Meeting the Demand for Unrelated Donors in the Midst of the COVID-19 Pandemic: Rapid Adaptations by the National Marrow Donor Program and Its Network Partners Ensured a Safe Supply of Donor Products.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on hematopoietic cell transplant (HCT) donor registries and transplant center (TC) practices is underreported. This article reports on the National Marrow Donor Program (NMDP) Be The Match Registry and its coordinating the provision of unrelated donor (URD) products to domestic and international TCs during the initial 3 months of the COVID-19 pandemic (March through May 2020). Specifically, NMDP data are presented for disease indications for transplant, URD search volumes and availability, graft requests and processing, courier utilization and performance, and conversion rates from formal donor search and workup to graft collection and shipment. Data following the onset of COVID-19 are compared to the immediate 3 months prior to the COVID-19 pandemic (December 2019 through February 2020) and the same quarter 1 year prior to COVID-19 (March through May 2019). During the initial onset of COVID-19 and compared to 1 year prior, TCs requested and the NMDP performed less donor searches. More multiple URD and direct to workup requests were processed by the NMDP, which likely reflected reductions in donor availability. Yet TCs continued to perform allogeneic transplants for acute disease indications like acute leukemia and myelodysplasia, using more cryopreserved grafts than before COVID-19. In comparison to prepandemic patient cycle conversion rates and durations, the NMDP was able to convert patient cycles at nearly the same or higher rates and in similar or shorter periods of time. Last, despite significant challenges caused by the pandemic, including interruptions in domestic courier services and travel restrictions, graft products were delivered to and received by TCs in similar periods of time than before COVID-19. Taken together, these data show that NMDP service line operations continued to function effectively during the early phases of the COVID-19 pandemic, ensuring requests for and delivery of URD products to domestic and international allogeneic HCT recipients.

Multimedia resources to support the recruitment of committed hematopoietic stem cell donors: Perspectives of the most-needed donors.

BACKGROUND: Recruitment of committed unrelated hematopoietic stem cell donors from the most-needed demographics remains a challenge for donor recruitment organizations worldwide. Multimedia resources are gaining attention as a modality to support recruitment efforts; however, there is a lack of guidance for the development of such tools. This qualitative study explores the perspectives of eligible stem cell donors on an educational whiteboard video about stem cell donation, generating insights into how whiteboard videos and related multimedia may be optimized for donor recruitment. STUDY DESIGN AND METHODS: Eight semistructured focus groups were conducted with 38 potential donors from the most-needed demographics (young, male, and non-Caucasian) after they had watched a 3.5-minute whiteboard video explaining key concepts in stem cell donation (https://youtu.be/V4fVBtxnWfM). Constructivist grounded theory was used to identify themes and to develop a framework for understanding participants' preferred features of recruitment multimedia. RESULTS: Participants identified a range of features contributing to the effectiveness of recruitment multimedia, adding that the whiteboard video is an effective, integrated, and readily accessible format for supporting donor recruitment. Topics that participants felt are important to address include knowledge gaps regarding donation procedures, concerns about donor safety, and the particular need for specific donor demographics. Suggested avenues for improvement include the addition of donor/recipient/patient personal experiences, attention-grabbing hooks, and a call to action including opportunities for further learning. CONCLUSIONS: Several considerations were generated to inform the development of future multimedia for donor education/recruitment and are relevant to donor recruitment organizations worldwide.

Graft Cryopreservation Does Not Impact Overall Survival after Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.

Living-unrelated kidney donor transplantation: Legalization in exceptional circumstances?

The prevalence of end-stage renal disease (ESRD) morbidity and mortality is mounting. Kidney transplantation offers a good means of survival and improves longevity of patients with ESRD. However, not everyone is fortunate to benefit from this lifesaving renal replacement therapy due to the lack of available kidneys, one of the many reasons. It eventually expands the number of patients on waiting list of kidney transplantation. At present, deceased and living-related kidney donor transplantation models are widely used, but with limited success to keep up with the pace of burgeoning ESRD. A debate over the legalization of unrelated living kidney donor transplantation has erupted lately. This short review articles focuses on issues surrounding kidney transplantation in Pakistan and draws an informed conclusion regarding pragmatic legalization of unrelated living kidney donor transplantation in exceptional circumstances. Finally, this article also offers a food for thought for countries facing analogous picture in the field of kidney transplantation.

