Cord Blood Bank Network Research Articles

Abstract 26 HLA Analysis of the Australian Cord Blood Banks: How Diverse Are Donors?

IntroductionThe network of public cord blood banks (CBB) in Australia, known as AusCord, is comprised of CBB located in Brisbane, Sydney, and Melbourne. The network stores almost 37,000 cord blood units (CBU) and has released more than 1,300 for transplantation.ObjectiveThe objectives of this study were (1) to determine the relative diversity of HLA allele subtypes, tissue types, and haplotypes at each of the banks and between the banks and (2) to identify common tissue types and haplotypes that could be utilized for clinical research and development of third party cell therapy products.MethodsHLA data was obtained for 36,782 CBU stored in the AusCord inventory. To standardize data format, high-resolution typing was converted to 2-digit typing. HLA allele subtypes were ranked from most to least common. A subset of Indigenous Australian and Pacific Islander HLA allele subtypes was interrogated to determine whether increased frequency correlated with declared ethnicity. Tissue types were separated into CBU that had HLA-A, HLA-B, HLA-C, and HLA-DRB1 typing (21,815 total) and CBU that did not have HLA-C typing (36,782 total). CBU tissue types were interrogated in 3 separate groups: searchable, searched, and released inventory. Haplotypes were confirmed where maternal typing was available (3,105 CBU).ResultsEthnicity screening for donors and strategic location of collection sites servicing ethnic minority communities resulted in banking of Indigenous Australian and Pacific Islander HLA. At a bank and network level, there was a similar frequency of specific HLA subtypes; however, when considering the tissue types, there was vast diversity (~75% unique with 8 allele typing). Whilst there is diversity, there was also a fraction of the inventory that exhibited repetitive tissue types that could be utilized for clinical research.DiscussionThe study demonstrates that cord blood collections are able to boost storage of diverse tissue types in, and unique to, a multicultural population such as Australia. This finding can guide policy development and funding, as well as operational decisions at the CBB. Furthermore, CBB are well positioned to support research and development activity aimed at discovery of new applications for cord blood units through supply of GMP grade cryopreserved products exhibiting common tissue types and haplotypes.

A comprehensive human leukocyte antigen analysis of 36 782 cord blood units stored in the Australian Public Cord Blood Banking Network

Background and aimsThe network of public cord blood banks (CBBs) in Australia, known as AusCord, comprises CBBs located in Brisbane, Sydney and Melbourne. A novel comprehensive analysis has been performed to determine whether the cryopreserved, searchable cord blood unit (CBU) inventory of approximately 36 000 units share similar tissue types or haplotypes. MethodsHuman leukocyte antigen (HLA) data was analysed using Microsoft Excel following standardisation of typing data. ResultsThe analysis has found that the majority of stored, searched and released CBU exhibit a tissue type that is unique within and between the CBBs. Therefore, each collection performed by the CBBs is likely to comprise a tissue type that is not already stored among the total AusCord inventory. HLA alleles (HLA-A*34, HLA-B*56, HLA-DRB1*08:03), which are uncommon in European populations, were associated with Pacific Islander and/or Indigenous Australian populations and confirmed to be more frequent among donors who, when screened, self-identified as these ethnicities. ConclusionsThese data indicate that (i) continued addition of CBU to existing inventories is likely to further increase the HLA diversity and (ii) screening donors for ethnicity or strategically locating collection sites where ethnic minorities reside can successfully result in collection of rare HLA associated with ethnic minority groups for whom finding donors might otherwise be more difficult.

First Application Of The EBMT Risk Score In Double Umbilical Cord Blood Transplantation For Hematological Malignancies: Significant Impact On Different Outcomes

