Superior physical and mental health of healthy volunteers before and five years after mobilized stem cell donation.

BACKGROUND: Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being "warm glow", hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally. METHODS: We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire. RESULTS: Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time. CONCLUSIONS: HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk-benefit assessment of volunteer HSPC donation. Trial registration National Clinical Trial NCT01766934.

Is split-dose better than single-dose? Results of Turkish Stem Cell Coordination Center (TURKOK) donors in the era of rising biosimilar G-CSF.

BACKGROUND: Turkish Stem Cell Coordination Center (TURKOK) carries out the procurement process of unrelated allogeneic hematopoietic stem cells in Turkey. This study aims to compare the efficacy of both once-daily and divided-dose G-CSF administration and the original and biosimilar G-CSF use and the frequency and severity of adverse events in TURKOK donors. METHOD: The study was conducted retrospectively with 142 healthy TURKOK donors. For PBSC mobilization, two different subcutaneous G-CSF programs were used as 10 µ/kg/day single-dose and 5 µ/kg/12 h. Neupogen (Amgen, Puerto Rico) and Tevagrastim (Teva, Kfar Saba, Israel) were used as G-CSF. All donors started apheresis on the fifth day, and all side effects were recorded during the procedure. RESULTS: Stem cell yield was similar between single-dose and divided-doses based on donor weight, favoring the split-dose based on recipient weight (P = .506 and P = .023, respectively). Both G-CSF posologies were comparable if the target CD34+ cell yield was ≥4 × 106 /kg. CD34+ cell yield was equivalent when evaluated against recipient weight, significantly favoring Tevagrastim vs Neupogen by donor weight (P = .740 and P = .021, respectively). Side effects, duration of pain, and need for analgesia favor Tevagratim over Neupogen. CONCLUSION: Split-dose may be recommended for cases where the need for large numbers of CD34+ cells to be harvested is anticipated due to significant cell yield relative to recipient weight. However, sufficient hematopoietic stem cells can be collected with both posology. Tevagrastim is non-inferiority effective to Neupogen. Side effects during administration are both low-grade and temporary.

Anonymity in EU Health Law: Not an Alternative to Information Governance.

Data sharing has long been a cornerstone of healthcare and research and is only due to become more important with the rise of Big Data analytics and advanced therapies. Cell therapies, for example, rely not only on donated cells but also essentially on donated information to make them traceable. Despite the associated importance of concepts such as 'donor anonymity', the concept of anonymisation remains contentious. The Article 29 Working Party's 2014 guidance on 'Anonymisation Techniques' has perhaps helped encourage a perception that anonymity is the result of data modification 'techniques', rather than a broader process involving management of information and context. In light of this enduring ambiguity, this article advocates a 'relative' understanding of anonymity and supports this interpretation with reference not only to the General Data Protection Regulation but also to European Union health-related legislation, which also alludes to the concept. Anonymity, I suggest, should be understood not as a 'technique' which removes the need for information governance but rather as a legal standard of reasonable risk-management, which can only be satisfied by effective data protection. As such, anonymity can be not so much an alternative to data protection as its mirror, requiring similar safeguards to maintain privacy and confidentiality.

Biosimilar G-CSF versus filgrastim and lenograstim in healthy unrelated volunteer hematopoietic stem cell donors.

The World Marrow Donor Organization recommends original granulocyte-colony stimulating factor (G-CSF) for the mobilization of stem cells in healthy unrelated hematopoietic stem cell donors. We report the comparison of a biosimilar G-CSF (Zarzio) with two original G-CSFs (filgrastim and lenograstim) in mobilization in unrelated donors. We included data of 313 consecutive donors who were mobilized during the period from October 2014 to March 2016 at the Medical University of Warsaw. The primary endpoints of this study were the efficiency of CD34+ cell mobilization to the circulation and results of the first apheresis. The mean daily dose of G-CSF was 9.1 µg/kg for lenograstim, 9.8 µg/kg for biosimilar filgrastim, and 9.3 µg/kg for filgrastim (p < 0.001). The mean CD34+ cell number per microliter in the blood before the first apheresis was 111 for lenograstim, 119 for biosimilar filgrastim, and 124 for filgrastim (p = 0.354); the mean difference was even less significant when comparing CD34+ number per dose of G-CSF per kilogram (p = 0.787). Target doses of CD34+ cells were reached with one apheresis in 87% donors mobilized with lenograstim and in 93% donors mobilized with original and biosimilar filgrastim (p = 0.005). The mobilized apheresis outcomes (mean number of CD34+ cells/kg of donor collected during the first apheresis) was similar with lenograstim, biosimilar filgrastim, and filgrastim: 6.2 × 106, 7.6 × 106, and 7.3 × 106, respectively, p = 0.06. There was no mobilization failure in any of the donors. Biosimilar G-CSF is as effective in the mobilization of hematopoietic stem cells in unrelated donors as original G-CSFs. Small and clinically irrelevant differences seen in the study can be attributed to differences in G-CSF dose and collection-related factors. Active safety surveillance concurrent to clinical use and reporting to donor outcome registry (e.g., EBMT donor outcome registry or WMDA SEAR/SPEAR) might help to evaluate the possible short- and long-term complications of biosimilar G-CSF.

