{"id":10939,"date":"2026-04-10T09:28:59","date_gmt":"2026-04-10T09:28:59","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/suzanna-van-walraven\/"},"modified":"2026-04-10T09:29:07","modified_gmt":"2026-04-10T09:29:07","slug":"suzanna-van-walraven","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/suzanna-van-walraven\/","title":{"rendered":"Suzanna Van Walraven"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":10942,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-10939","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Focus on the Donor","samenvatting":"Er is geen Nederlandse samenvatting beschikbaar. De Engelse samenvatting vind je <a href=\"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/suzanna-van-walraven\/\">hier<\/a>.","summary":"General discussion and future perspectives\n\nA theoretical model, based upon population genetics, estimating the likelihood of finding a well matched UD or CBU for white European patients and for patients with other ethnic backgrounds in the US. The model was based upon the donor and cord blood inventory of the National Marrow Donor Program (NMDP), which represents approximately 50% of all registrations worldwide, and taking availability and medical eligibility into account. They claimed a likelihood of over 95% for identifying an unrelated donor or cord blood unit for white Europeans and African-American patients. In our retrospective analysis, we were able to identify an acceptable stem cell source for 81% of non-NWE patients. The assumption of Gragert et al. that the donor population represents a true reflection of the patient population possibly overestimates the probability of finding an acceptable UD\/CBU in particular for non-NWE patients. Besides, a mismatched donor or cord blood are not always acceptable alternatives depending on the specific transplant protocol. Patients for whom no acceptable donor was identified in our study often originated from a mixed racial background. Donors with mixed genetic ancestry are probably least represented in the worldwide donor inventory. The importance of a donor\u2019s availability, especially in young male donors (since they are most likely to be requested) and ethnic minority groups is essential to explain during recruitment 31,32. It is necessary to revise recruitment strategies to prevent newly recruited donors from dropping out at any time during the verification typing and pre-donation process. Most donor registries have focused on the volume of their donor pool, but there is an urgent need to address the issue of donor attrition, since avoiding waste of money and efforts in this direction of recruitment can no longer be ignored 29,38. The startling fact that over 10% of registry donors is even unable to be located at time of a blood sample request, could be addressed in an awareness campaign (through social media, flyers or newsletters). Donor registries are unable to function as trackers and delays in the search could have serious consequences for patients, and these can be prevented.\n\nS, M, L, XL \u2013 donor registries\n\nCurrently there are a few ultra-large registries (with over 1 million registered donors) and a majority of small (<20,000 donors) and medium-sized registries (<100,000 donors) 39. Taking into consideration that the majority of products (>80%) is annually provided through five of the larger registries, of which two XL registries (responsible for 67% of all products) 3, the vulnerability of countries with S and M registries is evident. They have become dependent on stem cell products donated by foreign donors. It is unclear why the majority of requests is sent to the XL registries, since donors with \u2018common HLA phenotypes\u2019 are most likely present in their own national registries. It could be argued that national registries should be able to provide a certain percentage of stem cell products for their national patients. As a result of these developments and the economic crisis, S and M registries are facing difficult times and for new registries in emerging countries it is almost impossible to start up without sufficient financial support. Determining the optimal size and mix of the global donor inventory involves difficult decisions balancing competing objectives 27 and requirements. However, the need for new registries, in particular in emerging countries, is obvious since they add unique HLA phenotypes to the global donor inventory. Where in recent years approximately one in fifteen donors provided a new phenotype, the contribution of new registries such as the Brazilian registry added to BMDW in 2011, resulted for that year one in ten donors adding a new phenotype 40. In virtually all countries CB inventories have a much higher relative contribution of new HLA phenotypes to BMDW than the donors. It was stated in the BMDW annual report 2012 that CB banks are thus more successful in recruiting units from minority groups 40. A certain amount of these new phenotypes might originate from unique mixed ethnic backgrounds. This is extremely important for a number of those patients who would otherwise not have access to HSCT by lack of an acceptable (cord blood) donor. Yearly stem cells of less than 0.1% of all registered donors and approximately 0.8% of CBU are actually used for transplantation 3,41. Completeness of HLA typing has a strong impact on donation probabilities 42, since donors who are typed on high resolution are more likely to be requested. A possible explanation for the use of CBU being approximately tenfold higher than the proportion of available adult donors being utilized might be the phenotypic diversity and potential faster availability of CBU. The promising advantage of cord blood as a stem cell source for non-NWE patients underlines the importance of banking of high quality cord blood units for allogeneic transplantation, and in doing so compensating for the lack of minority donors in the donor pool 43. With the overall relatively small proportion of stem cell donors actually donating yearly, it is important to critically consider this before adding \u2018more of the same HLA\u2019 to the global donor pool. The introduction of next generation sequencing (NGS) will reduce the cost, while resolution of HLA typing is higher and determination of further parameters (blood group, CMV, KIR, etc.) easily possible, thus adding higher quality donors to the global donor pool. A Group of European Medium sized Registries are attempting to seek joined solutions for the challenges 44.