The European Group for Blood and Marrow Transplantation (EBMT) risk score provides a simple tool to assess chances and risks of hematopoietic stem cell transplantation (HSCT) for an individual patient from related and unrelated donors. To our knowledge, this score has never been applied in double umbilical cord blood transplantation (dUCBT). We recently published results of 136 patients who underwent dUCBT reported to the SFGM-TC registry from 23 centers between 2005 and 2007 (Labussiere et al., Exp. Hem. 2013). After having recorded the full data on CB units including HLA and sex, we decided to test the validity of the EBMT risk score and check its application in dUCBT. There were 88 males and 48 females with a median age of 41 years (range: 18 – 66), 76 patients with acute leukemias (42 AML, 27 ALL, 5 secondary AL and 2 Biphenotypic AL), 8 with chronic leukemias (5 lymphoid and 3 myeloid), 10 with myelodysplasic syndormes, 24 with Hodgkin and non Hodgkin lymphomas, 13 with multiple myelomas and 5 with other myeloproliferative diseases. Median interval between diagnosis and transplantation was 20.5 months (range: 3-385). At time of allogeneic transplantation, 41 patients were in first complete remission (CR1), 40 in ≥CR2 and 55 less than CR. Forty-six patients received myeloablative and 90 reduced intensity conditioning regimens. The EBMT risk score uses the 5 pre-transplant factors: age of the patient, disease status, time from diagnosis to transplant, kind of donor (related/unrelated), and donor-recipient sex combination with 0 to 1 or 2 points (pts) for each factor. Age was categorized as <20 years (0 pt; n= 6), 20 to 40 years (1 pt; n= 59) and >40 years (2 pts; n=71). For disease status we distinguished patients in CR1 at transplantation, (0 pt; n=41) from patients in CR >1 (1 pt; n=40) and patients not in CR (2 pts; n=55). Time from diagnosis to transplant was categorized into ≤12 months (0 pt; n=26) and >12 months (1pt; n=110). The adaptation of the new risk score concerned HLA and sex matching. Complete information concerning HLA typing was obtained from the database of the national network of cord blood banks on behalf of Eurocord. HLA typing was evaluated across 3 loci: HLA-A, -B and -DRB1; it was based on antigenic level for HLA-A and HLA-B, and on allelic level for HLA-DRB1. HLA matching showed patients with at least 4/6 HLA matching on HLA-A, -B and DRB1 without any mismatch on DRB1 alleles between the recipient and each UCB unit and the 2 units together (0 pt; n=77); patients with at least 4/6 HLA matching on HLA-A and -B between the recipient and each unit but without complete matching on DRB1 or with less than 4/6 HLA matching between the 2 units (1 pt; n=51), and finally patients with more than 2 mismatches on the three loci (2 pts; n=8). Donor-recipient sex combination separated all others (0 pt; n=73) from the male recipient with one female and one male cord blood unit (1pt; n=45) and male recipient with two female cord blood units (2 pts; n=18). Hence, we found 5 patients (4%) in score 1, 12 (9%) in score 2, 23 (17%) in score 3, 26 (19%) in score 4, 30 (22%) in score 5, 26 (19%) in score 6, 11 (8%) in score 7 and 3 (2%) in score 8. We pooled patients with scores 1-2; 3-4 and 5-8 as their outcomes were found to be similar. After a median follow-up of 49.5 months, the 3 years probabilities of overall and progression-free survivals for the whole population were 41% and 35% respectively. with a two-year cumulative relapse incidence of 28% (24.0 – 31.8). Interestingly patients with score 1-2 showed better overall survival rates than those with score 3-4 and 5-8 with a 3 years probability of 77%, 42% and 32% respectively (p=0.002); this was associated with a 3 years relapse incidence of 19%, 35% and 55% respectively (p=0.021), while the 3 years transplant related mortality (TRM) was 6%, 39% and 36% respectively (score 1-2 versus all others, p=0.02), Figure 1. [Display omitted] In conclusion, we found that the EBMT risk score can perfectly be applied to double UBCT with a significant impact on different outcomes; its use enables a better selection of patients who will benefit the more from this treatment strategy. Disclosures:No relevant conflicts of interest to declare.

Donor-derived 47, XXY in an unrelated cord blood transplant recipient

A 65-year-old Japanese male with therapy-related myelodysplastic syndrome was admitted for unrelated cord blood transplantation. A cord blood unit from a male donor was obtained from the Japan Cord Blood Bank Network. The patient then received a conditioning regimen consisting of fludarabine, intravenous busulfan, and total body irradiation. Successful engraftment was obtained. The bone marrow examination on day 28 revealed trilineage engraftment, and chimerism analysis by variable number of tandem repeat polymerase chain reaction confirmed complete donor chimerism. At that time, conventional cytogenetics of the bone marrow aspirate showed 20 out of 20 metaphases with the 47, XXY karyotype characteristic of Klinefelter syndrome. Klinefelter syndrome is the most common genetic cause of human male infertility with a reported prevalence of 0.1–0.2% in the general population. In Japan Cord Blood Bank Network, there is no informed consent from parents about the possibility that post-unrelated cord blood transplantation patient evaluation may reveal donor-origin inherited diseases including cytogenetic abnormality. It is desirable to have opportunities in Japan discussing whether parents will be notified of the possibility that post-unrelated cord blood transplantation evaluation may reveal donor-derived illness incidentally.

California Umbilical Cord Blood Collection Program: Addressing The Diversity Of The National Registry Through Creative Partnerships With Cord Blood Banks and Provision Of High-Quality Cord Blood Units For Research

