Following hematopoietic cell transplantation (HCT), recipients are subjected to extensive genetic testing to monitor the efficacy of the transplantation and identify relapsing malignant disease. This testing is increasingly including the use of large gene panels, which may lead to incidental identification of genetic and molecular information of potential donor origin. Deciphering whether variants are of donor origin, and if so, whether there are clinical implications for the donor can prove challenging. In response to queries from donor registries and transplant centers regarding best practices in managing donors when genetic mutations of potential donor origin are identified, the Medical Working Group of the World Marrow Donor Association established an expert group to review available evidence and develop a framework to aid decision making. These guidelines aim to provide recommendations on predonation consenting, postdonation testing of recipients, and informing and managing donors when findings of potential donor origin are identified in recipients post -transplantation. It is recognized that registries will have different access to resources and financing structures, and thus whenever possible, we have made suggestions on how recommendations can be adapted. (c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

To be cleared for hematopoietic stem cell (HSC) donation, potential donors must undergo a physical examination including blood testing to test their health status and eligibility to donate, ensuring safety for the donor and limiting the risk of transmitting infectious, genetic, or neoplastic diseases from the donated HSC product to the recipient. In Germany, the applicable national standards [1] require additional donor blood testing with serum protein electrophoresis (SPEP), to exclude the presence of monoclonal gammopathy of undetermined significance (MGUS) as part of this physical examination. MGUS is a premalignant plasma cell disorder in which plasma cells produce incomplete or non-functional monoclonal antibodies (paraproteins). Patients with MGUS have a life-long risk of developing multiple myeloma (MM), smoldering myeloma (SMM), or a related malignant disorder. The condition is usually discovered by the presence of serum monoclonal protein (M protein) that forms a peak (M gradient), usually in the gamma-globulin fraction, in SPEP [2]. MGUS is found in more than 3% of the population aged 50 years and older, its prevalence increases with age, and it is more often found in men than in women [3, 4]. The risk for MGUS patients to develop MM, SMM or a related malignant disorder is about 1% per consecutive year [4, 5]. Even if large quantities of plasma cells should not be transferred during HSC transplantation, a transfer of premalignant clonal cell populations to the recipient cannot be excluded. Transmission of MGUS has already been shown in solid organ transplantations [6]. In addition, blood-borne malignancies have been transferred by HSC transplantation [7, 8]. Therefore, registered donors with MGUS are ineligible for HSC donation and need to be identified and excluded during the physical examination with SPEP prior to donor clearance for HSC donation. However, in many countries, donor testing for MGUS is not carried out prior to HSC donation. Our findings highlight the need to include MGUS testing with SPEP for potential HSC donors prior to HSC collection as a standard to ensure both donor and specifically patient safety. In this work, we present data from DKMS Germany within a time period of 13 years (2009–2022) in which potential HSC donors were screened for MGUS during the physical examination prior to HSC collection. Based on these data, we analyzed the effect of MGUS testing with SPEP at this process step and discuss implications for HSC donation. Since 2009 (observation period: January 2009 until December 2022), DKMS Germany has had all potential HSC donors who were requested for donation tested for MGUS as part of the physical examination, taking place within 30 days prior to the planned collection date at the collection center. The method used to detect MGUS was SPEP. Immunofixation electrophoresis (IFE) was used to further differentiate the paraproteins. The total serum protein content was also determined on a routine basis. Furthermore, abnormal SPEP curves can further reveal other diseases such as antibody deficiencies. During the physical examination, no cases of MM or SMM were detected, but donors presenting abnormal SPEP curves (M gradient) indicating MGUS (defined as M protein concentration < 3 g/dL and absence of end-organ damage characterized by CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions)) [4, 9] were not cleared to proceed for donation. Cases were retested for MGUS via their general practitioner to either confirm or refute the original diagnosis. All deferred cases between 2009 and 2017 