\n\nReaching HSCT \u2013 clinical and non-clinical factors\n\nIn 2001 it was reported that overall only one third of eligible patients reached HSCT 45. Over a decade later the WMDA Annual Report demonstrates that 45% of patients for whom an unrelated donor search is initiated reach HSCT 2. This is most likely a subset of all eligible patients. A recent prospective study reported that an unrelated donor search for only 51% of patients without a family donor was initiated, without a clear explanation as to the reasons for the remaining patients being deferred 46. Reasons for not reaching transplantation are various; HSCT might be offered too late during therapy with clinical deterioration, in particular for intermediate\/high-risk leukemia patients, as probably the main disturbing factor 7,46, and the period to identify a donor could (and in some cases needs) to be decreased 47. The major non-clinical factor determining restraint of transplant is undoubtedly the lack of donors for non-NWE patients. We have proven for our Dutch patients that efficiency of the search process can affect feasibility of reaching transplantation to 70%, by reducing the amount of searches cancelled due to clinical deterioration of the patient to approximately 10%. To perform a search as efficient as possible donor registries have developed tools and methods to shorten the UD\/CBU search 49-53. Sharing such awareness and insights between donor registries and transplant centres might play a key role in improving transplantation figures.\n\nSafeguarding donors: the global approach\n\nSafety of stem cell donors considers mainly the suitability of the donor undergoing the procedure. Whether the donor is an infant or an adult, an anonymous person or a family member, their well-being and interests must always be kept in mind as a duty of care. Treating a healthy donor with an agent that is not of in his physical benefit demands responsibility from health professionals, and an approach where the safety of the donor comes first 54. With the introduction of Granulocyte Colony Stimulating Factors (G-CSF) in healthy volunteer individuals, the issue of (in particular) long-term safety has been addressed. In a recent study the short-term and long-term serious Adverse Events (SAE) of both bone marrow and peripheral blood stem cell donation were analysed 55. It was remarkable that the risk of short-term SAE was threefold higher in bone marrow donors. From the more long-term follow-up data it was confirmed that unrelated donors do not have an increased risk to develop a malignancy, auto-immune disease or thrombosis within three months after donation 55. The WMDA have adjusted their statement with regards to the use of G-CSF in healthy volunteers 56, however, although these comparisons have been stratified for age and gender with the general population, other confounders were generally not corrected for. It is also not known whether this statement equally applies for the related donor population, since the overall health in the unrelated donor population is probably better than in the related donor group or even the general population. For patients, older age no longer seems to be an absolute contra-indication for HSCT, but as previously mentioned, older patients have older siblings, and although age is not per se an indication for performance status 47, co-morbidities, and thus reasons to declare a person unsuitable for donation, are more often seen in elderly donors (this thesis). It is known that co-morbidities in related donors (RD) are more often accepted since \u2018related donors are willing to take a greater risk\u2019 57. The medical profession assumed for a long time that family members are naturally motivated by the prospect of saving the life of a loved one 58. It would subscribe the altruistic character and the principle of beneficence referred to as an aspect of human nature, that motivates to act in the interest of others 59. From this perspective it could be justified by the thought of Kant, that if a family donor really chooses to donate out of affection, his act would lack moral worth, because it would not be based on an obligation 59. However, it is unclear whether the above mentioned assumption of traditional altruistic thinking would make a relative feeling obliged to donate or deter him from free decision making 60. In extenso \u2013 could this imply violation of the basic ethic principle of autonomy, ascribing the right to choose and act freely? Violating or ignoring a person\u2019s autonomy is to treat that person merely as a means to an end, that is, in accordance with other requirements without regard to that person\u2019s own interests 59. In that light, the assumption could be an expression of the utilitarian view, that is, if the chance of the transplantation success is likely greater than the probability of the family donor to experience any harm, it is the donor\u2019s obligation to donate 59. The situation where the donor has not yet reached the age of adulthood or is not able to assent or to give informed consent, is even more complicated. If proxy consent for donation is given by a parent or a legal representative, this might implicate that the donor is used as means to an end, which would be contradictory with the principles of Kant\u2019s second formulation of the categorical imperative: the action is considered unacceptable, because the individual\u2019s physical integrity is ignored and his dignity diminished by locating his value in a donation activity 61. The American Academy of Pediatrics (AAP) has addressed ethical concerns in a policy and defined criteria that allow for the use of pediatric donors 62. Although the AAP has advised to have a system in place where (legal or