California's Umbilical Cord Blood Collection Program (UCBCP) is a unique, state-funded system designed to capture the diverse HLA profiles of its residents' umbilical cord blood units (CBUs) for public banking and use in unrelated transplants, while providing a source of high quality cord blood units for qualified researchers. The legislation's unifying directive to create a sustainable program to collect diverse California CBUs for banking and research guided the development of tools useful for the assessment of potential cord blood collection sites and partner cord blood banks. Here, we present the methodology utilized to develop the UCBCP network of collection sites and partner cord blood banks, and describe mechanisms for sustainability. The process of contract negotiations between the UCBCP, host hospital and partner cord blood bank (CBB) is preceded by identification and analysis of each party, with an emphasis on parameters that are directly related to the intent of the legislation. The Collection Site Assessment Tool evaluates hospitals based on, but not limited to the following criteria; birth rate, ethnic/racial diversity of patient population, proximity to partner cord blood bank, shipping logistics, shipping costs, preferred collection model, and space availability. Data are collected from the CA Dept. of Public Health and hospital staff. Our CBB Assessment Tool was developed as a scoring mechanism to evaluate proposals from cord blood banks wishing to be qualified to receive California's CBUs. Parameters considered include CBB licensure by the FDA, collection model, capacity, experience and CBB financials.By tailoring negotiations and contracts based on results from the assessment tools, each partnership between collection site and cord blood bank is uniquely suited to the needs of each party and promotes the UCBCP mission, which ultimately serves the patients who receive the transplants. This approach requires effort, creativity and transparency up front as term lists are created and negotiated, and success is dependent on reaching a consensus between hospital administrators, Labor and Delivery staff, CBB officials and the UCBCP, prior to contract signing. The number of contracts uniting hospital, CBB and the UCBCP range from 1-3, depending on the requirements of each party. UCBCP sustainability issues are covered under contracts between the CBB and the UCBCP, such as disbursement of CBUs that do not meet public banking criteria to researchers or fees paid to the UCBCP upon retrieval of a UCBCP-funded CBU for transplant. Distribution of high-quality CBUs for research is an important aspect of the legislation that also supports the UCBCP sustainability funding plan and is non-negotiable, although the UCBCP does provide funding and support for these activities. Our research-grade CBUs are provided fresh and are not manipulated, with an average volume of 94 mL and an average total nucleated cell count of 8.7 x 108. Our standards for research-grade CBUs are high to encourage the use of cord blood stem and progenitor cells in basic and pre-clinical studies, which also ultimately serves the transplant patient community. The flexible model the UCBCP has developed to increase cord blood collections in California can serve as a template for other states and collection programs. Disclosures:No relevant conflicts of interest to declare.

Global Hematopoietic Stem Cell Transplantation (HSCT) At One Million: An Achievement Of Pioneers and Foreseeable Challenges For The Next Decade. A Report From The Worldwide Network For Blood and Marrow Transplantation (WBMT)

Since the first report by Nobel laureate, the late E. Donnall Thomas (NEJM, 1957, 257), HSCT has developed from an experimental to an established curative treatment for many congenital or acquired disorders of the hematopoietic system. The key steps of this success story are linked to progress in tissue typing, donor selection, supportive care and immunosuppression and fostered by intensive collaboration of physicians around the world through outcome and donor registries.The WBMT, a federation and official Non-governmental Organization of the World Health Organization, has collected HSCT activity data from its member societies and from national registries not part of an international HSCT society. Data collection did include the first transplants by ED Thomas and the first global report by M. Bortin (Transplantation 1970, 571). European data were derived from the Med A form of the European Group for Blood and Marrow Transplantation-EBMT for the years 1965-1989 and from the annual activity survey since 1990. Non-European data back to 1969 were provided by the Center for International Blood and Marrow Transplant Research-CIBMTR, with additional recent data provided by the Asia-Pacific Blood and Marrow Transplantation Group (APBMT, since 1974), the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR, since 1980), the Eastern Mediterranean Blood and Marrow Transplantation Group (EMBMT, since 1984), the Canadian Blood and Marrow Transplantation Group (CGBMT, since 2002), the Latin American Blood and Marrow Transplantation Group (LABMT, since 2009) and the African Blood and Marrow Transplant Group (AFBMT, since 2010). Double reporting was minimized by crosschecking registries and unrelated donations. Missing data from a few regions in 2012 were extrapolated from previous years assuming a 5% increase.As of December 2012, the 1450 transplant centers from 72 countries over 5 continents had reported 1.000.000 HSCT (58% autologous, 42% allogeneic). The dramatic recent increase in rate of utilization of HSCT is illustrated by the fact that there were 10.000 HSCTs worldwide by 1985, 50.000 by 1990, 100.000 by 1994, 500.000 by 2004 and 1.000.000 by December 2012. The absolute and relative contribution differed significantly with Europe providing 53%, the Americas 31%, Australasia 14% and Eastern-Mediterranean and Africa 2% to the total HSCT number (allogeneic HSCT: 45%, 32%, 20% and 3%; autologous HSCT: 58%, 31%, 10% and 1%). The increase in activity has been almost linear over the past 55 years with two exceptions, a decrease in autologous HSCT for breast cancer from 1999 especially in the Americas and a decrease in allogeneic HSCT for CML after 2000 seen everywhere except in the Eastern-Mediterranean/African region. The rise in HSCT numbers during the last decade was mainly due to an increase in allogeneic HSCT from unrelated donors; the relative increase being highest in Australasia. Recent growth was primarily due to increases in activity in existing transplant centers, rather than in the number of transplant centers. The main indications for autologous HSCT today are lymphoproliferative disorders 87% (myeloma 46% and lymphoma 41%), solid tumors 8.6% and AML 2.75%; for allogeneic HSCT leukemias 73% (AML 34.6%; ALL 16.8%; CML 4%; myelodysplastic and myeloproliferative disorders 13.3%; CLL 2.9% and other leukemias 1%), lymphoproliferative disorders 14.3% and bone marrow failure syndromes 5.5%. In 2010, cord blood was used as stem cell source in 19% of unrelated HSCT.These data were compiled through collaboration of the global HSCT community. Global collaboration has also been essential for the diffusion of HSCT as a therapy and especially for unrelated HSCT. More than 22 million unrelated donors are available today from a global network (World Marrow Donor Association, WMDA) of donor registries and cord blood banks and about 30% of unrelated HSCT involve a donor and recipient in different countries. The success of HSCT serves as a model for organ repair by the use of healthy stem cells and as a model for global cooperation in meeting the needs of an international patient population. These data also illustrate the challenges for the global medical community in providing state of the art care in regions with constrained resources and the need to find ways to make the therapy more available in order to provide better outcomes for patients with life-threatening but potentially curable diseases. Disclosures:Gluckman:Cord use: Honoraria; gamida: Honoraria.

