Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

Implementation of a mentored professional development programme in laboratory leadership and management in the Middle East and North Africa.

Laboratories need leaders who can effectively utilize the laboratories' resources, maximize the laboratories'capacity to detect disease, and advocate for laboratories in a fluctuating health care environment. To address this need, the University of Washington, USA, created the Certificate Program in Laboratory Leadership and Management in partnership with WHO Regional Office for the Eastern Mediterranean, and implemented it with 17 participants and 11 mentors from clinical and public health laboratories in 10 countries (Egypt, Iraq, Jordan, Lebanon, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, and Yemen) in 2014. Designed to teach leadership and management skills to laboratory supervisors, the programme enabled participants to improve laboratory testing quality and operations. The programme was successful overall, with 80% of participants completing it and making impactful changes in their laboratories. This success is encouraging and could serve as a model to further strengthen laboratory capacity in the Region.

Implementation of a mentored professional development programme in laboratory leadership and management in the Middle East and North Africa

Laboratories need leaders who can effectively utilize the laboratories' resources, maximize the laboratories'capacity to detect disease, and advocate for laboratories in a fluctuating health care environment. To address this need, the University of Washington, USA, created the Certificate Program in Laboratory Leadership and Management in partnership with WHO Regional Office for the Eastern Mediterranean, and implemented it with 17 participants and 11 mentors from clinical and public health laboratories in 10 countries [Egypt, Iraq, Jordan, Lebanon, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, and Yemen] in 2014. Designed to teach leadership and management skills to laboratory supervisors, the programme enabled participants to improve laboratory testing quality and operations. The programme was successful overall, with 80% of participants completing it and making impactful changes in their laboratories. This success is encouraging and could serve as a model to further strengthen laboratory capacity in the Region

Les laboratoires ont besoin de directeurs à même d'utiliser les ressources internes de façon efficace, de maximiser leurs capacités à dépister les maladies, et d'oeuvrer pour le bien de ces établissements dans un environment de soins de santé en perpétuel changement. Pour répondre à ces besoins, l'Université de Washington [Etats-Unis], en partenariat avec le Bureau régional de l'OMS pour la Méditerranée orientale, a mis au point le Programme de certification en direction et gestion de laboratoire qui a été suivi par 17 participants et 11 mentors issus de laboratoires de santé clinique et publique dans 10 pays [Arabie saoudite, Egypte, Iraq, Jordanie, Liban, Maroc, Oman, Pakistan, Qatar et Yémen] au cours de l'année 2014. Conçu pour former les responsables de laboratoire aux compétences de direction et de gestion, le programme a permis aux participants de renforcer la qualité du dépistage et des opérations de leurs laboratoires. Le programme a été une réussite dans l'ensemble puisqu'il a été suivi jusqu'à son terme par 80% des participants et que ceux-ci ont ensuite pu mettre en place des changements réels dans leurs laboratoires. Ce succès est encourageant et pourrait servir de modèle afin de renforcer davantage encore les capacités des laboratoires dans la Région

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

A review of the genetic and long-term effects of G-CSF injections in healthy donors: a reassuring lack of evidence for the development of haematological malignancies.

In 2007 the WMDA responded to the publication of two manuscripts suggesting a causal link between G-CSF and myeloid malignancies in healthy donors by convening an international symposium to examine this issue. At the time, registries reviewed the long-term follow-up of their healthy donors, which suggested no excess of leukaemia in PBSC donors compared with BM donors. Although the evidence for an increased risk of malignancy in healthy donors was felt to be weak, it could not be excluded. The WMDA, therefore, issued a statement, to be included in all donor consent forms, stating that it was unknown whether G-CSF increased or decreased the risk of later developing cancer. In 2012, with 5 years of additional donor follow-up and the results of several genetic studies now available, the clinical working group of the WMDA again reviewed the data. On the basis of an assessment of a continuing lack of evidence for an increased risk of malignancy in donors receiving G-CSF, the WMDA has re-issued a more reassuring statement. The revised statement was circulated to all WMDA member registries in late 2012 to replace the existing statement in consent forms, which now conclusively states that, 'Studies following large numbers of unrelated donors have shown that the risk of developing cancer within several years after the use of G-CSF is not increased compared with donors not receiving G-CSF'. Herein we review the evidence on which this statement is based.

Allogeneic hematopoietic stem cell donation-standardized assessment of donor outcome data: a consensus statement from the Worldwide Network for Blood and Marrow Transplantation (WBMT).

