PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Young adults from underserved racial/ethnic groups are critically needed as unrelated hematopoietic stem cell (HSC) donors, yet they are more likely than other groups to opt out of donation after having matched a patient. Understanding which factors are most strongly associated with opting out among young underserved racial/ ethnic registered donors compared with their White counterparts will provide the basis for specific interventions to improve donor retention. We sought to determine the key, modifiable psychosocial, registry-related, and donation-related characteristics that are uniquely associated with opting out across 5 key racial/ethnic groups of young HSC donor registry members who had been contacted as a potential match for a patient. This study examines data from a large cross-sectional survey of young (age 18 to 30) registry members shortly after they preliminarily matched a patient (CT-stage) and continued toward or opted out of donation (CT-C and CT-NI), stratified by racial/ethnic group and sex. We assessed psychosocial, registry-related, and donation-related characteristics for all participants. We used chi-squared and F tests to assess differences between racial/ethnic groups. A separate logistic regression analysis for each racial/ethnic group was conducted to quantify adjusted associations between each variable and opting out. Then, we compared these associations across the racial/ethnic groups by evaluating the interaction effect between each variable and racial/ethnic group, with the same outcome (CT-C versus CT-NI) in question. Nine hundred thirty-five participants were surveyed, including 284 White, 165 Hispanic, 191 Black, 192 Asian/Pacific Islander, and 103 Multiracial/multiethnic participants. There were significant differences across racial/ethnic groups in values/goals, religious objections to donation, HSC-related medical mistrust, and parental involvement in donation decisions. Adjusted logistic regression subgroup analyses indicated that ambivalence was strongly associated with opting out across all racial/ethnic groups. Greater focus on intrinsic life goals (e.g., raising a family, becoming a community leader, influencing social values) was associated with opting out in the Multiracial/multiethnic, Hispanic, and Asian/Pacific Islander groups. Healthcare mistrust and insufficient registry contact was a significant factor for Hispanic participants. Protective factors against opting out included remembering joining the registry (Black participants), and parental support for donation decision (Asian/Pacific Islander participants). The performance of each logistic regression model was strong, with area-under-the curve ≥.88, CT-stage outcome classification accuracy ≥89%, and good fit between expected and observed opt-out probabilities. In the analysis across different racial/ethnic groups, the only significant interaction was race/ethnicity by whether more contact with the registry would have changed the decision at CT-stage; this variable was significant only for the Hispanic group. In the within-group analysis for Hispanic participants, the "more registry contact" variable was strongly associated with opting out (odds ratio 5.8, P = .03). Consistent with a growing body of HSC donor research, ambivalence was a key factor associated with opting-out for all racial/ethnic groups. Other key variables were differentially associated with opting-out depending on racial/ethnic group. Our study highlights key variables that registries should focus on as they develop targeted and tailored strategies to enhance commitment and reduce attrition of potential donors.

The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n = 40) or reducedintensity conditioning (RIC; n = 40), with the primary endpoint of 1-year overall survival (OS). The median follow- up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/ 8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy plat-form. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Attrition of young adult registry members is a significant issue impacting hematopoietic stem cell (HSC) donation registries, including the Be The Match registry in the US. The resulting limited supply of allogeneic HSCs, used to treat serious health conditions, has a stronger impact on racial/ethnic minority groups in the US. Compared with young white adults, young adults identifying with these minority groups are more likely to drop out of the donor registry when called to donate. However, the underlying psychosocial factors that differ between white and nonwhite registrants have not been fully investigated. The central goal of this study was to examine demographic, registry-related, and donation-related characteristics in a young, newly registered group of potential donors and to determine whether these characteristics differed by, or were distributed differently among, racial/ethnic groups. We conducted a cross-sectional survey in a random sample of young (age 18 to 30 years) newly registered members, stratified by racial/ethnic group and sex. Demographic, registry-related (eg, context and motive for joining the registry), and donation-related (eg, ambivalence, religious objections to donation, knowledge about donation) characteristics were assessed. The chi-square test and analysis of variance were used to examine differences among racial/ethnic groups. Discriminant function analysis was used to assess whether patterns of the 3 classes of characteristics were associated with membership in particular racial/ethnic groups. A total of 524 participants were surveyed. Joining online was most common among white individuals, whereas joining at college was most common among black and Hispanic individuals. Ambivalence toward donation was higher among Asian/Pacific Islanders compared with white or multiracial/multiethnic individuals. Discriminant function analysis revealed 4 psychosocial/attitudinal functions predicting membership in certain racial/ethnic groups. The function accounting for the most variance in responses included mistrust of HSC allocation, religious objections to donation, low parental support, and low knowledge level. This function discriminated significantly between the white and nonwhite groups. Another function also identified ambivalence as a discriminating factor, which was most strongly associated with Asian/Pacific Islanders. Among young adult members of an HSC donor registry, such factors as ambivalence, family concerns about donation, mistrust of HSC allocation, religious objections, and less knowledge about donation were more strongly associated with membership in the nonwhite groups compared with the white group. These factors are known to be associated with a higher risk of opting out after having been preliminarily matched with a patient. The finding that these characteristics are associated with racial/ethnic minority group membership provides targets for recruitment strategies aimed at improving retention of young registry members.