were included in a follow-up study and were routinely followed up for ten years (as are all actual stem cell donors) but the proportion of deferred donors which did not respond was high (around 40% of deferred cases and 57% of MGUS cases did not respond). In the period from January 2009 to December 2022, 4344 of 97,938 requested donors (4.4%; 1511/29,003 female, 2833/68,935 male), were not cleared to proceed to HSC donation. Besides the main reasons such as poor vein status or an enlarged spleen, another common reason for donor deferral was the diagnosis of potential MGUS: In 143 potential donors (0.15%; 38 females and 105 males) abnormal paraprotein was detected, corresponding to 3.3% of all non-clearances. In three cases (one MM and two SMM) disease progression was confirmed diagnostically within 1 year. Regardless of donor sex, 52% of all MGUS cases were identified in 40- to 49-year-old donors (Figure 1). The median age at donor request creation of the MGUS cases was 43 years (age range: 21–60 years). In comparison, the median age of all requested donors in the observed period was 28 years. Of the 143 donors who were not cleared due to an MGUS diagnosis, only four cases were detected with total serum protein above the reference range (≥ 84 g/L). Therefore, according to our data, testing of total protein alone was not suited to exclude monoclonal gammopathy in HSC donors since more than 97% of MGUS cases would have remained undetected if total serum protein concentration without SPEP had been used as a diagnostic measure. Monoclonal IgG kappa or lambda gammopathies were by far the most frequently diagnosed (76%, 109 cases), whereas IgM (11%, 16 cases) and IgA gammopathies (9%, 13 cases) were diagnosed less frequently. The rarest subclass was a biclonal gradient (IgG and IgA), which was detected only in two donors. In three cases no specific information was provided. In the further course, normal SPEP/IFE results were documented in 17 donors (12%) several months after abnormal paraprotein detection during the physical examination. Forty-five donors (31%) confirmed the MGUS diagnosis after consulting another doctor, whereas 81 donors (57%) did not disclose information about their MGUS status afterward. In addition, electrophoresis revealed 23 cases of antibody deficiency (0.5% of donor non-clearances). These cases would have remained undiagnosed otherwise and could have posed an additional risk for the HSC donor and recipient. Overall, our data revealed 0.15% MGUS cases in our study population which is consistent with data from other population cohorts, ranging from 0.05% to 6.1% depending on age, ethnicity, and geographic area [10]. Individuals requested for HSC donation are generally a positively selected population group that is younger and healthier compared to the general population, which explains why the incidence of MGUS that we observed is at the lower end of the reported range. According to our analysis, the vast majority of MGUS cases (139/143; 97.2%) would not have been detected without SPEP/IFE, and the affected donors would most likely have donated HSC. As a transmission risk of donor MGUS cannot be excluded, this is a strong argument in favor of routine testing for MGUS in the physical examination of potential HSC donors, especially as the costs and efforts of the corresponding tests (SPEP/IFE) are low. A specific donation risk for clinically asymptomatic donors with MGUS remains unknown, thus the execution of SPEP/IFE does not have a direct positive effect on donor safety. Nevertheless, it is beneficial for the donor to be aware of the presence of MGUS to establish routine disease monitoring and prevent associated complications or consequential organ damage. Taken together, the analysis of SPEP/IFE improves the quality and safety profile in HSC donor clearance during the physical examination and should become a standard diagnostic for potential HSC donors prior to donation wherever the medical infrastructure allows, specifically for older donors (> 40 years). Laura Kilinc and Thilo Mengling conceptualized and wrote the paper. Burkhardt Schleipen, Deborah Buk, Isabel Auer, and Thilo Mengling collected data. Laura Kilinc, Burkhardt Schleipen, Karen Ende, and Thilo Mengling analyzed data. Karen Ende and Alexander H. Schmidt contributed to the writing of the manuscript. All authors reviewed and approved the final manuscript. The authors have no funding sources to declare. The authors declare no conflict of interest. The authors have confirmed ethical approval statement is not needed for this submission. The authors have confirmed patient consent statement is not needed for this submission. The authors have confirmed clinical trial registration is not needed for this submission. The data collected for this study will be made available upon reasonable request; please contact the corresponding author Thilo Mengling: [email protected].

