Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

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.

Favorable recovery profiles and good reliability among youngest unrelated stem cell donors supports lowering the minimum donor registration age.

INTRODUCTION: Younger donor age in hematopoietic cell transplantation has been associated with improved overall and disease-free survival. Safety data on peripheral blood stem cell (PBSC) and bone marrow (BM) donation is well established, including in the <18-year old age group in the related setting. In response, Anthony Nolan became the first stem cell donor registry to lower the minimum age for unrelated donors to 16-years. MATERIALS AND METHODS: This retrospective study reviewed unrelated donors donating PBSC or BM for the first time between April 2015 and October 2017 since adoption of the lowered recruitment age. Data were collected from registry electronic database and structured follow-up questionnaires. Primary outcomes were turnaround time from VT to donation, optimal cell yield achievement, and physical and emotional recovery. RESULTS: Out of a total of 1013 donors, there were no differences between the different age groups in proportion of donors achieving optimal CD34+ or TNC (PBSC and BM, respectively). There was no increased central line requirement for younger donors or increased emergency telephone support. Youngest donors were more likely to report physical recovery 2 and 7 days post-PBSC (P = .024 and P = .015, respectively) as well as an earlier emotional recovery (P = .001) and fewer physical symptoms 1 week BM donation (P = .04). CONCLUSION: This study shows that younger donors are as reliable as older donors, and have favorable recovery profiles without need for increased support at any stage of the donation, supporting Anthony Nolan recruitment strategy and offering reassurance to donor registries considering the same.

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.

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.

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.

Outcomes After Donor Lymphocyte Infusion in Patients With Hematological Malignancies: Donor Characteristics Matter.

In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) or relapsed disease after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications after DLI. Indications for DLI were T-cell MC in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-full donor chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% versus 52.9%, P = .004) and cytomegalovirus negative (76.5% versus 52%, P = .004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% versus 53.5%, P = .013) and those attaining unfractionated whole blood (UWB) FDC after DLI (76.6% versus 28.6%, P < .001) had a survival benefit and subsequently a better graft-versus-host disease (GvHD)-free/relapse-free survival. Nineteen of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favorably in disease control (76.7% versus 12.5%, P = .012) and improved survival (45.5% versus 12.5%, P = .007). In the whole population, the cumulative incidence of acute GvHD (aGvHD) at day 100 after DLI was 23%, and chronic GvHD (cGvHD) at 1 year after DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, because patients with younger donors had a lower incidence of aGvHD (8% versus 36%, P = .021). The cGvHD was more likely to occur in patients who converted to T-FDC (34% versus 10.3%, P = .025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with less associated toxicity. Selection of younger male donors from stem cell registries can minimize the risk of GvHD and improve survival.

Serologic Responses following a Single Dose of SARS-Cov-2 Vaccination in Allogeneic Stem Cell Transplantation Recipients.

Immunocompromised individuals were not included in formal trials of SARS-CoV-2 mRNA vaccines. Subsequent studies in patients with hematologic malignancies and solid organ transplantation recipients suggest inferior responses to vaccination. We determined antibody responses to a single dose of vaccines in one of the most vulnerable patient groups, allogeneic hematopoietic cell transplantation (allo-HCT) recipients. Pfizer-BioNTech (PB) or AstraZeneca (AZ) SARS-CoV-2 vaccines were administered at least 3 months post-transplantation to 55 adult allo-HCT recipients. We found that older age and concurrent use of immunosuppressive medications were significantly associated with lack of antibody response to vaccination. Only 21% of patients on systemic immunosuppression mounted a response, compared with 58% of patients not on immunosuppression (P = .006). We also show that responses to the AZ vaccine may be superior to responses to the PB vaccine in this cohort. These findings highlight the need for novel immunogenic vaccine formulations and schedules in these highest-risk patients, as well as continued public healthy safety measures to protect the most vulnerable members of our society.

Determining the incidence of interstitial pneumonitis and chronic kidney disease following full intensity haemopoetic stem cell transplant conditioned using a forward-planned intensity modulated total body irradiation technique.

PURPOSE/OBJECTIVE: Total body irradiation (TBI) remains a key component of conditioning for allogeneic haemopoietic stem cell transplant (HSCT), with interstitial pneumonitis (IP) and chronic kidney disease (CKD) important late sequelae. We undertook a retrospective service evaluation of TBI patients treated with a forward-planned intensity modulated radiotherapy technique (FP IMRT). MATERIAL/METHODS: 74 adult patients were identified; all received step and shoot FP IMRT TBI, 14.4 Gy in 8 fractions over 4 days. Mean doses to the lungs and kidneys were 12-12.5 Gy. Toxicities were defined as per CTCAE v4.0: IP as multilobar infiltrates on CT with symptoms of dyspnoea, and renal dysfunction as an Estimated Glomerular Filtration rate (eGFR) < 60 ml/min/1.73 m2 for > 3 months. Secondary endpoints were overall survival (OS), progression free survival (PFS), cumulative incidence of non-relapse mortality (NRM), relapse risk and of acute and chronic GvHD. RESULTS: Patients received treatment for the following diagnosis: ALL/LBL (n = 37); AML (n = 33), CML-BC (n = 2) and High grade NHL (n = 2). The rate of IP due to any cause was 30%; positive microbiological evidence in 73% (16 /22). Idiopathic IP was seen in 8%, with only 4% (n = 3) having IP Grade ≥ 3. Two (4%) of 52 long term survivors developed CKD, one with thrombotic microangiopathy. 4 year NRM was 16% (CI 11-32%); no treatment related deaths in matched sibling or umbilical cord blood HSCT. CONCLUSION: FP IMRT TBI, reducing dose to the lungs and kidneys, has lower rates of idiopathic IP and CKD compared to the literature. This technique is safe and effective conditioning for full intensity HSCT.

Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function.

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover.

Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation.

Vitamin D was discovered 100 years ago and since then multiple studies have consistently proved its effect on bone health and mineral metabolism. Further research has also explored its so-called "non-classical" biological effects, encompassing immune regulation and control of cell proliferation and differentiation. Vitamin D downregulates pro-inflammatory immune cells and subsequently their cytokine production, while enhancing the anti-inflammatory subsets, thus mediating inflammation and fostering a more tolerogenic environment. Its biological action is exerted through the vitamin D receptor, a nuclear receptor that mediates gene transcription and is expressed in most cells from the innate and adaptive immunity. Owing to its immune-modulatory properties, its role in cancer pathophysiology, hematology disorders and stem cell transplantation has also been investigated. Vitamin D deficiency causes immune imbalance and cytokine dysregulation, contributing to some autoimmune diseases. In the hematopoietic stem cell transplant setting this could lead to complications such as acute and chronic graft-versus-host disease, ultimately impacting transplant outcomes. Other factors have also been linked to this, including specific polymorphisms of the vitamin D receptor in both stem cell donors and recipients. Nevertheless, studies thus far have shown conflicting results and the use of vitamin D or its receptor as biomarkers has not been validated yet, therefore there are no evidence-based consensus guidelines to guide clinicians in their day-to-day practice. To gain more insight in this topic, we have reviewed the existent literature and gathered the current evidence. This is an overview of the role of serum vitamin D and its receptor as biomarkers for clinical outcomes in patients undergoing hematopoietic stem cell transplantation. Further prospective studies with larger cohorts are warranted to validate the viability of using serum vitamin D, and its receptor, as biomarkers in potential stem cell donors and patients, to identify those at risk of post-transplant complications and enable early therapeutic interventions.

Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML.

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

Role of Race/Ethnicity in Donor Decisions about Unrelated Hematopoietic Progenitor Cell Donation: Exploring Reasons for Higher Attrition among Racial/Ethnic Minorities.

There are more than 30 million potential unrelated hematopoietic progenitor cell (HPC) donors listed on international registries, but 30% to 50% are unavailable after matching a patient. In the United States racial/ethnic minorities opt out of donation at higher rates, and a previous study identified factors associated both with attrition and ethnic group membership. Attrition among minorities is also higher in the Anthony Nolan UK registry (35% in white British [WB] and 56% in nonwhite British [NWB]), but it is not clear what factors produce higher attrition in the United Kingdom and whether they are similar to those found in the United States. Three hundred fifty-seven UK potential donors who matched a patient completed a questionnaire. Key factors were compared by donation decision (continue or opt out) and by race/ethnicity (WB versus NWB). The pattern of UK results was compared with that of the previous US study for variables assessed in both studies. Across WB and NWB donors, higher attrition was associated with poorer physical/mental health, greater ambivalence, and more concerns about donation. Donors who opted out also reported less interaction with the registry, and 16% indicated that more interaction with the registry would have changed their decision. Those opting out of the registry and minorities were both more likely to report religious objections to donation and to mistrust the fairness of HPC allocation. The pattern of findings was similar in UK and US samples. Registries should maintain contact with potential donors after recruitment, aiming to educate members about the donation procedure and to address potential misconceptions associated with religious beliefs and HPC allocation.

Transplant center practices for psychosocial assessment and management of pediatric hematopoietic stem cell donors.

Understanding the potential emotional and psychological risks of pediatric sibling HSC donation is an area of research that remains in its infancy. A cross-sectional survey was distributed electronically to directors at all CIBMTR and EBMT centers to describe current transplant center practices for obtaining assent, preparation for the physical/emotional experiences of donation, and monitoring the post-donation well-being of pediatric donors (<18 years of age). Respondents were 45/91 (49%) and 66/144 (46%) of CIBMTR and EBMT centers, respectively. Although 78% of centers reported having a mechanism in place to ensure donor free assent, centers also reported only limited assessment of psychosocial suitability to manage the emotional risks of donation. More than half of centers reported no psychosocial follow-up assessment post-donation. Few centers have policies in place to address donor psychological needs. Future investigations should include medical and psychosocial outcomes following full integration of comprehensive psychosocial screening and surveillance of pediatric donors.