Successful Kidney Transplant from Donors with Sickle Cell Disease: A Case Series of Six Transplants.

People with sickle cell disease experience a high incidence of chronic kidney disease and end-stage kidney disease, secondary to tubular and glomerular effects of vaso-occlusion-induced hypoxia. Because of concerns of suboptimal kidney function, sickle cell donors are usually not considered for kidney donation, even if the rest of the parameters are acceptable for organ donation. A significant gap exists between the number of organ donors and the number of candidates waiting for a kidney transplant in the United States. To bridge the gap, we need to consider using nontraditional donors. We report kidney transplant outcomes in 6 recipients from 4 sickle cell kidney donors. Intracranial hemorrhage and sepsis were the causes of the death in donors, and no donor was in sickle cell crisis at the time of donation. None of the recipients experienced delayed graft function, and all recipients achieved excellent allograft function. The earliest allograft failure was at 27 months in a recipient who developed early acute rejection, while the longest follow-up was 10 years with adequate kidney function. In conclusion, given the shortage of kidneys for transplantation and demonstrated good outcomes, we propose that kidneys from sickle cell donors can be safely used.

Development and characterization of a cell donor registry for virus-specific T cell manufacture in a blood bank.

Adoptive cell therapy using virus-specific T cells (VST) is a strategy for treating common opportunistic viral infections after transplantation, particularly when these infections do not resolve through antiviral drug therapy. The availability of third-party healthy donors allows for the immediate use of cells for allogeneic therapy in cases where patients lack an appropriate donor. Here, we present the creation of a cell donor registry of human leukocyte antigen (HLA)-typed blood donors, REDOCEL, a strategic initiative to ensure the availability of compatible cells for donation when needed. Currently, the registry consists of 597 healthy donors with a median age of 29 years, 54% of whom are women. The most represented blood groups were A positive and O positive, with 36.52% and 34.51%, respectively. Also, donors were screened for cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Almost 65% of donors were CMV-seropositive, while less than 5% were EBV-seronegative. Of the CMV-seropositive donors, 98% were also EBV-seropositive. High-resolution HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies were determined in the registry. Prevalent HLA alleles and haplotypes were well represented to ensure donor-recipient HLA-matching, including alleles reported to present viral immunodominant epitopes. Since the functional establishment of REDOCEL, in May 2019, 87 effective donations have been collected, and the effective availability of donors with the first call has been greater than 75%. Thus, almost 89% of patients receiving an effective donation had available at least 5/10 HLA-matched cell donors (HLA-A, -B, -C, -DRB1, and -DQB1). To summarize, based on our experience, a cell donor registry from previously HLA-typed blood donors is a useful tool for facilitating access to VST therapy.

Prospective donors' perspectives on hematopoietic cell donation for cell and gene therapy research and development.

Aim: To explore prospective donors' attitudes and perceptions toward donating hematopoietic stem cells (HSCs) for novel treatments research and development (R&D). Methods: A survey was launched by Anthony Nolan (AN) to assess prospective donors' willingness to donate HSCs for novel therapies R&D, and their degree of comfort with the AN collaborating with and receiving payment from external organizations. Results: Most participants (87%) were willing to donate for novel treatment R&D and were comfortable with AN collaborating with external organizations and receiving payment (91% and 80%, respectively). Conclusion: Results reveal an overall positive response toward donating HSCs for R&D. These findings can support stakeholders and policymakers in outlining donation practices that uphold donors' safety and welfare.

Recent interest in the development of cell-based novel treatments using stem cells from healthy donors as opposed to patients' own stem cells may place pressure on stem cell donor registries to adapt and provide donor stem cells to the cell and gene industry. Since stem cell donor registries were originally established to connect patients in need of stem cell transplantation with matched willing stem cell donors, this shift in practice might result in several implications. Therefore, Anthony Nolan (AN), an unrelated stem cell donor registry in the UK, launched a survey to explore the willingness of potential donors to donate stem cells for novel treatment research and development (R&D). The results show that most participants (87%) would be willing to donate stem cells for novel treatment research and development. Most participants were comfortable with AN collaborating with external organizations (91%) and receiving payment from these organizations (80%). Additionally, some participants provided written responses that explained their answers to the questions in the survey. While some participants had positive views on collaborations with external establishments, others had apprehensions over their donations leading to profiteering. Moreover, participants had concerns over their privacy, especially if external collaborations with pharmaceutical companies were to take place. Informed consent and transparency over the nature of collaborations could relieve some of the above-mentioned concerns. These findings can support stakeholders and policymakers in outlining donation practices that uphold donors' safety and welfare.

