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The safety and integrity of the blood supply is of paramount importance for delivering optimal medical care. Additionally, blood safety is of utmost importance to the United States public. Pathogen testing of donated blood products has been adapted and developed with the goal of eliminating the risk of transfusion-transmitted infectious disease. Currently, blood safety interventions are focused on excluding persons at risk for transfusion-transmissible infections from donating blood and on detecting the presence of transfusion-transmissible agents in donated blood. These interventions are intended to be complementary and function to isolate, and ideally, eliminate, the risk of exposure to known pathogenic agents by transfused blood components. We provide an overview of the strategies and techniques utilized to ensure the safety of the blood supply in the U.S. [ABSTRACT FROM AUTHOR]

Background: The most common instruments used for extracorporeal photopheresis (ECP) treatment in the United States are the UVAR XTS and the CELLEX devices (Therakos, West Chester, PA). When compared to the UVAR XTS instrument, the efficacy of the CELLEX instrument to arrest the decline in lung function in patients with chronic lung allograft dysfunction (CLAD) related to bronchiolitis obliterans (BOS) has not been previously evaluated.Methods: The relative efficacy of the CELLEX vs UVAR XTS ECP instruments was assessed by comparing the difference in rates of FEV1 decline before and after ECP treatment and survival in two series of lung allograft recipients with BOS who had been treated with these instruments.Results: Similar Slope Difference values for change in rate of decline (6 months Post ECP - Pre ECP) were observed between the two cohorts (UVAR XTS: 85 ± 109 mL/month vs CELLEX: 76 ± 128 mL/month, p=0.72). A similar percentage of patients responded to ECP (UVAR XTS: 77% vs CELLEX: 89%; p=0.36) i.e., as defined as a positive difference in slope between the rate of decline of FEV1 before and 6 months after ECP. Survival at either 6 (p=0.89) or 12 (p=0.8) months after the start of ECP was not associated with instrument used despite a trend in higher early mortality (34% vs 17%, p=0.054) in the patients who were predominately treated with the CELLEX.Conclusions: Our data support the use of the CELLEX for prospective studies designed to evaluate the merits of ECP in this population. [ABSTRACT FROM AUTHOR]

Ten hours after plasma exchange, with continuous insulin and dextrose infusion, plasma triglycerides were 186 mg/dL. GLO:1YB/01dec20:trf16016-fig-0001.jpg PHOTO (COLOR): 1 Apheresis exchange tubing cassette (Spectra Optia, Terumo BCT, Lakewood, Colorado) during therapeutic plasma exchange. The blue arrow indicates patient whole blood entering the apheresis instrument from the ECMO circuit. [Extracted from the article]

Background In pretransfusion testing at our institution, unexplained reactions are reported as antibody of undetermined specificity ( AUS) after antibodies against Food and Drug Administration-specified red blood cell antigens have been ruled out. The frequency, laboratory features, and natural history of these reactions are not well defined. Study Design and Methods We retrospectively examined AUS reported at a single institution between July 1, 2009, and December 31, 2011. For AUS reported in the first quarter of 2012, the reference workup and antibodies identified during subsequent testing were reviewed to characterize the laboratory features and natural history of AUS. Results A total of 8121 antibodies were detected in 6058 patients during the study period. AUS was reported 1442 times (18%) and was the single most reported event, followed by anti- E (18%) and anti- K (14%). In the first quarter of 2012, AUS was reported in 174 unique patients. Most AUS (78%) reacted with two cells or less tested in gel and most reactions (98%) were 1+ or weaker. Forty-five patients presenting with AUS for the first time had repeated antibody workup later. AUS persisted in 31 cases for 2 to 60 days. AUS disappeared in 14 cases, seven of which developed a total of 10 new antibodies (three anti- E; one anti- D; one anti- C; two anti- Jkb; and one each of anti- Lea, anti-s, and warm autoantibody) in 3 to 21 days (median, 8 days). Conclusion AUS is a common finding with our pretransfusion testing method. These reactions are heterogeneous and may represent antibodies against low-prevalence antigens, non- RBC antigens, or developing antibodies that are clinically significant. [ABSTRACT FROM AUTHOR]

Description: Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children. Methods: These guidelines are based on a systematic review of randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay. Recommendation 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence). Recommendation 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence). Recommendation 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence). Recommendation 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence). [ABSTRACT FROM AUTHOR]