Young adults enrolled in hematopoietic stem cell (HSC) donation registries, including the Be The Match registry in the United States, often opt out of the registry when a potential recipient is identified. This results in a limited supply from the most desirable allogeneic source of HSCs used in transplantation to treat serious health conditions. The differences in demographic, psychosocial, registry-related, and donation-related characteristics between those who continue to donation and those who opt out may elucidate the modifiable risk factors for attrition, but these characteristics have not been extensively studied in young donors up to age 30 years. Our goal was to study demographic, psychosocial, registry-related, and donation-related characteristics in a group of young HSC donor registry members who had recently been contacted about a potential recipient, to determine the key characteristics that differ between those who continued toward donation and those who opted out and to examine the extent of these differences. We conducted a cross-sectional survey in a random sample of young (age 18 to 30 years) current and former registry members, stratified by race/ethnicity and sex. Demographic, psychosocial (eg, life goals, HSC allocation mistrust), registry-related (eg context and motive for joining the registry), and donation-related (eg, ambivalence, religious objections to donation, knowledge about donation) characteristics were assessed. Chi-square and 2-sample t tests were used to examine differences between those who continued (CT-C group) and those who opted out (CT-NI group). Hierarchical logistic regression was used to estimate adjusted covariate effects on the odds of opting out. A total of 935 participants were surveyed. Donation-related knowledge was higher in the CT-C group than in the CT-NI group. HSC allocation mistrust, religious objections, and concerns about donation were higher in the CT-NI group. After adjusting for covariates in a logistic regression model, we found that having more intrinsic life goals, having more ambivalence, and talking with registry staff only once/twice were significantly associated with opting out of the registry. Ambivalence had the strongest association with opting out. In contrast, remembering joining the registry, believing that parents would support donation, and having medical concerns were significantly associated with continuing toward donation. This effect of medical concerns on donation was discovered only after adjusting for the related but distinct ambivalence variable, with the remaining effect of medical concerns relating to engagement with the donation process and information-seeking. The model had strong discriminative ability (area under the receiver operating characteristic curve = .92) and classification accuracy (86.6%). Our data indicate that among young adult members of a national HSC donor registry, ambivalence and limited contact with registry staff were more strongly associated with opting out of donation. Medical concerns were associated with continuing toward donation. Further studies are needed to confirm a causal link between medical concerns and continuing to donation among young donors. Our study suggests that these concerns might not be directly related to attrition, whereas other factors (eg, ambivalence, low donation-related knowledge) are associated with attrition and thus should be targeted for attrition reduction strategies.