The number of allogeneic hematopoietic SCTs performed globally each year continues to increase, paralleled by an increased demand for donors of therapeutic cells. Donor characteristics and collection procedures have undergone major changes during recent decades, and further changes are foreseen. Information on short- and long-term donor outcomes is of crucial importance to ensure maximal donor safety and availability. Current data, predominantly from unrelated donors, give reliable information on the frequent early events associated with donation-most of them of mild-to-moderate intensity. Information on the type and relative risk of serious adverse reactions is more limited. Moreover, only few data exist on long-term donor outcome. On the basis of this need, recommendations for a minimum data set for prospective donor follow-up were developed in a workshop with the participation of an international group of investigators actively involved in allogeneic stem cell donation under the auspices of and approved by the Worldwide Network for Blood and Marrow Transplantation. Establishment of a standardized global follow-up for both, related and unrelated, donors will enable monitoring of the short- and long-term safety profiles of hematopoietic cell donation and form a solid basis for future donor selection and counseling.

WMDA guidelines for subsequent donations following initial BM or PBSCs.

Unrelated donor SCT activity is increasing, and in 5-10% of cases a subsequent donation of stem cells or donor lymphocytes may be requested. Second donations of stem cells are not associated with an increased chance of donor complications, but the yield of CD34+ cells may be lower in some donors. It is acceptable practice for any registry to request subsequent donations and it is recommended that donors should be counselled about this possibility before their first donation. Guidance is provided on the requirements for further medical assessment, the procedures used to agree requests, frequency and timing of donation and timing and duration of donor follow up.

Unrelated hematopoietic stem cell donors as research subjects.

Requests for participation of unrelated stem cell donors in research transplant protocols are becoming more frequent. World Marrow Donor Association calls on donor registries to participate in research activities. Here, we discuss various implications of research participation and make some recommendations as how to make this possible.

Donor safety: the role of the WMDA in ensuring the safety of volunteer unrelated donors: clinical and ethical considerations.

Since the beginning of hematopoietic stem cell harvesting from volunteer unrelated donors, ensuring donor safety has been a necessary goal of all parties involved in the process. As donation of BM or PBSCs is not in the interest of the donor's own physical health, donor registries and transplantation centers must take into account both medical and ethical aspects involved in the donation procedure. One of the principal goals leading to the formation of the World Marrow Donor Association (WMDA) was to establish internationally acceptable standards for all aspects of unrelated donor care.

The US National Marrow Donor Program role in unrelated donor hematopoietic cell transplantation.

The National Marrow Donor Program (NMDP) is headquartered in Minneapolis, Minnesota, USA. Established in 1986, the NMDP currently operates the world's largest registry of unrelated adult donors and umbilical cord blood (UCB) units. Since its inception, the NMDP has benefited from continuous financial support provided by the US government through a series of contracts and grant awards. This funding has supported a large network of donor centers and the recruitment of millions of potential adult hematopoietic cell (HC) donors. More recently, the federal government has also supported a national registry for UCB units and expansion of the available UCB inventories. Today, the NMDP registry lists more than 6.7 million adult donors and 68,000 UCB units. Seventy-seven percent (5.2 million) of the adult donors and virtually all of the UCB units are fully typed for HLA A, B and DR. An additional 5 million donors are available for search through international collaborations. The NMDP currently facilitates more than 3600 recipients each year totaling more than 29,000 transplants since 1987.

Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.

The National Marrow Donor Program (NMDP) maintains a registry of approximately 4 million volunteer unrelated donors for patients in need of a stem cell transplant. When several comparably HLA-matched volunteers are identified for a patient, various criteria are used to select a donor. A retrospective analysis of 6978 bone marrow transplantations facilitated by the NMDP from 1987 to 1999 was conducted to study the effects of various donor characteristics on recipient outcome. The evaluation addressed possible effects of donor age, cytomegalovirus serologic status, ABO compatibility, race, sex, and parity on overall and disease-free survival, acute and chronic graft-versus-host disease (GVHD), engraftment, and relapse. Age was the only donor trait significantly associated with overall and disease-free survival. Five-year overall survival rates for recipients were 33%, 29%, and 25%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.0002). A similar effect was observed among HLA-mismatched cases (28%, 22%, and 19%, respectively). A race mismatch between recipient and donor did not affect outcome. The cumulative incidences of grade III or IV acute GVHD were 30%, 34%, and 34%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.005). The corresponding incidences of chronic GVHD at 2 years were 44%, 48%, and 49% (P = 0.02). Recipients with female donors who had undergone multiple pregnancies had a higher rate of chronic GVHD than recipients with male donors (54% versus 44%; P <.0001). The use of younger donors may lower the incidence of GVHD and improve survival after bone marrow transplantation. Age should be considered when selecting among comparably HLA-matched volunteer donors.