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has deeply impacted hematopoietic stem cell (HSC) donation and transplantation. Numerous changes in practice have been introduced, and monitor-ing the impact of these changes on donations and transplantations is of vital importance. As part of a global response to this pandemic, the World Marrow Donor Association (WMDA) asked that its member registries and cord blood banks submit SARS-CoV-2-related adverse events to the WMDA-operated Serious Product Events and Adverse Reactions (SPEAR) database. Here we review SARS-CoV-2-related SPEAR events that occurred in 2020. The WMDA SPEAR Committee reviewed reports submitted via an online tool. The Committee reviewed each report following the European Union definitions of a serious adverse event or reaction and determined the imput-ability and its impact. Reports submitted in 2020 were included in this analysis. A total of: 74 such reports were received, and events were classified as donor-related (n = 41; 55.4%), recipient -related (n = 3; 4.1%), technical issues (n = 31; 41.8%), or transport-related issues (n = 4; 5.4%). Five cases appeared in multiple categories. The most frequently reported adverse events were of cells being unused. Many of these cases were caused by the uncoupling of the donation and transplantation consequent on the cryopreservation of products, as well as technical issues related to cell viability. Experience in some registries suggests that these issues have become less frequent as transplantation centers have become used to the changes in practice. Lessons learned include the importance of confirming recipient eligibility before the start of donor mobilization or collec-tion and of minimizing the time between cell collection and transplantation. Transplantation centers should famil-iarize themselves with the expected cell losses when peripheral blood stem cell and bone marrow products are cryopreserved and should have validated viability assays in place for quality assurance. Reassuringly, there were no reports of donors becoming severely unwell because of G-CSF or transmission of SARS-CoV-2 to recipients and only 1 report of complete failure of transport of a donation.& COPY; 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The contribution of related donors to the globally rising number of allogeneic haematopoietic stem cell transplantations (HSCT) remains increasingly important, particularly because of the growing use of haploidentical HSCT. Compared with the strict recommendations on the suitability for unrelated donors, criteria for related donors allow for more discretion and vary between centres. In 2015, the donor outcome committee of the Worldwide Network for Blood and Marrow Transplantation (WBMT) proposed consensus recommendations of suitability criteria for paediatric and adult related donors. This Review provides updates and additions to these recommendations from a panel of experts with global representation, including the WBMT, the European Society for Blood and Marrow Transplantation donor outcome committee, the Center for International Blood and Marrow Transplant Research donor health and safety committee, the US National Marrow Donor Program, and the World Marrow Donor Association, after review of the current literature and guidelines. Sections on the suitability of related donors who would not qualify as unrelated donors have been updated. Sections on communicable diseases, clonal haematopoiesis of indeterminate potential, paediatric aspects including psychological issues, and reporting on serious adverse events have been added. The intention of this Review is to support decision making, with the goal of minimising the medical risk to the donor and protecting the recipient from transmissible diseases.

American Journal of HematologyVolume 96, Issue 3 p. E91-E92 CORRESPONDENCEOpen Access A DKMS (German Bone Marrow Donor Center) view on cryopreservation of unrelated donor stem cell products during the Covid-19 pandemic Alexander H. Schmidt, Corresponding Author Alexander H. Schmidt [email protected] orcid.org/0000-0003-0979-5914 DKMS, Tübingen, Germany Correspondence Dr. Alexander H. Schmidt, DKMS, Kressbach 1, 72072 Tübingen, Germany. Email: [email protected]Search for more papers by this authorDeborah Buk, Deborah Buk DKMS, Tübingen, GermanySearch for more papers by this authorStefanie N. Bernas, Stefanie N. Bernas orcid.org/0000-0002-9700-6710 DKMS, Tübingen, GermanySearch for more papers by this authorThilo Mengling, Thilo Mengling orcid.org/0000-0002-1349-1094 DKMS, Tübingen, GermanySearch for more papers by this authorElke Neujahr, Elke Neujahr DKMS, Tübingen, GermanySearch for more papers by this authorMarcel R. M. van den Brink, Marcel R. M. van den Brink orcid.org/0000-0003-0696-4401 Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USASearch for more papers by this author Alexander H. Schmidt, Corresponding Author Alexander H. Schmidt [email protected] orcid.org/0000-0003-0979-5914 DKMS, Tübingen, Germany Correspondence Dr. Alexander H. Schmidt, DKMS, Kressbach 1, 72072 Tübingen, Germany. Email: [email protected]Search for more papers by this authorDeborah Buk, Deborah Buk DKMS, Tübingen, GermanySearch for more papers by this authorStefanie N. Bernas, Stefanie N. Bernas orcid.org/0000-0002-9700-6710 DKMS, Tübingen, GermanySearch for more papers by this authorThilo Mengling, Thilo Mengling orcid.org/0000-0002-1349-1094 