There is a lack of evidence about how health-related quality of life (HRQoL), including psychosocial factors, might affect donation-related experiences and clinical markers in the context of hematopoietic stem cell donation. The broader literature suggests that psychological factors, including anxiety and depression, are associated with higher levels of inflammatory burden leading to poorer postprocedural outcomes including longer hospital stays and increased pain perception. In this study, we aimed to evaluate whether predonation HRQoL markers predict toxicity profile and stem cell yield after peripheral blood stem cell (PBSC) donation in healthy donors. The study population comprised adult granulocyte colony-stimulating factor mobilized PBSC-related donors (RD) (n = 157) and unrelated donors (URD) (n = 179) enrolled in the related donor safety study (RDSafe) and Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 clinical trials. Pre-donation HRQoL was assessed using the Short-Form-12 (SF-12) in RDSafe and SF-8 questionnaire in BMT CTN 0201 (higher score is better). The aims of this study were to (a) determine the impact of pre-donation HRQoL on peri-collection pain and acute toxicities experienced and (b) to investigate the pre-procedural HRQoL indicators on stem cells yield. URDs were younger than RDs (median age 35 versus 63). A higher proportion of RDs were female (50% versus 40%) and obese (41% versus 35%). A higher proportion of RD PBSC donations required 2 days or more of apheresis (44% versus 21%). More RD collections were lower volume procedures (<18L, 16% versus 28%), and required a central line (28% versus 11%). RDs were more likely to report pre-donation grade 1-2 pain (27% versus 8%) and other toxicities (16% versus 6%). Among RDs, a lower pre-donation physical component summary (PCS) score was associated with significantly more grade 2-4 pain at 1 month (P = .004) and at 1-year after donation (P = .0099) in univariable analyses. In multivariable analysis, pre-donation PCS remained significantly associated with grade 2-4 pain 1 month after donation (P = .0098). More specifically, RDs with predonation PCS scores in the highest quartile were less likely to report pain compared with donors with PCS scores in the lowest quartile (odds ratio 0.1; 95% confidence interval 0.01-0.83; P = .005). There was also a trend toward higher grade 2-4 pain at 1-year post-donation among RDs with lower predonation PCS score (P = .018). Among URDs, neither PCS nor mental component summary (MCS) scores were associated with pain or toxicities at any time point after donation based on the univariable analysis. Because of low rates of postdonation grade 2-4 pain and toxicities, multivariable analysis was not performed in the URD setting. Moreover, there was no correlation between preapheresis HRQoL score (PCS or MCS) and PBSC collection yield in either the RD or URD setting. Our study demonstrates that pre-donation HRQoL scores are significantly associated with the toxicity profile after PBSC donation in the RD setting, with adult RDs with lower predonation physical HRQoL experiencing higher levels of pain at 1 month and persisting up to 12 months after a PBSC collection procedure. There were no such associations found in URD. Our findings can help clinicians identify donors at higher risk of pain with donation, and lead to personalized information and interventions for specific donors. Lack of correlation between predonation HRQoL and stem cell yield may be due to a small sample size and warrants further evaluation.

PURPOSE Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning–based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Pre-harvest autologous blood collection from bone marrow (BM) donors is performed to meet potential post-operative transfusion needs. This study examines the impact of autologous blood transfusion on BM donor's health and safety. The study included first-time unrelated BM donors from the United States whose BM harvest was facilitated by the National Marrow Donor Program (NMDP) centers between 2006 and 2017. Examination of 7024 BM donors revealed that 60% received at least one unit of autologous blood. The donors who received autologous blood were older, had lower hemoglobin pre-harvest, underwent longer duration of anesthesia, and higher volume BM harvest. Only donors who underwent high-volume BM harvest, defined as a BM harvest volume >27% of donor's blood volume, benefited from autologous transfusion. After a high-volume BM harvest, autologous blood transfusion was shown to decrease grade 2 to 4 collection-associated toxicities within 48 h of BM donation (p = 0.010) and shorten the time to donor-reported "complete" recovery from donation-associated symptoms (p < 0.001). Therefore, autologous transfusion could be avoided as support of marrow donation in the majority of unrelated BM donors and should be limited to cases where the planned BM harvest volume is expected to exceed 27% of donor's blood volume.

• Hesitancy centered on the risk of COVID-19 infection for self or family members. • For some, the pandemic increased the desire to help others by donating. • Remote school and work reduces some logistic hurdles. • Information about transmission containment is desired. • Impact on a recipient if a potential donor chooses not to donate is desired.