Influence Of Acute and Chronic Graft-Versus-Host Disease On Outcome After Allogeneic Hematopoietic Stem Cell Transplantation For Chronic Myelomonocytic Leukemia

▪ IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option for chronic myelomonocytic leukemia (CMML), with the possibility that the graft-versus-CMML (GvL) effect has an important role for survival after allo-HSCT. In a clinical situation, GvL effect was assumed to closely correlate with graft-versus-host disease (GVHD). This study aimed to evaluate the influence of acute and chronic GVHD on long-term outcomes for patients with CMML that were treated with allo-HSCT. Patients and MethodsData were obtained from the Transplant Registry Unified Management Program, which includes three data sources of the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, and the Japan Cord Blood Bank Network. There was a total of 177 records of CMML patients who were 16 years of age or older and had received allo-HSCT between January 1, 1987 and December 31, 2010. Of those, 141 patients had received allo-HSCT without in-vivo or ex-vivo T-cell depletion, and survived with neutrophil engraftment, which were subjects for this analysis. The probability of overall survival (OS) was estimated by Kaplan-Meier method. Disease-associated mortality was estimated with the use of cumulative incidence curves to accommodate the competing events. Semi-landmark plots were used to illustrate the effects of GVHD on OS and cumulative incidence of disease-associated mortality using the median days of the occurrence of GVHD. Univariate and multivariate Cox proportional hazards regression models were used to evaluate variables potentially affecting OS. Fine and Gray proportional hazards models were used to evaluate variables potentially affecting disease-associated mortality. In these hazard models, the occurrence of GVHD was treated as time-varying covariate. ResultThe median age of recipients was 49 years old. There were 68 transplants from HLA-matched related donor, 10 from HLA-mismatched related donor, 53 from unrelated bone marrow donor, and 10 using unrelated cord blood. One hundred one and 40 patients received myeloabrative and reduced intensity conditioning, respectively. Median survival times after allo-HSCT was 2.8 years. Estimated OS and cumulative disease-associated mortality at 3 years after allo-HSCT were 47.3% (95% confidential interval, 38.5-55.7) and 18.2% (12.2-25.1), respectively. Acute GVHD of grades 1 and 2-4 occurred in 25 and 62 patients, respectively. The median onset of acute GVHD of any grade after allo-HSCT was 22 days (range, 6-80). The analysis using semi-landmark plots revealed that the development of grade 1 acute GVHD was significantly associated with a better OS (p=0.015) and a lower disease-associated mortality (p=0.012) compared with the absence of acute GVHD. However, in multivariate analysis, the emergence of grade 1 acute GVHD was not associated with OS (Hazard ratio (HR) [95% confidential interval], 2.12 [0.69-6.51]; P=0.189) and disease-associated mortality (HR, 1.71 [0.60-4.86]; p=0.31). With a median day of chronic GVHD occurrence after allo-HSCT of 138 (range, 57-669), limited and extensive chronic GVHDs occurred in 17 and 39 patients, respectively. The analysis using semi-landmark plots revealed that the development of limited chronic GVHD related to better OS (p<0.001) and lower disease-associated mortality (p<0.001) compared with the absence and extensive chronic GVHD. In multivariate analysis, OS tended to be better for patients with limited chronic GVHD than the absence of chronic GVHD (HR, 3.86 [0.83-17.9]; P=0.085), while the absence of chronic GVHD possibly affected with the higher disease-associated mortality compared with the emergence of limited chronic GVHD, with a borderline statistical significance (HR, 3.92 [0.91-16.9]; P=0.067). ConclusionOur results showed the efficacy of allo-HSCT for patients with CMML and suggested an important role of GvL linked to chronic GVHD on the better outcome of the patients after receiving allo-HSCT. Disclosures:Fukuda:the Japanese Ministry of Health, Labour, and Welfare: Research Funding.