DKMS, Tübingen, GermanySearch for more papers by this authorElke Neujahr, Elke Neujahr DKMS, Tübingen, GermanySearch for more papers by this authorMarcel R. M. van den Brink, Marcel R. M. van den Brink orcid.org/0000-0003-0696-4401 Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USASearch for more papers by this author First published: 24 December 2020 https://doi.org/10.1002/ajh.26081Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: In his commentary,1 Devine describes the position of the National Marrow Donor Program (NMDP) of the United States regarding cryopreservation of allogeneic hematopoietic cell grafts during the Covid-19 pandemic. We thank the author for addressing this important topic, which constitutes undoubtedly one of the biggest challenges for unrelated stem cell donor registries during the Covid-19 pandemic. The NMDP and DKMS (German Bone Marrow Donor Center or Deutsche Knochenmarkspenderdatei) as two globally leading registries are working closely together on this and other pandemic-related issues.2 Nevertheless, both organizations seem to have had somewhat different experiences with cryopreservation during the pandemic, which then led to partially different assessments and conclusions, as we will describe. Based on our experience with DKMS donors from Germany, we have seen a substantially higher rate of non-transfused cryopreserved products than mentioned in the commentary by Devine1: Between March 1, 2020 and November 15, 2020, 2396 of the 3960 stem cell products collected (60.5%; 63.2% of peripheral blood stem cell (PBSC) and 36.7% of bone marrow (BM) products) were cryopreserved. Of these cryopreserved products, 79 (3.3%; 3.0% of PBSC and 8.1% of BM products) will definitely not be transfused (data retrieval date: November 23, 2020). Another 178 cryopreserved products (7.4%) have not yet been transfused, and many of these products have already passed the originally planned transplantation date. At this time, we expect that ultimately 5%–8% of the cryopreserved products will not be transfused. This rate is not substantially higher than it was before the Covid-19 pandemic (3.1%–6.9% in 2019; the uncertainty results from cases that are still open). However, only 4.7% (262/5603) of all stem cell products were cryopreserved during that period. Therefore, the expected absolute number of non-transfused cryopreserved products collected in 2020 is about one order of magnitude higher than in 2019 (8–18).3 Of course, each DKMS donor must agree to the cryopreservation of their stem cell product prior to collection with the understanding that it may not be transfused. It is rare that a donor refuses this consent. Accordingly, donors who are informed that their product will not be transfused are generally disappointed but understanding. These observations from donor registry practice indicate that the communication challenges associated with non-transfused stem cell products from unrelated donors may generally be manageable. However, all parties operate under the ethical obligation of avoiding these cases as much as possible. Moreover, stem cell donations are associated with small but existing risks as well as inconveniences such as side effects of stem cell mobilization for PBSC donors and postoperative pain for BM donors.4, 5 We propose that three aspects must be considered in order to minimize the risk of non-transfusion of unrelated donor products and thus to do full justice to the altruistic commitment of unrelated donors: First, a careful case-by-case assessment must be made as to whether cryopreservation is really necessary to ensure that the stem cell product will be available at the transplant center at the required time. This is because the restrictions imposed by the Covid-19 pandemic vary greatly in terms of time and geography. In the initial phase of the pandemic in March 2020, for example, the transport of stem cell products across national borders was uncertain for a few days before new processes were quickly established.2, 6 Since then, these processes have enabled the safe handling of transports between many countries, especially those with many donors and recipients of stem cell products such as Germany and the USA. Even the second wave of the pandemic, which has hit Europe hard for several weeks now, has not changed this situation. As a result, no conditioned patient waiting for a stem cell product from a donor registered with DKMS Germany was left without that product due to logistical or transport issues. In addition to the safety of product transport, the impact of the pandemic on donor availability is also a factor that must be considered when deciding for or against cryopreservation in each individual case. At DKMS Germany, the pandemic has not significantly affected donor non-availability rates at the workup level, that is, at the final process step before stem cell collection. The corresponding values are 19.3% (1340/6943) for 2019 and 19.4% (955/4915) during the Covid-19 pandemic (from March 1, 2020 to November 15, 2020). Until November 15, 19 donors were not available at workup level for SARS-CoV-2 related reasons. This represents only 2.0% of all cases of donor non-availability at work-up level during the same period. Again, no conditioned patient was left without stem cell product due to donor non-availability. Second, it is important to keep the planned time between collection and transfusion of cryopreserved