Approximately 7% of unrelated hematopoietic stem cell donors are asked to donate stem cells a subsequent time to the same or a different recipient. Recent studies have shown that donation-related symptoms for second donations are similar to those for the first donation. Little is known about differences in stem cell mobilization and yields for subsequent peripheral blood stem cell (PBSC) and bone marrow (BM) collections. We hypothesized that CD34(+) cell yields and total nucleated cell (TNC) concentrations for subsequent PBSC or BM donations are lower than those at the first donation. We also evaluated the factors influencing stem cell yields in healthy unrelated second-time donors. Data were gathered from the Center for International Blood and Marrow Transplant Research database on 513 PBSC and 43 BM donors who donated a second time between 2006 and 2017 through the National Marrow Donor Program. Among the second-time PBSC donors, we found significantly lower preapheresis peripheral blood CD34(+) cell counts (68.6 x 10(6)/L versus 73.9 x 10(6)/L; P = .03), and collection yields (556 x 10(6) versus 608 x 10(6); P = .02) at the second donation compared to the first. This decrease at the subsequent donation was associated with a shorter interdonation interval, lower body mass index (BMI), and a lower total G-CSF dose. In most instances, suboptimal mobilizers at their first donation donated suboptimal numbers of stem cells at their subsequent donations. Among repeat BM donors, the TNC concentration was lower at the second donation. The small size of this group precluded additional analysis. Overall, when considering repeat donations, increasing the interdonation intervals and evaluating for BMI changes should be considered to optimize stem cell yields. Some of these parameters may be improved by increasing G-CSF dose in PBSC donors within permissible limits. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

The incidence and risk factors for severe adverse events (SAEs) in related donors (RD) of hematopoietic cell transplants is unknown. The Related Donor Safe study is a prospective observational cohort of 1680 RDs and represents an opportunity to examine characteristics of SAEs in RDs. In this cohort, we found that SAEs were reported in a total 12 (0.71%) RDs. Of these, 5 SAEs occurred in bone marrow donors (5/404, 1.24%), and 7 (7/1276, 0.55%) were in donors of peripheral blood stem cells. All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. There were no donor fatalities. Of the 12 RDs who experienced an SAE, 10 were either overweight or obese. Five of the 12 RDs had predonation medical conditions that would have resulted in either possible or definite ineligibility for donation were they being assessed as unrelated donors. These SAE data will be useful in the counseling of prospective RDs before planned donation and may be helpful in identifying donors who should be considered medically unsuitable for donation.