Viability of umbilical cord blood mononuclear cell subsets until 96 hours after collection

Umbilical cord blood (UCB) is a good source of hematopoietic stem cells for transplantation and cell therapy. In 2006, the Brazilian Public Network of Cord Blood Banks was founded; however, because our country is large, logistic problems could hamper the collection of numerous samples. Our aim was to evaluate the viability of several UCB cell subsets until 96 hours after collection, to examine whether this delay would be acceptable for processing and freezing the samples. Two experiments were performed: in the first one, volume reduction of the UCB units was carried out before analysis. In the second one, analysis was carried out with no previous manipulation. Samples were stored at room temperature and one aliquot was taken daily for analysis. We examined CD34+ cell, B-cell precursor, mature B and T lymphocyte, monocyte, granulocyte, and mesenchymal stem cell (MSCs) concentrations. Thirty-six UCB units were analyzed. CD34+ cells and mature T lymphocytes increased (viability 99%). Mature B lymphocytes and MSCs decreased, maintaining viability. Granulocytes decreased with loss of viability. Monocytes and immature B lymphocytes remained stable. Clonogenic assays showed a decrease in colony-forming unit (CFU) number in UCB units stored for 96 hours. UCB manipulation did not influence cell viability. All cell subsets remained viable until 96 hours after collection. CD34+ cells and T lymphocytes increased, probably due to the loss of other subsets. CFU growth during the period analyzed and confirmed stem cell functionality, despite the decrease at 96 hours. Results demonstrated that UCB units could probably be processed up to 96 hours after collection.

Advances in unrelated cord blood transplants in malignancies.

Cord blood is an unlimited source of hematopoietic stem cells (HSCs) for allogeneic HSC transplant. Since the first human cord blood transplant performed 20 years ago, cord blood banks have been established worldwide for collection and cryopreservation of cord blood for allogeneic HSC transplant. More than 500 000 cord blood units are now available for international exchange of cord blood units. A global network of cord blood banks and transplant centers has been established for a common inventory and study of clinical outcomes. Results of unrelated allogeneic cord blood transplants in malignant and nonmalignant diseases, in adults and children, show that, compared with HLA-matched unrelated bone marrow transplant, cord blood has several advantages including prompt availability of the transplant, decrease of graft versus host disease and better long-term immune recovery resulting in a similar long-term survival. Several studies have shown that the number of cells is the most important factor for engraftment while some degree of HLA mismatches is acceptable. Progresses in this field are expected to facilitate engraftment including ex vivo expansion of stem cells, intra-bone injection of cord blood cells and double cord blood transplants.

Allogeneic cord blood transplantation for adult acute lymphoblastic leukemia: retrospective survey involving 256 patients in Japan

We investigated the efficacy of cord blood transplantation (CBT) for adult acute lymphoblastic leukemia (ALL) by reviewing medical records of 256 patients reported to the Japan Cord Blood Bank Network between June 1997 and August 2006. Cumulative incidence of neutrophil engraftment at day 100 was 78%. Infused CD34-positive cell dose (>1 × 10(5) cells/kg) was associated with successful neutrophil engraftment. Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 37%. A 2-year disease-free and overall survival (OS) rates were 36% and 42%, respectively. Multivariate analysis showed that age (51 or older vs younger than 50) (hazard ratio 1.9, 95% confidence interval (CI), 1.3-2.8, P=0.001), disease status (non-remission vs remission) (hazard ratio 2.2, 95% CI, 1.5-3.2, P<0.0001), grade III-IV acute GVHD (hazard ratio 2.0, 95% CI, 1.2-3.2, P=0.006) and absence of chronic GVHD (hazard ratio 2.4, 95% CI, 1.1-5.1, P=0.02) were negatively associated with OS. CBT is effective for some patients with advanced ALL. It is worth considering for further evaluation.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.

Guidelines for the development and validation of new potency assays for the evaluation of umbilical cord blood

The following commentary was developed by the National Marrow Donor Program Cord Blood Advisory Group and is intended to provide an overview of umbilical cord blood (UCB) processing, summarize the current state of potency assays used to characterize UCB, and define limitations of the assays and future needs of the cord blood banking and transplant community. The UCB banking industry is eager to participate in the development of standardized assays to uniformly characterize cellular therapy products that are manufactured in a variety of ways. This paper describes the desired qualities of these assays and how the industry proposes to co-operate with developers to bring relevant assays to market. To that end, the National Marrow Donor Program (NMDP) Cord Blood Bank Network is available to serve as a resource for UCB testing material, research and development consulting, and product/assay testing in an accredited UCB manufacturing environment.

