomonocytic Leukemia: Molecular Pathogenesis Informs Current Approaches to Therapy and Hematopoietic Cell Transplantation

Juvenile myelomonocytic leukemia (JMML) is a rare childhood leukemia that has historically been very difficult to confidently diagnose and treat. The majority of patients ultimately require allogeneic hematopoietic cell transplantation (HCT) for cure. Recent advances in the understanding of the pathogenesis of the disease now permit over 90% of patients to be molecularly characterized. Pre-HCT management of patients with JMML is currently symptom-driven. However, evaluation of potential high-risk clinical and molecular features will determine which patients could benefit from pre-HCT chemotherapy and/or local control of splenic disease. Furthermore, new techniques to quantify minimal residual disease burden will determine whether pre-HCT response to chemotherapy is beneficial for long-term disease-free survival. The optimal approach to HCT for JMML is unclear, with high relapse rates regardless of conditioning intensity. An ongoing clinical trial in the Children’s Oncology Group will test if less toxic approaches can be equally effective, thereby shifting the focus to post-HCT immunomanipulation strategies to achieve long-term disease control. Finally, our unraveling of the molecular basis of JMML is beginning to identify possible targets for selective therapeutic interventions, either pre- or post-HCT, an approach which may ultimately provide the best opportunity to improve outcomes for this aggressive disease