Pediatric Blood & CancerVolume 68, Issue 1 e28574 LETTER TO THE EDITOR Fatal capillary leak syndrome in a child with acute lymphoblastic leukemia treated with moxetumomab pasudotox for pre-transplant minimal residual disease reduction Nirali N. Shah, Corresponding Author Nirali N. Shah Nirali.Shah@nih.gov orcid.org/0000-0002-8474-9080 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Correspondence Nirali N. Shah, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Email: Nirali.Shah@nih.govSearch for more papers by this authorJennifer Schneiderman, Jennifer Schneiderman Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IllinoisSearch for more papers by this authorDenison Kuruvilla, Denison Kuruvilla Clinical Pharmacology and Safety Sciences, AstraZeneca, San Francisco, CaliforniaSearch for more papers by this authorDeepa Bhojwani, Deepa Bhojwani Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this authorTerry J. Fry, Terry J. Fry Pediatric Oncology, Children's Hospital Colorado, Denver, ColoradoSearch for more papers by this authorPaul L. Martin, Paul L. Martin Pediatric Oncology, Duke University Medical Center, Durham, North CarolinaSearch for more papers by this authorKirk R. Schultz, Kirk R. Schultz Division of Hematology and Oncology, British Columbia Children's Hospital, Vancouver, British Columbia, CanadaSearch for more papers by this authorLewis B. Silverman, Lewis B. Silverman Pediatric Hematology and Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MassachusettsSearch for more papers by this authorJames A. Whitlock, James A. Whitlock Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorBrent Wood, Brent Wood Department of Pathology, University of Washington, Seattle, WashingtonSearch for more papers by this authorInna Vainshtein, Inna Vainshtein Clinical Pharmacology and Safety Sciences, AstraZeneca, San Francisco, CaliforniaSearch for more papers by this authorAlexia Adams, Alexia Adams National Marrow Donor Program/Be the Match, Minneapolis, MinnesotaSearch for more papers by this authorDennis Confer, Dennis Confer National Marrow Donor Program/Be the Match, Minneapolis, Minnesota Center for International Blood and Marrow Transplant Research, Minneapolis, MinnesotaSearch for more papers by this authorMichael A. Pulsipher, Michael A. Pulsipher orcid.org/0000-0003-3030-8420 Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this authorSonali Chaudhury, Sonali Chaudhury Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IllinoisSearch for more papers by this authorAlan S. Wayne, Alan S. Wayne Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this author Nirali N. Shah, Corresponding Author Nirali N. Shah Nirali.Shah@nih.gov orcid.org/0000-0002-8474-9080 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Correspondence Nirali N. Shah, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Email: Nirali.Shah@nih.govSearch for more papers by this authorJennifer Schneiderman, Jennifer Schneiderman Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IllinoisSearch for more papers by this authorDenison Kuruvilla, Denison Kuruvilla Clinical Pharmacology and Safety Sciences, AstraZeneca, San Francisco, CaliforniaSearch for more papers by this authorDeepa Bhojwani, Deepa Bhojwani Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this authorTerry J. Fry, Terry J. Fry Pediatric Oncology, Children's Hospital Colorado, Denver, ColoradoSearch for more papers by this authorPaul L. Martin, Paul L. Martin Pediatric Oncology, Duke University Medical Center, Durham, North CarolinaSearch for more papers by this authorKirk R. Schultz, Kirk R. Schultz Division of Hematology and Oncology, British Columbia Children's Hospital, Vancouver, British Columbia, CanadaSearch for more papers by this authorLewis B. Silverman, Lewis B. Silverman Pediatric Hematology and Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MassachusettsSearch for more papers by this authorJames A. Whitlock, James A. Whitlock Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorBrent Wood, Brent Wood Department of Pathology, University of Washington, Seattle, WashingtonSearch for more papers by this authorInna Vainshtein, Inna Vainshtein Clinical Pharmacology and Safety Sciences, AstraZeneca, San Francisco, CaliforniaSearch for more papers by this authorAlexia Adams, Alexia Adams National Marrow Donor Program/Be the Match, Minneapolis, MinnesotaSearch for more papers by this authorDennis Confer, Dennis Confer National Marrow Donor Program/Be the Match, Minneapolis, Minnesota Center for International Blood and Marrow Transplant Research, Minneapolis, MinnesotaSearch for more papers by this authorMichael A. Pulsipher, Michael A. Pulsipher orcid.org/0000-0003-3030-8420 Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this authorSonali Chaudhury, Sonali Chaudhury Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IllinoisSearch for more papers by this authorAlan S. Wayne, Alan S. Wayne Pediatric Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaSearch for more papers by this author First published: 22 September 2020 https://doi.org/10.1002/pbc.28574Read the full textAboutPDF 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 No abstract is available for this article. Volume68, Issue1January 2021e28574 RelatedInformation