ethical) approval is required prior to donation, it was argued that this might not sufficiently protect the interests of the pediatric donor and modification of the policy with more emphasis for the donor\u2019s rights, competence, and consent was proposed 63. Harvesting stem cells is a medical procedure that potentially imposes risks and violates the bodily integrity of the donor. The argument of \u2018best interest\u2019 remains questionable, since the outcome of the HSCT, and thus the potential benefit for the donor can not be predicted. The debate on quality of life versus medical emancipation became public with the novel \u2018My Sister\u2019s Keeper\u2019 65, where a 13 year old girl lived with the knowledge that she was conceived to rescue her sister, suffering from leukemia. She literally became the \u2018altruist by proxy-donor\u2019 66, seeking for legal medical emancipation after multiple donations, and prior to donating her kidney. The novel made clear that abstaining the right of decision-making leaves the basic principle of autonomy worthless, even in minors 65. Apart from the AAP policy, strict regulations or guidelines for practice with respect to the suitability, treatment, and follow-up of minor donors are still lacking. Even small policy changes could be beneficial for minor donors. For example, limiting the volume of bone marrow to be harvested from young donors could prevent them from requiring blood transfusions. Furthermore, HSCT outcome in children with high-risk leukemia has improved over time, regardless of donor source 67. Also, during the decision-making process, the search for an alternative donor (if time allows for) should be considered.\n\nInternationally there now is a leading opinion that the suitability of the stem cell donor is of importance for all parties involved 68. This was acknowledged by the transplant society with the establishment of the EBMT Donor Outcome Committee in 2012. Furthermore the FACT\/JACIE standards version 5 explicitly addresses donor care issues 69. Since then initiatives to develop and implement more strict guidelines for related donor care have been reported 70,71. Awareness for the interests of the related donors was raised through international collaboration. The World Health Organization (WHO) has addressed the need for protecting the health and welfare of living donors including appropriate long-term follow-up 72. Interestingly, a comparable discussion is being held in the field of living kidney donors, where governmental support is considered essential to set up a national system for life-long donor follow-up 73,74. The Worldwide Network for Blood and Marrow Transplantation (WBMT), a non-governmental organisation focusing on collaboration between existing international societies was established to promote excellence in stem cell transplantation and donation 75. Through several successive Donor Outcome Workshops consensus was sought for suitability donor outcome data and lately the need of in particular pediatric and elderly donors were specifically addressed, with the aim of providing written consensus guidelines (Vienna 2013). The development of a European Union funded Master in Donor Health Care (a Dutch initiative) is also underscoring that care for the donor of organs, tissues, and cells is taken seriously. With regards to serious (product) events and adverse reactions (S(P)EAR), the WMDA has developed a reporting system, adding to the high quality standards of donor care management 76. One of the major advantages of the WMDA S(P)EAR system is the possibility to send out a \u2018Rapid Alert\u2019 to communicate in a timely matter with the donor registries and transplant community, whenever appropriate. For the related donors no such system is yet in place. There is a strong justification for bringing the related donor care in line with those for unrelated donors, especially in addressing adverse events in this group 77. The establishment of a reporting system to cover adverse events of all living donors globally would be a major achievement and there is a substantial need to further investigate and develop this global challenge.\n\nFuture considerations \u2013 estimating the need for unrelated donors\n\nThe dynamic field of HSCT is continuously subject to changes. New drug developments and stem cell treatment protocols are rapidly following each other and being explored. Besides HLA matched related and unrelated UD and CB the use of targeted (autologous) immune cells for cancer treatment is under investigation. The extent of involvement and the final role of allogeneic donors in the future is thus unclear and this directly affect the activities of all donor registries. Chronic myeloid leukemia (CML) was less than two decades ago only curable by HSCT and patients are now successfully treated with tyrosine kinase inhibitors 78. Similar developments are on their way for chronic lymphocytic leukemia 79. If results of autologous tumor targeted T-cell therapy can be confirmed in larger randomized controlled trials this may ultimately lead to a decrease of the proportion of HSCTs 80. Another development is the renewed interest in transplantation with related haploidentical donors, followed by a high dose Cyclophosphamide given early after HSCT to reduce the incidence of Graft versus Host disease and graft rejection, resulting for leukemia in at least comparable outcome as with HLA identical or matched unrelated donors 81. In 2013, 40% of the patients in Italy received a haploidentical graft; Bacigalupo mentioned a 10% reduction of the financial cost in his transplant centre while increasing the number of transplantations performed by 20% 82. Regional differences in use of allogeneic donors are large, and associated with national income, thus widening the gap between more or less affluent countries 3,83. As an additional effect of the economic crisis, TCs need to investigate ways to cut the costs of HSCT, without depriving the standard of quality care 84, and keeping the treatment accessible 85. Although in-hospital patient days are the main part of expenditure, cost of unrelated donor selection and