Non-HLA barriers to unrelated donor stem cell transplantation.

A prospective survey involving 544 searches of the US National Marrow Donor Program (NMDP) Registry was conducted to identify reasons why many patients who have apparent HLA-matched donors do not proceed to transplant. Coordinators at NMDP transplant centers, patients and referring physicians were surveyed shortly after the initial search, and follow-up surveys were sent to the coordinators as the search was ongoing. The death of the patient, worsening of the patient's medical condition and length of the search process were the most commonly cited barriers to transplantation. Other times a decision was made not to transplant through the NMDP due to the use of a donor from another source, a preference for chemotherapy or immunotherapy, hesitancy on the part of the transplant physician or patient, or because the patient did not require a transplant. Responses differed between U.S. and international cases. An unrelated donor outside the NMDP was the most common reason cited by international coordinators (46%), whereas the death of the patient was the most common reason among US coordinators (13%). The death of the patient was the second most common reason cited by international coordinators at 9%. Financial problems were listed by 41% of US coordinators as a potential barrier at the time of initial search, but only 5% indicated this as an actual barrier on a follow-up survey. Finances were cited as the most important reason 3% of the time overall, and 6% for African Americans and Asian/Pacific Islanders.

Non-conservative substitutions distinguish previously uncharacterized HLA-A molecules.

The extent of class I HLA polymorphism is not yet realized, and to provide a glimpse of the HLA-A polymorphism which remains undetected, we have analyzed approximately 3,700 National Marrow Donor Program (NMDP) Donor/Recipient Pair Retrospective Study Samples with HLA-A DNA sequence-based typing (SBT). Seventeen new HLA-A alleles were detected, with a total of 19 nucleotide substitutions distinguishing these new alleles from their closest HLA-A relatives. Nearly all of the new alleles differ by single nucleotide substitutions; a majority of these substitutions can be explained by gene conversion events but 6 alleles likely originated by point mutation. Fifteen of the 19 nucleotide substitutions translate into amino acid differences in the molecule. Structurally, the inferred amino acid alterations were non-conservative in terms of chemical property, and most substitutions were positioned in 1 or more of the specificity pockets which determine peptide binding. Although these new alleles were identified in a primarily Caucasian sample population, 9 of the 17 new HLA-A alleles were found in samples of non-Caucasoid origin. A new allele detection rate of 1 in approximately 200 individuals in our data set would, therefore, be higher in a non-Caucasoid sample population. In summary, the single nucleotide substitutions that distinguish undetected HLA-A alleles translate into functionally distinct HLA-A molecules. Further studies of the role of HLA-A in transplantation, in disease association, and in evolution must therefore accommodate the discovery of new alleles differing by single nucleotides.

The National Marrow Donor Program. Meeting the needs of the medically underserved.

BACKGROUND: The National Marrow Donor Program operates the world's largest registry of volunteer unrelated stem cell donors. In recent years, the program has focused on building a large and diverse donor file. After initial recruitment, however, months or years may elapse before a potential donor is contacted on behalf of a searching patient. Here, the author begins to explore factors that influence donor availability at the confirmatory typing stage of the search process. METHODS: Over a 1-year period from March 1, 1999 through February 29, 2000, the author evaluated donor unavailability rates at the confirmatory typing stage of the search process. Unavailability rates by donor racial/ethnic group and by donor center were evaluated. To determine the consistency within individual donor centers, the author compared donor unavailability during the first 6 months of the observation period with unavailability during the second 6 months. RESULTS: Donor unavailability at confirmatory typing was higher among donors registered with domestic (U.S.) donor centers. The self-identified racial or ethnic group of the donor also affected the likelihood the donor will be available when requested. Between individual donor centers, there were large differences in the overall donor unavailability. Rates of donor unavailability tended to remain consistent at individual centers over time. CONCLUSIONS: This study suggests that procedures used at individual donor centers may dramatically impact donor unavailability. Future initiatives should undertake to identify best practice models for donor recruitment, retention, and subsequent contacts.

Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program.

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 x 10(8)/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non-African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell-depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 x 10(9)/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P <.0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.