Peripheral blood stem cells (PBSCs) have been increasingly used for allogeneic hematopoietic cell transplantation instead of bone marrow stem cells. Current National Marrow Donor Program policy recommends 5 days of daily filgrastim, followed by either 1 or 2 days of apheresis for unrelated donors, depending on collection center choice. To date, there are no published studies comparing the differences in donor experience between 1 day and 2 days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers between 2006 and 2016. Of these 22,348 donors, 20,004 (89.5%) had collection on 1 day, and the other 2344 (9.5%) had collection over 2 days. Information on why donors underwent apheresis in 1 day or 2 days was not available. Donors who underwent apheresis in 1 day were more likely to be male (67% versus 46%; P < .001), younger (age <30 years, 48% versus 36%; P < .001), and have a higher body weight (83.0 kg versus 75.9 kg; P< .001) and body mass index (BMI; >30, 30% versus 22%; P < .001). Successful collection of the requested CD34(+) cell count was achieved on the first day in 82% of 1-day collections and in 16% of 2-day collections. Despite not administering filgrastim the evening after the first day of collection in patients who underwent 2 days of apheresis, the median concentration of CD34' cells/I, in the product was higher on the second day of apheresis compared with the first day (23.8 x 10(6) CD34(+)/L. on day 1 versus 28.7 x 10(6) CD34(+)/L. on day 2; P< .001). Donors who underwent collection in 1 day were less likely to experience citrate toxicity (36% versus 52%; P< .001), hospitalization (1% versus 6%; P< .001), and other side effects related to apheresis (Modified Toxicity Criteria incidence: 20% versus 26%; P < .001). Female sex, older age, collection via central lines, and higher BMI were factors associated with greater likelihood for the development of toxicity, whereas less toxicity was noted in those with higher CD34(+) counts and more blood processed on the first day of collection. We conclude that although unrelated donors can be successfully collected in 1 day or 2 days, 1-day apheresis procedures were associated with less overall toxicity, and thus we recommend single-day collections, especially if the requested number of cells have been collected in 1 day. (C) 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy

Background: In hematopoietic cell transplantation (HCT), there is an increasing recognition of the risks of transferring clonal hematopoiesis from donors to recipients. It is unknown whether HCT centres screen for clonal hematopoiesis in related donors (RDs), and how such findings are managed. Methods: We conducted an international survey of 609 HCT centers to understand if HCT centres screen for CH, and whether candidates with this finding are excluded from donation. The survey consisted of questions about their approach to assessing otherwise healthy RDs with normal blood counts. Findings: The response rate was 280/609 (46%). Routine testing for CH is performed for monoclonal gammopathy of undetermined significance [MGUS] (18.9% of centres), monoclonal B-cell lymphocytosis [MBL] (5.0%), and gene sequencing for somatic mutations (3.6%). Bone marrow biopsies are performed in healthy RDs in 6% of responding centres, with an additional 6.7% performing this test in sub-groups, especially in older donors. Respondents recalled detecting at least one case of MGUS (17.8% of respondents), MBL (9.9%) or cytogenetic abnormalities (7.7%). Donor deferral was recommended in 62% of respondents if there were findings of MGUS, 60.4% for MBL, 74% for clonal cytogenetics, and 62.8% for somatic mutations. Interpretation: An appreciable proportion of HCT centres routinely screen for disorders of CH in blood or marrow from RDs. There is uncertainty about whether CH constitutes grounds for donor exclusion. We recommend the development of guidelines and standardization of screening for CH. Funding: Center for International Blood and Marrow Transplantation (CIBMTR) and National Marrow Donor Program (NMDP). Declaration of Interest: Dr Seftel reports reports grants from Teva, personal fees from Shire, personal fees from Pfizer, personal fees from Jazz, personal fees from Amgen, outside the submitted work. Mr. Logan does not have any competing interests. Dr. Shah does not have any competing interests. Dr. Confer does not have any competing interests. Dr. Shaw does not have any competing interests. Dr. Switzer does not have any competing interests. Dr. Pulsipher does not have any competing interests. Ms. Kiefer does not have any competing interests. Ms. Kuxhausen does not have any competing interests. Dr. Lee does not have any competing interests. Dr. Burns does not have any competing interests. Dr. Chitphakdithai does not have any competing interests. Dr. O’Donnell does not have any competing interests.Ethical Approval: This survey was approved by the National Marrow Donor Program.