Milestones in umbilical cord blood transplantation

Since the first human cord blood transplant, performed in 1988, cord blood banks have been established worldwide for collection and cryopreservation of cord blood for allogeneic hematopoietic stem cell transplant. Umbilical cord blood (UCB) has now become one of the most commonly used source of hematopoietic stem cells for allogeneic transplantation. Today a global network of cord blood banks and transplant centers has been established for a common inventory with an estimated 600,000 UCB have been banked and more than 20,000 UCB units distributed worldwide for adults and children with severe hematological diseases. Several studies have shown that the number of cells is the most important factor for engraftment while some degree of HLA mismatches is acceptable. The absence of ethical concern, and the unlimited supply of cells explain the increasing interest of using cord blood for developing regenerative medicine.

Milestones in umbilical cord blood transplantation

Much has been learned about umbilical cord blood (UCB) since the first human cord blood transplant was performed back in 1988. Cord blood banks have been established worldwide for the collection, cryopreservation and distribution of UCB for allogeneic haematopoietic stem cell transplantation. UCB has now become one of the most commonly used sources of haematopoietic stem cells for allogeneic transplantation. Today, a global network of cord blood banks and transplant centres has been established with a large common inventory, allowing for more than 20000 transplants worldwide in children and adults with severe haematological diseases. Several studies have been published on UCB transplant, assessing risk factors such as cell dose and human leucocyte antigen mismatch. New strategies are ongoing to facilitate engraftment and reduce transplant-related mortality and include the use of reduced-intensity conditioning regimen, intra-bone injection of cord blood cells, double cord blood transplants or ex vivo expansion of cord blood cells. The absence of ethical concern and the unlimited supply of cells explain the increasing interest of using UCB for developing regenerative medicine.

Unrelated Umbilical Cord Blood Transplantation for Patients with Primary Immunodeficiency: A Report From the Registry of the Japan Cord Blood Bank Network

AbstractAbstract 3524 Background:Umbilical cord blood (UCB) has been increasingly used as a hematopoietic stem cell (HSC) source for patients with primary immunodeficiency (PID) with varying degree of success; however, the information on outcome of UCB transplantation (UCBT) for these patients is still limited. We report here the results of unrelated UCBT carried out for 88 PID patients between 1998 and 2008, consecutively registered on the Japan Cord Blood Bank Network (JCBBN) Patients & Methods:JCBBN is a national unrelated UCB bank network supported by the Ministry of Health, Labor, and Welfare of Japan, and currently 11 regional UCB banks are affiliated. The registry of JCBBN collects recipients' clinical information at 100 days post transplantation, and further recipients' information on survival, disease status, and long-term complications are annually renewed by follow-up forms. Of the 88 PID patients registered, 39 were severe combined immunodeficiency (SCID), 23 were Wiskott-Aldrich syndrome (WAS), 7 were chronic granulomatous disease (CGD), 5 were severe congenital neutropenia (SCN), and 14 were other primary immunodeficiencies. The analysis on engraftment, survival, incidence of graft-versus-host disease (GVHD), and finally, risk factors for overall mortality were carried out in the present study. Results:Sixty-seven patients (76%) achieved stable engraftment. The cumulative incidence of neutrophil recovery at day 100 post-transplant was 77% (95% confidence interval [CI], 66% - 85%), and no statistical difference was observed among the disease groups (SCID vs. WAS vs. others, P = 0.21) and the conditioning types (myeloablative conditioning [MAC] vs. reduced intensity conditioning [RIC], P = 0.80). Twenty-nine out of 88 patients were fully-matched for HLA-A, -B, and -DRB1, while 59 received HLA-mismatched transplantation. The cumulative incidence of grade 2 – 4 acute GVHD at day 100 was 28% (95%CI, 19% - 38%), and the incidence was higher in WAS patients compared to non-WAS patients (P = 0.02). There was a trend for higher incidence of grade 2 – 4 acute GVHD in ≥2 HLA-antigens mismatched UCBT, however, not statistically significant (P = 0.071). Chronic GVHD was observed in 9 recipients, and its cumulative incidence at day 180 was 13% (95%CI, 7% - 23%). Sixty-two PID recipients were alive at last-follow-up, and 5-year overall survival rate (5Y-OS) for all 88 patients was 69% (95% CI, 64% - 74%). 5Y-OS for SCID and WAS were 71% and 82%, respectively. The main cause of death before day 100 post-transplant was infection (17/19), while that after day 100 was GVHD (5/7). Eight patients with previous history of HSC transplantation were excluded in the further risk factor analysis. Pre-transplant infections, no conditioning, ≥2 HLA-antigen mismatched UCB donor, and diagnosis other than SCID/WAS/SCN were associated with poor prognosis, and all these remained as significant poor prognostic factors in multivariate analysis. In addition, UCBT with RIC was associated with good prognosis (P = 0.011). Conclusions:We conclude that unrelated UCB can be considered as a candidate HSC source for PID patients who do not have an HLA-matched sibling donor. Control of pre-transplant infection and selection of HLA-matched donor will lead to a better outcome. UCBT with RIC might benefit for PID patients, however, prospective evaluation is needed. Disclosures:No relevant conflicts of interest to declare.