products as short as possible. Ideally, conditioning of the patient should begin immediately after the product has been received and cryopreserved. This implies especially that the recipient's transplant eligibility needs to be confirmed before the collection procedure starts, as required by the World Marrow Donor Association.7 We emphasize this point because the deterioration of the patient's status (including patient death) was – in clear distinction to the dataset described by Devine1 – by far the most frequent reason for non-transfusion of cryopreserved products during the pandemic (62 cases; 78.5%). In several of these cases, the patient's transplant eligibility was not verified shortly before the collection, thus causing unnecessary stem cell collections from unrelated donors. It is our experience that this specific problem was less frequent before the Covid-19 pandemic. However, even then, the deterioration of the patient status was the main reason for not transfusing cryopreserved products. Third, cryopreservation should be avoided if there is a high probability that process-related cell count and/or viability losses will lead to a product that is not used. Dissatisfaction with product characteristics as cell count or viability was the second most common cause of non-transfusion (11 cases; 13.9%). Risk factors include an unfavorable donor/patient weight ratio, bone marrow as stem cell source and a long transport time before cryopreservation. The latter issue can be resolved by cryopreservation at or near the collection center. Of the 2396 cryopreserved products from German DKMS donors, 96 (4.0%) were cryopreserved at or near the collection center. Therefore, we believe that it is not necessary to select a slightly inferior ("roughly equivalent") domestic donor in such cases as proposed by Devine.1 In summary, cryopreservation of stem cell products from unrelated donors was and is an important tool to overcome the logistical challenges associated with the Covid-19 pandemic and to ensure that conditioned patients receive the stem cell products they need safely and on time. However, the resulting significant increase of non-transfused unrelated donor stem cell products is problematic and requires careful consideration of the best approach in each individual case. After the end of the pandemic, it is essential to return to the conventional practice with predominantly fresh products from unrelated donors. FINANCIAL DISCLOSURES None. FUNDING INFORMATION None. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1Devine SM. Transplantation of allogeneic cryopreserved hematopoietic cell grafts during the COVID-19 pandemic: a National Marrow Donor Program perspective. Am J Hematol. 2020. https://doi.org/10.1002/ajh.26052. [Epub ahead of print]. 2Devine S, Schmidt A. Against all odds—unrelated stem cell transplants in coronavirus times. Cancer Lett. 2020. https://cancerletter.com/articles/20200327_7/. 3Schmidt AH, Buk D, Platz A, Van den Brink MRM. Cryopreservation for all is no option in unrelated stem cell transplantation (Comment to: Dholaria B, et al. Securing the graft during pandemic: are we ready for cryopreservation for all?. Biol Blood Marrow Transplant. 2020; 26(11): e298- e299. https://doi.org/10.1016/j.bbmt.2020.08.011. 4Pulsipher MA, Chitphakdithai P, Logan BR, et al. Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation. Blood. 2014; 123: 3655- 3663. https://doi.org/10.1182/blood-2013-12-542464. 5Schmidt AH, Mengling T, Hernandez-Frederick CJ, et al. Retrospective analysis of 37,287 observation years after peripheral blood stem cell donation. Biol Blood Marrow Transplant. 2017; 23: 1011- 1020. https://doi.org/10.1016/j.bbmt.2017.02.014. 6Mengling T, Rall G, Bernas SN, et al. Stem cell donor registry activities during the COVID-19 pandemic: a field report by DKMS. Bone Marrow Transplant. 2020. https://doi.org/10.1038/s41409-020-01138-0. [Epub ahead of print]. 7 World Marrow Donor Association. WMDA SEAR Rapid Alert 20200713. 2020. https://wmda.info/wp-content/uploads/2020/08/F-DC-001-20200713-SEAR-Rapid-Alert2.pdf. Citing Literature Volume96, Issue3March 2021Pages E91-E92 This article also appears in:COVID-19 and Hematology ReferencesRelatedInformation

Annually more than 21,000 volunteer unrelated hematopoietic stem cell donations are performed worldwide for patients with life-threatening diseases such as acute leukaemia. Donor safety issues and donor protection is one of the top priorities for the international cooperation of unrelated hematopoietic stem cell donor registries represented by the World Marrow Donor Association (WMDA). With this new global reporting system for serious events and adverse reactions (S(P)EARs), the WMDA aims to become the global leading online platform for hematopoietic stem cell donor organisations to report their S(P)EARs from both unrelated and family donors. Software developer Cogapp developed the platform using a Knack environment based on requirements of experienced reporters and reviewers. On July 1st WMDA launched a robust online reporting system for S(P)EARs in order to provide accurate information about potential risks to donors. The collected data about S(P)EARs occurring in donors will be analysed and used to provide statistics on the type of reports being submitted and to put in place best practices to mitigate such effects and occurrences. Via the annual S(P)EAR reports the results will be disseminated worldwide.