The experiences of parents and caregiver(s) whose child received an organ from a living anonymous liver donor.

BACKGROUND: Anonymous living donor transplantation is a potential strategy to address the shortage of available organs for transplant. A living anonymous donor (LAD) is a donor with no biological connection and whose identity is unknown to the recipient. This study captured the lived experiences of pediatric liver transplant recipient families whose child received an organ from a LAD. METHODS: Qualitative data collection and analysis were guided by a theoretical framework of phenomenology. Data analysis highlighted themes through an inductive process of reviewing transcript paragraphs to code for significant statements that represented key concepts and captured depth of experience. RESULTS: A total of nine interviews were conducted with 10 participants. Data analysis yielded themes of emotional turbulence through their transplant journey. Pre-transplant experiences were characterized by feelings of helplessness and desperation. Receiving a LAD transplant prompted shock, relief, and acceptance of the donation. Post-transplant experiences were characterized by altered life-perspectives and varied levels of connectedness to the donor, marked by gratitude and concern for donor well-being. CONCLUSION: Anonymous donation in liver transplantation is perceived by recipient families as a remarkable gift and a viable donor option. Our preliminary findings can be used to inform strategy development regarding future delivery of care.

Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR.

Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.

Living Unrelated Kidney Transplantation: Does It Prevent Deceased-Donor Kidney Transplantation Growth?

OBJECTIVES: It is usually assumed that an active livingdonor transplant program inhibits the growth of a deceased-donor kidney transplant program. In our 33-year experience, we found the contrary to be true. MATERIALS AND METHODS: From 1984 until 2017, we performed a total of 4966 kidney transplant procedures. All cases were registered through the Collaborating Transplant Study (Heidelberg, Germany). RESULTS: During the first 16 years, only living-donor kidney transplant procedures were done. Our first unrelated living-donor kidney transplant procedure was in 1986 and involved a wife to husband donation. This breakthrough in our country was the first in our unrelated living-donor kidney transplant program. In 2000, the Iranian Parliament passed the deceased-donor transplant act, and we have started deceased-donor kidney transplants since then. Despite a jam-packed living-donor kidney transplant program, our deceased-donor kidney transplant program has grown steadily since then and now comprises more than 50% of our kidney transplant procedures. When we compared the outcome of these programs, the 5-year survival from Collaborating Transplant Study report of 3527 cases of 114 living-related donor procedures was 90%. The 5-year survival rates for living unrelated-donor (n = 2689) and deceased-donor (n = 724) transplant procedures were 88% and 83%, respectively (P = .001). CONCLUSIONS: Our data showed that deceased-donor kidney transplant procedures have steadily increased despite an active unrelated living-donor kidney transplant program. Wait lists for kidney transplant can be significantly reduced by following our model, both in developed and in developing countries.

Availability of HLA-allele-matched unrelated donors: estimation from haplotype frequency in the Japanese population.

A human leukocyte antigen (HLA)-matched unrelated donor is the primary alternative donor for allogeneic hematopoietic cell transplantation in Japan. In considering an optimal donor registry size, the availability of HLA-matched donors is important. In this study, the probability of finding an HLA-A, -B, -C, and -DRB1 allele-matched donor was estimated using two different methods based on the haplotype frequencies in the Japanese population: an actual measurement method (AMM) and a formula method (FM). According to AMM, the probabilities of finding an HLA-matched donor were 40.5% in 100,000 donors, 54.4% in 300,000, 60.0% in 500,000, and 63.4% in 700,000. On the other hand, according to FM, the probabilities were 47.8% in 100,000 donors, 59.9% in 300,000, 65.3% in 500,000, and 68.8% in 700,000. The probabilities increased by 8.6 or 7.7%, 3.2 or 3.1%, 2.1 or 1.9%, and 1.6 or 1.3% in AMM or FM, respectively, as the registry size increased by 100,000. The rate of increase in the probability of finding an HLA-matched donor will become smaller as the registry size increases due to the diversity of haplotypes. Therefore, it is important to set a target donor registry size for efficient donor recruitment by considering the haplotype frequencies in the population.