DEK/NUP214 Fusion Gene Predicts Good Outcome In Acute Myeloid Leukemia In Complete Remission After Allogeneic Hematopoietic Stem Cell Transplantation

AbstractAbstract 2386 IntroductionAcute myeloid leukemia (AML) with chromosomal translocation (6;9)(p23;q34) results in a chimeric fusion gene between DEK/NUP214 (formerly DEK/CAN), and is a rare disease, accounting for approximately 1% of cases. This entity is considered to be a good indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to its poor prognosis and non-responsiveness to chemotherapy. However, whether the prognosis of patients with exclusive DEK/NUP214 abnormality is improved by allo-HSCT has not been demonstrated. We conducted a retrospective study to examine the outcomes of allo-HSCT in AML patients with the DEK/NUP214 gene using the databases of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japan Cord Blood Bank Network (JCBBN). MethodsWe identified de novo AML patients who underwent transplant between January 1996 and December 2007 with no prior treatment by allo-HSCT. Clinical features and outcomes of the patients with DEK/NUP214 abnormality and 3 different control groups (patients with chromosome 7 abnormalities, complex karyotype or normal karyotype) were compared. ResultsOf 4517 AML cases meeting the above criteria, the number of patients with normal karyotype, chromosome 7 abnormalities, complex karyotype and DEK/NUP214 abnormality was 2227, 139, 416 and 64, respectively. The median age of each group was 41, 37, 41 and 34 years, respectively; patients with the DEC/NUP214 abnormality were significantly younger than those with the complex karyotype, and patients with normal chromosomes. Gender was not biased among the groups. Overall survival (OS) of the patients with DEC/NUP214 abnormality at 5 years was 49%, which was superior to the OS of the patients with normal karyotype, chromosome 7 abnormalities and complex karyotype (44%, 30% and 27%, respectively; P < 0.0001; Figure). This trend was significant in HSCT grafts with bone marrow and peripheral blood stem cells. In patients with DEK/NUP214 abnormality, none of the following factors improved survival; combination of gender between patient-donor, dose of total body irradiation prior to HSCT; and use of prophylactic immunosuppressants for graft-versus-host disease. However, the status at HSCT had a significant impact on outcome (5-year OS: 66% in patients in complete remission (CR) at HSCT vs. 31% in non-CR patients; P < 0.001). Analysis exclusively for the patients in CR at HSCT showed similar results as above. [Display omitted] ConclusionOur results suggest that patients with the DEK/NUP214 abnormality are more likely to respond to allo-HSCT. Allo-HSCT should be particularly recommended for patients experiencing CR after prior remission-induction chemotherapy. Disclosures:No relevant conflicts of interest to declare.

Survey On Directed Family Cord Blood Banking for Transplantation Among the National Cord Blood Bank Network in Italy.

Abstract 4195Directed family cord blood (DCB) storage provides hemopoietic stem cell source for transplantation (HSCT) for families with an existing or a potentially future recipient with HSCT curable disease (D). The National CB Banks Network in Italy (ITCBN) has a leading role in providing public DCB service for high-risk families, in compliance to GITMO directives for eligibility criteria (HSCT curable D: malignant MD, non MD, inherited ID). To provide best cost-effective practices recommendations it is important to report on DCB procedures and HSCT rate (HSCT-R) among public Banks. By 12.12.2008 almost 1800 DCB units were stored in 18 Italian Banks and 104 (9%) issued for HSCT. The present survey aims at summarizing the over 15 yrs DCB experience among 5 ITCBN Banks active since 1997 (range 1990-1997), and including 670 DCB units. ResultsPreliminary analysis reports a 94% overall compliance to eligibility criteria directives, and overall HSCT- R for an alive sibling of 12% (63/522); the 63 HSCT were 97% matched, for curing ID in 84% and with 72 % overall survival outcome. Different policies among Banks were compared (Bank vs others: 1) eligibility criteria distribution : Bank PV06 DCB for MD <50% (42% vs 55-67%), Banks Rm04,R04 significant DCB for non sibling recipient (parent with MD) (17-24% vs 0.5%-2%), Bank T02 with significant (53/261) DCB for future sibling with ID (20% vs 2-5%); 2) Timing of HLA typing: Banks T02,FI03,PV06 with DCB following prenatal HLA (20-27% vs 0%), Banks FI03,Rm04,PV06 with CB HLA typed at birth (61-73% vs 23-25%). Significant HSCT-R (37/177=21 %) was reported by PV06 (HLA selection based storage). Lowest HSCT-R by Rm04,R04 (3/101=3%-5/98=5%) (parental mismatch). At T02 when excluding DCB for future sibling (low birth rate), and autologous (11 ID) HSCT-R increased from 6% (15/261) to 9% (15/170) Conclusion.Advice for public long-term DCB storage should depend on HLA compatibility, potential recipient, disease progression, and likelihood/ timing of using DCB; Italian CB Banks are actively cohoperating to find best public banking practices to ensure a CDB storage system that is ethical, cost effective and responsive to patient needs. Disclosures:No relevant conflicts of interest to declare.