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.

Adverse event (AE) and adverse reaction (AR) reporting are key components of patient safety and surveillance systems. Review and analysis of this data yields opportunities for process improvement, product information and interventions, and can lead to improved patient outcomes and donor safety overall. AE and AR reporting for cellular therapy products is fragmented and not well characterized in a central reference. This review article, authored by experts from various organizations, serves to summarize the current state of reporting and offers opportunities for streamlining and coordination, as well as key reference for professionals in this field.

DKMS is a leading stem cell donor registry with more than 9 million donors. Donor registry activities share many touch points with topics from immunogenetics or population genetics. In this two-part review article, we deal with these aspects of donor registry work by using the example of DKMS. In the second part of the review, we focus on donor typing of non-HLA genes, the impact of donor age, gender and CMV serostatus on donation probabilities, the identification of novel HLA, KIR and MIC alleles by high-throughput donor typing, the activities of the Collaborative Biobank and pharmacogenetics in the donor registry context.

The COVID-19 pandemic has serious implications also for patients with other diseases. Here, we describe the effects of the pandemic on unrelated hematopoietic stem cell donation and transplantation from the perspective of DKMS, a large international donor registry. Especially, we cover the development of PBSC and bone marrow collection figures, donor management including Health and Availability Check (HAC), transport and cryopreservation of stem cell products, donor recruitment and business continuity measures. The total number of stem cell products provided declined by around 15% during the crisis with a particularly strong decrease in bone marrow products. We modified donor management processes to ensure donor and product safety. HAC instead of confirmatory typing was helpful especially in countries with strict lockdowns. New transport modes were developed so that stem cell products could be safely delivered despite COVID-19-related travel restrictions. Cryopreservation of stem cell products became the new temporary standard during the pandemic to minimize risks related to transport logistics and donor availability. However, many products from unrelated donors will never be transfused. DKMS discontinued public offline donor recruitment, leading to a 40% decline in new donors during the crisis. Most DKMS employees worked from home to ensure business continuity during the crisis.

Donor safety is of utmost importance in the setting of hematopoietic stem cell donation. Follow-up is indicated to detect potential long-term risks for donors. We sent a follow-up questionnaire to 15,445 donors of peripheral blood stem cells (PBSCs) or bone marrow (BM) within a retrospective study design. The return rate was 91.3%, resulting in 37,287 observation years for PBSC donors and 25,656 for BM donors. Most donors assessed their health conditions as very good or good and had not been hospitalized or received long-term medical treatment including prescribed medication for more than 4 weeks since donation. Although there were no differences in the frequency of reported health events, BM donors more often rated their general health as very good or good. Ninety-five percent of donors after BM or PBSC donation would consider a second stem cell donation. In total, 93 malignancies were reported. The standardized incidence ratio (SIR) for a diagnosis of any type of cancer after PBSC donation was .94 (95% CI, .70 to 1.24) with a SIR below 1 indicating a lower risk than in the age- and sex-matched population. The SIR for a diagnosis of leukemia was 0 (95% CI, 0 to 1.88). In summary, we found no evidence that either PBSC or BM donation are associated with increased risks of malignancies or other severe health problems.