stem cell products, in particular the cost of (double) cord blood, are also subject to discussion 84,86,87. The cost effectiveness of HSCT with the several available stem cell sources (including haploidentical stem cells) is under investigation 88. A concern that was expressed is that in countries where a fixed-rate system for reimbursement is negotiated with health insurance companies, transplantation with double cord might become prohibitive. It was suggested to look into ways to keep the use of cord blood both profitable and affordable 87. The current discussion is focused on the pricing of stem cell products in general, and of cord blood in particular. A \u2018one-price-policy\u2019 or a price based upon the TNC of a unit (smaller units \u2013 lower prices) would positively affect patients (money is no longer an argument not to choose the best match). There is evidence that increasing the ethnic diversity of cord blood inventories lead to more patients reaching HSCT (this thesis) demonstrating cord blood banks the need to develop policies to increase ethnic diversity 89. Raising public awareness is important to reach the goal of covering HLA diversity even within a country 90. The likelihood of CBUs to be used over time is besides HLA, directly related to the total nucleated cell count (TNC) 91. Units with higher TNC are more likely to be selected for transplantation 91. It is known that non-NWE units often contain less TNC, probably related to shorter labor time but their contribution to the diversity should be considered 89. Other policies to make units better serviceable are the provision of maternal HLA typing, since a beneficial effect of non-inherited maternal antigens (NIMA) and inherited paternal antigens (IPA) of a cord blood have shown a positive impact on engraftment and relapse risk and a reduced graft versus host disease 92,93. Also, the efficacy of matching cord blood on high resolution HLA-A, -B, -C and -DRB1 was recently shown to be associated with lowest non-relapse mortality after transplantation with cord blood for acute leukemia and myelo-dysplastic syndrome 94, indicating that complete high resolution typing of new cord blood units is important.\n\nDonors and (future) research\n\nOver the past decades motivations, experiences, and perspectives of being a stem cell donor and donating stem cells, have been studied 95. Recently the introduction of new mobilizing agents and the use of bio-similars have created a need for donors to remain subject of prospective studies 96,97. Donor retention, recruitment strategies, and safety of stem cell donation in particular by the related donors of all ages remain subject of interest for future research. The Leiden University Medical Centre is one of the oldest HSCT centres in Europe, and the basis of Europdonor Foundation, the Dutch National Stem Cell Donor Registry, providing the opportunity to perform long-time follow-up studies in unrelated and related, pediatric, and adult donors. Such long-term effects of stem cell donation include also cognitive, emotional, and psychosocial factors. Course of Life questionnaires completed by our pediatric donor cohort will undergo final analysis in the near future, allowing more insights into the transition into adulthood after bone marrow donation in early childhood. Furthermore, we will report on pain management investigated in a prospective cohort of related and unrelated donors. The relation between stress and mobilization and the sense of Coherence are further subjects to be analysed in above mentioned donor cohorts. All donors included in our studies gave informed consent and the study was approved by the Ethical Review Board of the Leiden University Medical Centre. However, situations can occur where donors indirectly become a research subject (i.e. the donation is part of an experimental or research protocol). By donating stem cells, donors have proven to be altruistic and thus most likely would agree with their involvement in clinical research 98. The WMDA requires additional approval for donation by a donor registry and informed consent of the donor 99, which might cause a delay in transplantation. The procedures associated with experimental therapy (not considered standard of clinical care) also increased clinicians\u2019 awareness to the fact that donors are individuals with legitimate rights 100,101. It remains challenging to harmonize the interests of all parties involved 102, in particular if multiple or prolonged donations are involved in the protocol. It is important to address the acceptability of exposing a donor to a research protocol for the benefit of the recipient, and give advice according to the international standards on human research 103, also to prevent extensive delay, caused by an additional independent protocol review performed on behalf of a donor registry. The role of the unrelated donor might become less explicit in the future, but donation of stem cells by family donors will probably continue. It is in the interest of all parties involved to find the best balance between patients\u2019 needs and donors\u2019 interests and to accomplish long-term safety for future donors.","auteur":"Suzanna Van Walraven","auteur_slug":"suzanna-van-walraven","publicatiedatum":"28 januari 2015","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/suzannavanwalraven?iframe=true","url_download_pdf":"","url_epub":"","ordernummer":"FTP-202604100924","isbn":"978-90-819208-2-7","doi_nummer":"","naam_universiteit":"Universiteit Leiden","afbeeldingen":10943,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Leiden","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10939","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=10939"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10939\/revisions"}],"predecessor-version":[{"id":10940,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10939\/revisions\/10940"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/10942"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=10939"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=10939"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}