Background Despite increasing donor options for allogeneic transplantation, including matched/mismatched related donors, matched unrelated donors and cord blood units, a proportion of patients do not find a donor. This is especially relevant in patients from racial/ethnic minorities. Post-transplant cyclophosphamide (PTCY) has successfully overcome barriers related to HLA-mismatching in the related donor setting. We hypothesized that transplantation with a mismatched unrelated donor (MMUD) using PTCY would be feasible and associated with high engraftment and acceptable GVHD incidence. Methods We performed a prospective Phase II study of MMUD bone marrow (BM) transplantation with PTCY for patients with hematologic malignancies. Patients with a suitable HLA matched related or URD were excluded. Patients received a fresh BM graft, followed by PTCY on days +3, +4, Sirolimus/MMF starting on Day+5. Matching for 4-7/8 at HLA-A, -B, -C, and –DRB1 was permitted. We enrolled 80 patients (40 full intensity conditioning [FIC]; 40 reduced intensity conditioning [RIC]) at 11 transplant centers in the U.S. between Dec 2016 and March 2019. Regimen intensity was at the center's discretion. Results Characteristics are shown in Table 1. Importantly, 48% of patients were non-white/Hispanic, 55% had an HCT-CI >2 and 34% had a KPS of 1 HLA allele, 59% were under 30. Overall survival and non-relapse mortality at 100 days were 92% and 5% in the FIC arm, and 90% and 7.5% in the RIC arm (Table 2). Neutrophil recovery was 98% in both arms, with no primary graft failure in the FIC arm, and 7.5% in the RIC arm. Peripheral blood donor chimerism was >75% at all timepoints. Acute GVHD grade III-IV at day 100 was relatively high at 25% in the FIC arm but very low at 2.6% in the RIC arm. Viral reactivations were high (Table 3). Conclusion These early (day 100) results of our prospective study show high rates of engraftment with acceptable rates of GVHD in recipients of MMUD transplantation with PTCY, despite a high degree of HLA mismatch. An important finding is that ethnic minorities represent almost 50% of the study population, showing that this approach expands access to patients in need of potentially curative therapy. BK and HHV-6 virus reactivation/infection were common, the clinical significance of which requires further study. Understanding the risks for and impact of graft failure and acute GVHD is being studied as follow up continues.

Background Despite international unrelated donor (URD) registries listing >36 million volunteer donors, 25-80% of U.S. patients lack an HLA-matched (8/8 alleles) URD, with greater disparities in access for ethnic minorities. We hypothesized that hematopoietic cell transplantation (HCT) with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCY), a strategy successful in overcoming genetic disparity in related haplo-identical donor HCT (haplo HCT) would be associated with similar outcomes to haplo HCT and expand access to HCT. Selecting a MMUD may have benefits over a haplo donor, such as removing risk associated with donor specific antibodies, and allowing for preferential selection of other favorable donor factors, such as younger age. Methods The NMDP/BTM performed a prospective phase II study of MMUD bone marrow (BM) HCT with PTCY for patients with hematologic malignancies, with the primary hypothesis that 1-year overall survival (OS) would be 65% or greater. Patients with a suitable HLA matched sibling or URD were excluded. Matching for 4-7/8 at HLA-A, -B, -C, and -DRB1 was permitted. 80 patients enrolled (40 myeloablative conditioning (MAC) - using cyclophosphamide/TBI (n=6), busulfan/cyclophosphamide (n=3) or fludarabine/ busulfan (n=31); 40 reduced intensity conditioning (RIC) - using fludarabine/cyclophosphamide/TBI) at 11 U.S. transplant centers between Dec 2016 and March 2019. Patients received a fresh BM graft, PTCY on days +3, +4, with sirolimus/mycophenolate mofetil starting on day +5. Regimen intensity was at the center's discretion. We compared outcomes to three groups of contemporaneous controls, all receiving PTCY, whose data was collected by CIBMTR: MMUD using peripheral blood stem cells (PBSC) (n=143), and haplo using BM (n=398) or PBSC (n=1191). All analyses used standard stepwise Cox regression modeling, performed separately for MAC and RIC cohorts. The main variable of interest was the donor/graft type (all groups compared to the trial cohort of MMUD BM). Statistical significance is p=0.05. Results The study achieved its primary endpoint with 1-year OS of 76% (90% CI: 67.3-83.3) in the entire cohort; survival and GVHD-/relapse-free survival (GRFS, defined in table 1) were 72% and 37% in the MAC cohort and 79% and 53% in the RIC cohort, respectively. Additional study outcomes are shown in Table 1. Median patient age was 49 years old (yo) (range: 18-66, MAC) and 60 yo (range: 23-70, RIC). HCT were performed for acute leukemia (n=58), MDS (n=2), lymphoma (n=17) and CLL (n=3). Disease risk index was low (n=11), intermediate (n=63), high (n=13) or very high (n=4). KPS was <90 and HCT-CI was ≥3 in 43% and 54% of patients, respectively. Notably, 48% of patients were ethnic minorities and 39% were <7/8 HLA matched with their donor. 59% of donors were <30 yo and 55% ABO matched with the recipient. Multivariate analysis comparing the study population to the comparator groups found no significant differences in OS (figure 1), GRFS, PFS, NRM or II-IV grade aGVHD in either the MAC or RIC setting, and no differences in III-IV aGVHD or relapse in the RIC setting. In the MAC setting, there was significantly lower grade III-IV aGVHD in haplo BM (HR 0.12, p=0.001), haplo PBSC (HR 0.45, p=0.026), with a trend in MMUD PBSC (HR 0.37, p=0.078), compared to the study subjects. Relapse risk was lower in haplo BM (HR 0.44, p=0.023) and haplo PBSC (HR 0.42, p=0.005), but not significantly different to MMUD PBSC (HR 0.52, p=0.119) when compared to study subjects. Additionally, younger donor age was associated with lower NRM and less aGVHD in the MAC setting and better GRFS, DFS, lower grade III-IV aGVHD, cGVHD and NRM in the RIC setting. Conclusion Our prospective study demonstrated that outcomes using MMUD in the setting of PTCY are similar to those obtained using a haplo donor. Approximately half of the study participants were ethnic minorities, a figure consistent with expectations based on donor availability within registries, but exceeding expectations in accrual to a prospective study. These results support the feasibility of using volunteer MMUDs to expand access to HCT, especially for ethnically diverse patients. Next steps include expanding the MMUD PTCY approach to incorporate PBSC as a graft source and prospectively studying questions related to selection based on donor characteristics and additional GVHD prophylaxis agents. Disclosures Shaw: Orca Bio: Consultancy. Khimani:Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Shah:Cell Vault: Research Funding; Celgene: Consultancy, Honoraria; Verastim: Consultancy; Lily: Consultancy, Honoraria; TG Therapeutics: Consultancy; Incyte: Consultancy; Miltenyi Biotec: Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria. Farhadfar:CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Hardy:Kite/Gilead: Other: Advisory Board Member; Incyte Corporation: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Kite/Gilead: Honoraria, Research Funding; Miltenyi Biotec: Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Celgene: Honoraria. Komanduri:Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Consultancy; Kiadis: Consultancy. Luznik:Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy; WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Devine:Magenta Therapeutics: Consultancy. Bolanos-Meade:Incyte: Other: DSMB Fees.

Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

Multiple investigations have documented the health-related quality-of-life (HRQoL) and donation-related experiences of unrelated donors (URDs), but similar investigations of the related donor (RD) experience have been less common. The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell (HSC) donors from predonation through 1 year postdonation. This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant/donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation. At predonation, related donors were less ambivalent about donation (t = -3.30; P = .001), more satisfied with their decision to donate (t = 2.65; P = .009), and more likely to define themselves as donors (t = 2.94; P = .004) than were URDs. However, related donors were more concerned about the use of needles (odds ratio [OR] = 2.19; P = .012), about who would pay for the procedure (OR = 2.80; P = .011), and the possibility that they would feel responsible if the transplant failed (t = 2.31; P = .022). Shortly postdonation, related donors were more likely to report donation-related pain (t = 2.50; P = .013) and lightheadedness (OR = 3.63; P = .028). At 1 year postdonation, related donors were less likely to be fully recovered from donation (OR = 0.10; P = .010) and more likely to report a longer recovery period following donation (t = 2.57; P = .011), although this latter finding was primarily due to the percentage of related versus unrelated donors not fully recovered at 1 year postdonation (10% versus 1%). Taken together, these findings suggest that current related donor management practices may be sufficient in preparing related donors for the psychological aspects of donation but that there may be more to do in terms of calibrating the description of donation-related experiences and recovery time to the related donor group (i.e., descriptions of donation experiences based on unrelated donation may not provide best estimates of experience for this group). (C) 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy

Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count >= 500/mm(3)) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n = 48) or unlicensed UCB (n = 382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.