Occult hepatitis B virus (HBV) infections have gained much attention in terms of transmissibility and reactivation.1 Here, we report the case of a healthy stem cell donor with serological evidence of a resolved HBV infection who became temporarily HBV DNA–positive in the blood after stimulation with granulocyte colony-stimulating factor (G-CSF). A 51-year-old man from the German Bone Marrow Donor Center was identified as human leukocyte antigen matching (10/10) stem cell donor for a 44-year-old female patient diagnosed with precursor B-cell acute lymphoblastic leukemia in the United Kingdom. This donor was a well-known blood donor since 2009 and was previously tested positive for antibody to hepatitis B core antigen, antibody to hepatitis B e antigen, and antibody to hepatitis B surface antigen (anti-HBs). During the diagnostic workup the serological findings could be confirmed and HBV DNA was not detected. Thus, in accordance with German regulations, this donor was considered eligible for stem cell donation. The donor started G-CSF treatment, and at day 5 cluster of differentiation 34 (CD34)–positive stem and progenitor cells were collected. At this time HBV DNA (pooled tested, detection limit 257 IU/mL) tested negative. The product was shipped from the German apheresis center to the UK transplantation center and infused after myeloablative conditioning of the patient had been completed. Six days after transplantation, testing of the product at the transplantation center revealed the presence of 26 IU/mL HBV DNA, which could be confirmed by testing backup samples (product and blood) (Table 1; Supporting Information). Therefore, the stem cell recipient immediately started lamivudine treatment and has tested negative for HBV DNA (last test day +130) ever since. Anti-HBs of the recipient was negative before transplantation but temporarily positive after transplantation (Supporting Information). (−7 days) Serum (+16 days) Serum HBV DNA testing of the donor was again negative at day 16 after apheresis. Anti-HBs titration and neutralizing experiments using hepatitis B surface antigen (HBsAg) from different genotypes specified the presence 3,300 IU/L anti-HBs in the blood of the donor highly capable of neutralizing HBsAg from different genotypes. Parts of the HBV DNA detected in the product could be amplified and genotyped, which was classified as genotype D and carried specific mutations. Two mutations (S204N/S207N) were located at the C terminus and one (T140S) in the a-determinant of HBsAg, which has been associated with immune escape rendering anti-HBs ineffective.2 This is the first case of a stem cell donor who became temporarily positive for HBV DNA following treatment with G-CSF. Because G-CSF treatment induces proliferation of hepatocytes or hepatic progenitor cells in humans and other animals, it is tempting to speculate that here the G-CSF treatment resulted in the proliferation of hepatocytes harboring HBV covalently closed circular DNA.3 However, further studies are needed to link HBV reactivation and cell proliferation and to address a potential role of CD34+ cells for the detectability of HBV DNA.4 In accordance with previous observations, the presence of anti-HBs did not always provide protection from HBV reactivation.5 At least in this case the presence of HBsAg mutations might have also contributed to the noneffectiveness of anti-HBs. At the moment it cannot be excluded that the G-CSF treatment coincided with the detection of HBV DNA in the blood and did not cause it. However, because the donor regularly gave blood from 2009 to 2014 without evidence of transmitting HBV and the HBV DNA levels immediately fell below the detection limit after the cessation of G-CSF therapy, it might be possible that the G-CSF treatment was responsible for the transient detectability of low levels of HBV DNA, which could not be detected by the pooled analysis of samples. It remains unclear whether infectious particles were circulating in the blood of the donor at the time of cell collection. The immediate antiviral treatment of the recipient prevented any comments on the infectivity of the CD34-positive cell product. Therefore, more studies are needed to explore the impact of G-CSF treatment on occult HBV infections and the potential risk of transmitting HBV through cell products. Especially, the screening of blood and cell products after G-CSF treatment using highly sensitive polymerase chain reaction protocols could give further insight into the frequency of HBV DNA positivity and would also help to identify samples which could be used for scrutinizing HBV infectivity. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.28667/suppinfo. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

More than 12 000 volunteer unrelated hematopoietic stem cell donations are undertaken annually, and the World Marrow Donor Association established an expert committee to examine all reports of adverse events affecting donors globally, eventually making such reporting a necessary part of World Marrow Donor Association accreditation. The committee evaluates and responds to reported events in a nonpunitive confidential process designed to alert the community of rare events which might be missed by local follow-up. Each report is evaluated by the committee for imputability (causal link between the donation and the adverse event) and compared with that submitted by the reporting registry. In 2014, there were 50 reports received from 16 different registries in 15 countries. There were 16 reports of malignancies arising in donors including 3 hematologic malignancies. All but 2 of the 16 occurred more than a year after donation. There were 4 reports of autoimmune phenomena in donors all occurring more than a year postdonation. Of the 30 remaining events, 6 were allergic, 4 cardiac, 3 gastrointestinal, 2 infections, 2 pulmonary, and 13 miscellaneous. Causation was assessed differently to the reporting registry in 17 events with 6 thought to be less likely causally linked to the donation and 10 more likely with 1 requiring more information. Volunteer unrelated hematopoietic stem cell donation is a safe and effective altruistic contribution to the treatment of patients with life-threatening hematologic disorders. A decade of detailed examination of adverse donor events has contributed to the safety of these donations.