Virus-Specific T Cells From Cryopreserved Blood During an Emergent Virus Outbreak for a Potential Off-the-Shelf Therapy.

During the first outbreak of an emergent virus, methods need to be developed to rapidly establish suitable therapies for patients with high risk of severe disease caused by the pathogen. Considering the importance of the T-cell response in controlling viral infections, adoptive cell therapy with virus-specific T cells has been used as a safe and effective antiviral prophylaxis and treatment for immunocompromised patients. The main objective of this study was to establish an effective and safe method to cryostore whole blood as starting material and to adapt a T-cell activation and expansion protocol to generate an off-the-shelf antiviral therapeutic option. Additionally, we studied how memory T-cell phenotype, clonality based on T-cell receptor, and antigen specificity could condition characteristics of the final expanded T-cell product. Twenty-nine healthy blood donors were selected from a database of convalescent plasma donors with a confirmed history of SARS-CoV-2 infection. Blood was processed using a fully automated, clinical-grade, and 2-step closed system. Eight cryopreserved bags were advanced to the second phase of the protocol to obtain purified mononucleated cells. We adapted the T-cell activation and expansion protocol, without specialized antigen-presenting cells or presenting molecular structures, in a G-Rex culture system with IL-2, IL-7, and IL-15 cytokine stimulation. The adapted protocol successfully activated and expanded virus-specific T cells to generate a T-cell therapeutic product. We observed no major impact of post-symptom onset time of donation on the initial memory T-cell phenotype or clonotypes resulting in minor differences in the final expanded T-cell product. We showed that antigen competition in the expansion of T-cell clones affected the T-cell clonality based on the T-cell receptor ß repertoire. We demonstrated that good manufacturing practice of blood preprocessing and cryopreserving is a successful procedure to obtain an initial cell source able to activate and expand without a specialized antigen-presenting agent. Our 2-step blood processing allowed recruitment of the cell donors independently of the expansion cell protocol timing, facilitating donor, staff, and facility needs. Moreover, the resulting virus-specific T cells could be also banked for further use, notably maintaining viability and antigen specificity after cryopreservation.

Health-related quality of life in peripheral blood stem cell donors and bone marrow donors: a prospective study in Japan.

Understanding of the impact of stem cell donation on donors' health-related quality of life (HRQOL) remains limited. A prospective observational study of eligible unrelated donors enrolled in the Japan Marrow Donor Program was conducted to compare HRQOL and adverse events (AEs) between peripheral blood stem cell (PBSC) and bone marrow (BM) donors. In total, 107 PBSC donors and 108 BM donors were enrolled. HRQOL scores for physical status were significantly lower in BM donors 1 week post-harvest (P < 0.001), but there were no significant differences between the two groups at baseline or 3 months post-harvest. PBSC donors were more likely to experience AEs before harvest (P < 0.001). However, at harvest, moderate-to-severe AEs were more common in BM donors (P = 0.001). After harvest, all grades of AEs were significantly higher in BM donors (P < 0.001). Among BM donors, a lower total physical score at baseline [odds ratio (OR) 1.21], female sex [OR 2.71], and young donors (OR 3.08) were risk factors for moderate-to-severe AEs at harvest, while among PBSC donors, only female sex (OR 4.86) was a risk factor. Our findings show better HRQOL during PBSC donation. These data help support decision-making by potential donors.

A dispermic chimerism detected in a Taiwanese potential unrelated hematopoietic stem cell donor.

Chimerism is defined as the presence of 2 or more than 1 genetically distinct cell populations in an organism. Dispermic chimeras are derived from the fertilization of 1 or 2 matured nuclei by 2 sperms. We here report detection of a healthy and phenotypically normal female with normal ABO red blood cell typing in whom dispermic chimerism was suspected after 3 alleles were identified at multiple human leukocyte antigen (HLA) loci using molecular HLA analysis. Molecular HLA typing showed the donor to have 3 HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles in blood, saliva and nail samples. In addition, 3 of her 9 short tandem repeat loci also showed to have 3 distinct alleles in blood, nail and saliva specimens. In all investigations, the third alleles were attributed to a dual paternal contribution. This case represents a dispermic chimerism, with 2 paternal and 1 maternal haplotypes variably distributed throughout body tissues in a healthy and phenotypically normal female without abnormalities in erythrocyte ABO blood group. The origin of this chimerism is probably due to the fertilization of a single egg and its polar body, or a parthenogenetic egg, by 2 sperms.

HLA-A*33:03:31, a novel variant of HLA-A*33:03, discovered in a Taiwanese individual.

One nucleotide substitution of HLA-A*33:03:01 results in a novel allele, HLA-A*33:03:31.