Is a matched unrelated donor search needed for all allogeneic transplant candidates?

Donor availability for allogeneic transplantation remains an important factor in determining outcomes of a successful transplant. We examined outcomes of 242 patients treated over 3 years who had a matched unrelated donor (MUD) search at our institution. One hundred sixty patients (66%) had a 10 of 10 MUD identified, and 85 (53%) proceeded to MUD transplantation. White patients and those with common haplotypes were more likely to have a MUD identified (odds ratio [OR], 7.4 [P < .0001]; OR, 41.6 [P < .0001]), and were more likely to proceed to transplantation with a MUD (OR, 11.2 [P < .0001]; OR, 85.1 [P = .002]). In addition, patients who were newly diagnosed/in remission at the time of MUD search had a higher probability of receiving a transplant (OR, 2.01 [P = .013]) and better progression-free survival (PFS; P < .0001). In multivariate analysis for patients who received a transplant, donor type did not influence PFS at 3 years, which was 40% for MUD and 57% for haploidentical transplants, respectively (hazard ratio, 1.2 [P = .50]). In conclusion, race, haplotype frequency, and disease status at the time of MUD search influence the probability of identifying a MUD and receiving a transplant. Patients with a low likelihood of receiving a MUD transplant may proceed to a haploidentical transplant as soon as indicated, as this approach does not appear to compromise transplant outcomes.

Validation of an Algorithm to Predict the Likelihood of an 8/8 HLA-Matched Unrelated Donor at Search Initiation.

A strategy to rapidly determine if a matched unrelated donor (URD) can be secured for allograft recipients is needed. We sought to validate the accuracy of (1) HapLogic match predictions and (2) a resultant novel Search Prognosis (SP) patient categorization that could predict 8/8 HLA-matched URD(s) likelihood at search initiation. Patient prognosis categories at search initiation were correlated with URD confirmatory typing results. HapLogic-based SP categorizations accurately predicted the likelihood of an 8/8 HLA-match in 830 patients (1530 donors tested). Sixty percent of patients had 8/8 URD(s) identified. Patient SP categories (217 very good, 104 good, 178 fair, 33 poor, 153 very poor, 145 futile) were associated with a marked progressive decrease in 8/8 URD identification and transplantation. Very good to good categories were highly predictive of identifying and receiving an 8/8 URD regardless of ancestry. Europeans in fair/poor categories were more likely to identify and receive an 8/8 URD compared with non-Europeans. In all ancestries very poor and futile categories predicted no 8/8 URDs. HapLogic permits URD search results to be predicted once patient HLA typing and ancestry is obtained, dramatically improving search efficiency. Poor, very poor, andfutile searches can be immediately recognized, thereby facilitating prompt pursuit of alternative donors.

The Stem Cell Club: a model for unrelated stem cell donor recruitment.

BACKGROUND: Patients with blood, immune, or metabolic diseases may require a stem cell transplant as part of their treatment. However, 70% of patients do not have a suitable human leukocyte antigen match in their family, and need an unrelated donor. Individuals can register as potential donors at stem cell drives, where they provide consent and a tissue sample for human leukocyte antigen typing. The ideal donors are young, male, and from a diversity of ethnic backgrounds. However, in Canada, non-Caucasian males ages 17 to 35 years represent only 8.8% of listed donors. STUDY DESIGN AND METHODS: The Stem Cell Club is a non-profit organization founded in 2011 in Canada that aims to augment recruitment of the most needed donors. The initiative published a recruitment toolkit online (www.stemcellclub.ca). Currently, there are 12 chapters at universities across Canada. RESULTS: To date, the Stem Cell Club has recruited 6585 potential registrants, representing 1.63% of donors on Canada's donor-database. Of the recruited registrants, 58.3% were male; 60.3% of males self-reported as non-Caucasian, and 78.5% were ages 17 to 25 years. From 2015 to 2016, the initiative recruited 13.7% of all ethnically diverse males ages 17 to 35 years listed in Canada's donor database. Data from this initiative demonstrate sustainability and performance on key indicators of stem cell drive quality. CONCLUSION: The Stem Cell Club has developed a capacity to recruit 2600 donors annually, with the majority being males with a high degree of ethnic diversity. The initiative enhances the quality of Canada's unrelated donor-database, improving the chances that patients in need of an unrelated donor will find a match for transplant. The Stem Cell Club is a model relevant to recruitment organizations around the world.