Abstract Introduction: HSC donation is an established procedure with few, manageable short term side effects. As donation is, especially for unrelated volunteer donors, an entirely altruistic act with no direct health benefits, careful and systematic long-term follow-up is crucial. However, interpretation of follow-up data requires a suitable control group. Here, we report first results from a matched pair donor follow-up study. Since 2009, DKMS has extended the routine questionnaire-based donor follow-up to a control group of registered potential stem cell donors who had not actually donated at that time. Donors in the control group (CG) were matched for age, sex and, if possible, HLA to stem cell donors. Eligibility for controls was evaluated using the standard health questionnaire from confirmatory typing stage. After study recruitment, controls were sent identical follow-up questionnaires in the same intervals as real donors. As of July 1st, 2015, our data set for analysis extended to 170,484 questionnaires (58,306 from 21,633 unrelated donors (URD), and 112,178 from 65,543 controls (CG)). Of the URD, 17,472 have donated peripheral blood stem cells (PBSC), 3,735 bone marrow and 145 are donors of both, marrow and PBSC. For statistical reasons, 281 donors requested for donation but deferred at medical pre-examination are included in the donor group. Results: A total of 157 malignancies (excluding ICD-10 C44 neoplasms of skin other than malignant melanoma) have been reported (URD 63, CG 94). In multivariate analysis, significantly more malignancies were observed in females (p <0.001; OR 2.07, 95% CI 1.55 - 2.78), and with increasing age. No difference in the overall malignancy incidence was seen between the URD and control group. In both groups, incidences were significantly lower than the expected rates based on the standard incidences in the German population (standard incidence ratio (SIR) 0.64, 95% CI 0.54 - 0.74). SIR analysis for single ICD malignancy groups revealed significant or close to significant scarcity of reported neoplasms of the lung, oral cavity and colon, all known to correlate with certain health-related behavior (smoking, misuse of alcohol, diet). Due to the administration of GCSF to healthy volunteers for PBSC donation, any hematological malignancies in this group are of particular interest. In the URD group, 1 single case of leukemia (AML) and 2 cases of lymphoma (2 Hodgkin's lymphoma, 1 cutaneous T-cell lymphoma) have been reported from PBSC donors. Because eligibility for the control group was assessed by a confirmatory typing (CT) stage health questionnaire without physical examination, we have included potential donors who where originally cleared at CT stage but deferred during work-up process for medical reasons as part of the URD group for enhanced comparability ('intention to donate'). One case of multiple myeloma was seen in this subgroup (reason for deferral: monoclonal gammopathy). No cases were reported from donors who had donated via bone marrow extraction. In the control group, a total of 8 hematological malignancies were reported (2 Hodgkin's lymphoma, 4 NHL, 1 multiple myeloma, 1 Langerhans cell histiocytosis). No increased incidences of hematological malignancies were observed in either the URD or control group. Discussion: For evaluation of long-term HSC donor follow-up, the applicability of general population data for comparison must be discussed critically. Our data suggest that registered donors as a group are distinct from the general population regarding health-related behavior and attitude or disease susceptibility. Malignancy incidences lower than expected from epidemiological data can most likely be explained by selection effects. People willing to donate stem cells likely represent a healthy sample of the general population. While incomplete reporting cannot be ruled out, it should have affected both URD and CG in the same way. Thus, our approach to include registered potential donors as a control sample is a viable and thorough approach to identify (late) health hazards, further increasing safety and confidence for volunteer stem cell donors. Even more, our study will allow to evaluate donor follow-up data where epidemiological data is insufficient or not applicable, e.g. for autoimmune diseases or general well-being. Disclosures No relevant conflicts of interest to declare.