History of cord blood transplantation

Since the first human cord blood transplant, performed 20 years ago, cord blood banks have been established worldwide for the collection and cryopreservation of cord blood for allogeneic hematopoietic stem cell transplant. A global network of cord blood banks and transplant centers has been established for a common inventory and study of clinical outcomes. Results of unrelated allogeneic cord blood transplants in malignant and nonmalignant diseases, in adults and children, show that, compared with HLA-matched unrelated BM transplant, cord blood has several advantages, including prompt availability of the transplant, decrease of GVHD and better long-term immune recovery resulting in a similar long-term survival. Several studies have shown that the number of cells is the most important factor for engraftment, although some degree of HLA mismatches is acceptable. Developments are expected to facilitate engraftment, including ex vivo expansion of stem cells, intrabone injection of cord blood cells and double cord blood transplants. In addition to hematopoietic stem cells, cord blood and placenta contain a large number of nonhematopoietic stem cells. In the absence of ethical concern, the unlimited supply of cells explains the increasing interest of using cord blood for developing regenerative medicine.

Survival after cord blood transplantation from unrelated donor as a second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia

The Japan Cord Blood Bank Network (JCBBN) reports the treatment of 22 children with acute myeloid leukemia (AML) who received umbilical cord blood transplantation from unrelated donors (CBT) as their second hematopoietic stem cell transplantation (HSCT). Provided by the JCBBN, between February 1997 and September 2006, 22 patients had CBT as a second HSCT. In the initial HSCT, eight received autologous, seven received CBT, and the remaining had allogenic BMT. At the time of CBT as a second HSCT, seven were in the second complete remission (CR2), two in the third CR (CR3), the remaining were not in remission. Reduced intensity conditioning (RIC) conducted for 10 cases and myeloablative conditioning (MAC) for 12 cases. The overall survival rate was 31.3%, 5 years after CBT. Second complete remission at second transplantation was favorable prognosis (58.3 +/- 18.6%, compared with 17.1 +/- 10.8% for the non-CR group. Mortality after CBT as a second HSCT accounted for 15 cases, 8 from treatment-related mortality. In conclusion, CBT combined with RIC as second HSCT may be useful against a recurrence of AML in children after the initial HSCT.

Cleanliness Is Next to Godliness

This paper discusses the role of litigation in reducing the spread of hospital-acquired infections. Given the prophylactic nature of litigation, it is suggested that legal action serve as part of a multifaceted approach to improving American medical care and that there be a balance between the burden of an environment occasioned by the specter of potential lawsuits with the benefit of improved care through pecuniary responsibility for failing to meet the standard of care. This paper concludes that while we should not over-employ litigation in the health care environment, we should also not abandon it. It is one treatment modality for the illnesses that compromise the American health care system. Robert Steinbuch is an associate professor of law at the University of Arkansas at Little Rock [Arkansas], William H. Bowen School of Law. Steinbuch received a bachelors in political science and a masters in political theory from the University of Pennsylvania in Philadelphia. Thereafter, he earned his juris doctor at the Columbia University School of Law in New York City. Steinbuch has testified before the US Senate, Committee on the Judiciary and the US House of Representatives, Committee on the Judiciary on issues including public safety. Currently, Steinbuch serves on the board of trustees of the Society of Chest Pain Centers, an international accrediting health care organization. The society is a nonprofit international society that bridges cardiology, emergency medicine, and other professions focused upon improving care for patients with acute coronary syndromes and other acute heart conditions. The society promotes protocol-based medicine, often through a chest pain center model, to address the timely diagnosis and treatment of acute coronary syndromes and acute heart failure. It is focused on promoting the adoption of process improvement science by health care providers. Additionally, Steinbuch serves as a commissioner on the Arkansas Commission for the Newborn Umbilical Cord Blood Initiative. The 11-member commission will establish and oversee a statewide network that will contribute to a central bank of blood donated from umbilical cords otherwise discarded after childbirth. Once the network has been established, Arkansas will be connected to a national and international network of cord blood banks that supply potentially life-saving cells for transplants to children and adults with cancer all over the world. The University of Arkansas School of Medical Sciences, which has one of the largest adult blood cell transplant centers in the country, will serve as the statewide network”s main storage site. Steinbuch currently teaches business associations, law and economics, legal profession and evidence. He has published numerous papers on topics such as health law, commercial law, criminal procedure, and election law, in both medical and legal journals. He often focuses his research on the intersection of law and process improvement in health care and other public services.