Prospective Evaluation of Unrelated Donor Cord Blood and Haploidentical Donor Access Reveals Graft Availability Varies by Patient Ancestry: Practical Implications for Donor Selection.

The availability of cord blood (CB) and haploidentical (haplo) donors in all patient populations is not established. We have investigated the addition of haplo-CD34+ cells to CB grafts (haplo-CBT) to speed myeloid engraftment. Thus, we have prospectively assessed CB and haplo donor availability in adult patients without 8/8 HLA-allele matched unrelated donors (URDs). Analysis of 89 patients eligible for haplo-CBT revealed 4 distinct patient groups. First, 6 patients (7% of total, 33% non-European) underwent CBT only as they had no suitable family members to type. In group 2, 49 patients (45% non-European) received haplo-CBT using the first haplo donor chosen. Group 3 (n = 21, 76% non-European) underwent CBT with/without haplo. In this group, the first haplo donor chosen failed clearance in 20 patients and transplantation was too urgent to permit donor evaluation in 1. Fifty-three haplo donors were evaluated (2 to 6 per patient) for 21 group 3 patients, and 43 of 53 (81%) haplos failed clearance for predominantly medical and/or psychosocial reasons. Group 4, (n = 13, 85% non-European with a high median weight of 96 kilograms) had no CB grafts with/without no haplo donors. Overall, African patients had the worst donor availability with only 65% having a suitable CB graft and only 44% having a suitable haplo donor. Additionally, in non-European patients, a greater number of haplos required evaluation/patient to secure a suitable haplo graft. Although these data should be confirmed in a larger study, it suggests that there are barriers to the availability of both CB and haplo grafts in adult patients without 8/8 URDs, especially in those with African ancestry, and has multiple practical implications for patient management.

Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants.

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.

In celebration of Ruggero Ceppellini: HLA in transplantation.

The availability of hematopoietic cell transplantation as curative therapy for blood disorders has been dramatically improved through a better understanding of the human leukocyte antigen (HLA) barrier. Although a fully compatible unrelated donor is preferable, transplantation from donors with a limited degree of HLA mismatching is associated with acceptable outcomes in many cases. Research on the limits of HLA mismatching, and the features that define permissible HLA mismatches will continue to enable transplantation to be more broadly available to patients in need.

Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely.

BACKGROUND: Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry®. We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. MATERIALS AND METHODS: New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A˜C˜B˜DRB1˜DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. RESULTS: The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non-White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. CONCLUSION: Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process.

Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy.

Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.

Identification of DPB1 Permissive Unrelated Donors Is Highly Likely.

HLA-DPB1 permissive matching based on T cell epitope (TCE) groups should be considered when selecting among equally matched HLA-A, -B, -C, -DRB1 unrelated hematopoietic stem cell donors to improve patient survival. Previous studies have defined 3 TCE groups based on functional assays of alloreactivity. Combinations of donor and recipient DPB1 alleles with low immunogenic potential identify permissive donors, who provide no increased risk of mortality compared with DPB1-matched donors. To determine the likelihood of identifying a DPB1 permissive-matched (includes both allele-matched and DPB1-permissive mismatched) unrelated donor for patients with high-resolution matches at 10/10 HLA-A, -B,- C, -DRB1, and -DQB1 in the Be The Match Registry, preliminary search requests from United States' transplant centers for 595 DPB1-typed patients were evaluated for existence of a DPB1 permissive-matched donor, identified either among already typed donors or by prospective DPB1 typing. The baseline DPB1 permissive match rate was 69% and improved to 80% after additional donor DPB1 typing (median, 4 donors per patient). When seeking a 10/10-matched, young (18- to 32-year-old) donor in the registry, the probability of finding a DPB1 permissive-matched donor started lower at 59% and improved to 70% after additional DPB1 testing. Our results show that most patients with a 10/10 match can find a DPB1 permissive-matched donor.