Genetic Findings of Potential Donor Origin following Hematopoietic Cell Transplantation: Recommendations on Donor Disclosure and Genetic Testing from the World Marrow Donor Association.

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.

Serious Stem Cell Donation Events and Recipient Adverse Reactions Related to Severe Acute Respiratory Syndrome Coronavirus 2: Review of Reports to the World Marrow Donor Association.

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 monitoring 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 imputability 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 collection and of minimizing the time between cell collection and transplantation. Transplantation centers should familiarize 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.

Suitability of haematopoietic cell donors: updated consensus recommendations from the WBMT standing committee on donor issues.

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.

Stem cell donor registry activities during the COVID-19 pandemic: a field report by DKMS.

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.

New global reporting system for serious (product) events and adverse reactions in hematopoietic stem cell donation and transplantation.

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.

Adverse event reporting for cellular therapy products: Current status and future directions.

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.

Immunogenetics in stem cell donor registry work: The DKMS example (Part 2).

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.

Immunogenetics in stem cell donor registry work: The DKMS example (Part 1).

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.

Retrospective Analysis of 37,287 Observation Years after Peripheral Blood Stem Cell Donation.

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.

Safety of Living Donation of Hematopoietic Stem Cells.

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.

Safety and efficacy of hematopoietic stem cell collection from mobilized peripheral blood in unrelated volunteers: 12 years of single-center experience in 3928 donors.

We present results of peripheral blood stem cell (PBSC) mobilization, collection, and follow-up from 3928 consecutive unrelated stem cell donors. Assessments were performed prospectively at baseline, leukapheresis, 1 month, 6 months, and annually after PBSC donation. During follow-up, side effects were recorded by return post questionnaires. The median CD34+ cell counts on day 5 were 67.5/microL in male and 51/microL in female donors. Bone pain and headache were the most common side effects of recombinant human granulocyte-colony stimulating factor. Central venous access was required for 23 donations (0.6%). Throughout the follow-up, the absolute neutrophil counts were slightly below the initial baseline values but remained within the normal range. The majority of the donors reported good or very good health. Malignancies occurred in 12 donors (0.3%), among whom were 1 case of acute myeloid leukemia, 1 case of chronic lymphatic leukemia, and 2 cases of Hodgkin disease. Only the incidence of Hodgkin lymphoma differed significantly from an age-adjusted population. In conclusion, 7.5 microg/kg per day lenograstim proved to be safe and effective for mobilizing hematopoietic stem cells for allogeneic transplantation. Long-term monitoring of healthy PBSC donors remains important to guarantee the safety standards of PBSC mobilization and collection.

Proteasome inhibition results in TRAIL sensitization of primary keratinocytes by removing the resistance-mediating block of effector caspase maturation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts potent cytotoxic activity against transformed keratinocytes, whereas primary keratinocytes are relatively resistant. In several cell types, inhibition of the proteasome sensitizes for TRAIL-induced apoptosis by interference with NF-kappaB activation. Here we describe a novel intracellular mechanism of TRAIL resistance in primary cells and how this resistance is removed by proteasome inhibitors independent of NF-kappaB in primary human keratinocytes. This sensitization was not mediated at the receptor-proximal level of TRAIL DISC formation or caspase 8 activation but further downstream. Activation of caspase 3 was critical, as it only occurred when mitochondrial apoptotic pathways were activated, as reflected by Smac/DIABLO, HtrA2, and cytochrome c release. Smac/DIABLO and HtrA2 are needed to release the X-linked inhibitor-of-apoptosis protein (XIAP)-mediated block of full caspase 3 maturation. XIAP can effectively block caspase 3 maturation and, intriguingly, is highly expressed in primary but not in transformed keratinocytes. Ectopic XIAP expression in transformed keratinocytes resulted in increased resistance to TRAIL. Our data suggest that breaking of this resistance via proteasome inhibitors, which are potential anticancer drugs, may sensitize certain primary cells to TRAIL-induced apoptosis and could thereby complicate the clinical applicability of a combination of TRAIL receptor agonists with proteasome inhibitors.