BACKGROUND: Little information exists on the specific transfusion-related acute lung injury (TRALI) risk reduction practices used by multiple blood collecting institutions in the United States. STUDY DESIGN AND METHODS: An AABB-appointed TRALI working group designed a set of questions about TRALI risk reduction for platelets (PLTs) and plasma. AABB member institutions were asked to respond via an Internet-based survey during a 3-week period in August through September 2009. RESULTS: Valid responses were received from 47 US blood centers (accounting for 1.57 million apheresis PLT units and 3.15 million whole blood–derived transfusable plasma units) and 56 hospital blood collectors. Among the blood centers, 87 and 98% had initiated some PLT and plasma risk reduction, respectively. HLA antibody testing of plateletpheresis donors was performed by 20 (43%) blood centers. There was substantial variation in the number of pregnancies (from one to more than four) that triggered testing and most centers did not screen based on a transfusion history. Almost all centers had policies to redirect HLA antibody–positive donors to whole blood donation and to potentially retest HLA antibody–negative donors. There were no blood centers performing HNA antibody testing. Sex-based risk reduction policies for plasma included all male, or predominantly male, and never-pregnant females; these varied by blood center, blood group, and method of plasma collection. A majority of centers indicated increased production of plasma frozen within 24 hours after phlebotomy. CONCLUSIONS: Almost 3 years after the publication of the initial AABB bulletin on this issue, TRALI risk reduction strategies are commonly employed at most US blood centers. However, procedures are not uniform. [ABSTRACT FROM AUTHOR]

By early 2021, over 25,000 units of CCP were transfused every week in the United States (US) to patients with COVID-197 under conditions that varied in regard to the patient's disease severity, timing of the transfusion, and the number of units transfused. Keywords: blood center operations; FFP transfusion; transfusion practices (adult) EN blood center operations FFP transfusion transfusion practices (adult) 1313 1323 11 04/10/21 20210401 NES 210401 INTRODUCTION Convalescent plasma (CP) has been used as passive immunotherapy for the prevention and treatment of infectious diseases for more than 100 years.1,2 The lack of proven therapies during the early months of the COVID-19 pandemic, a favorable safety profile3,4 and early evidence for efficacy in adults5,6 led to the widespread use of CCP. In addition, there are specific patient populations who could possibly benefit, including pediatric patients, pregnant women, immunosuppressed patients, and other populations at high risk for development of severe or critical COVID-19 disease. As COVID cases surge, the supply of CCP has been outstripped by demand, resulting in the need for more thoughtful use so that transfusions are limited to patients for whom CCP is likely to be effective. [Extracted from the article]

Importance: Red blood cell transfusion is a common medical intervention with benefits and harms. Objective: To provide recommendations for use of red blood cell transfusion in adults and children. Evidence Review: Standards for trustworthy guidelines were followed, including using Grading of Recommendations Assessment, Development and Evaluation methods, managing conflicts of interest, and making values and preferences explicit. Evidence from systematic reviews of randomized controlled trials was reviewed. Findings: For adults, 45 randomized controlled trials with 20 599 participants compared restrictive hemoglobin-based transfusion thresholds, typically 7 to 8 g/dL, with liberal transfusion thresholds of 9 to 10 g/dL. For pediatric patients, 7 randomized controlled trials with 2730 participants compared a variety of restrictive and liberal transfusion thresholds. For most patient populations, results provided moderate quality evidence that restrictive transfusion thresholds did not adversely affect patient-important outcomes. Recommendation 1: for hospitalized adult patients who are hemodynamically stable, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). In accordance with the restrictive strategy threshold used in most trials, clinicians may choose a threshold of 7.5 g/dL for patients undergoing cardiac surgery and 8 g/dL for those undergoing orthopedic surgery or those with preexisting cardiovascular disease. Recommendation 2: for hospitalized adult patients with hematologic and oncologic disorders, the panel suggests a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (conditional recommendations, low certainty evidence). Recommendation 3: for critically ill children and those at risk of critical illness who are hemodynamically stable and without a hemoglobinopathy, cyanotic cardiac condition, or severe hypoxemia, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). Recommendation 4: for hemodynamically stable children with congenital heart disease, the international panel suggests a transfusion threshold that is based on the cardiac abnormality and stage of surgical repair: 7 g/dL (biventricular repair), 9 g/dL (single-ventricle palliation), or 7 to 9 g/dL (uncorrected congenital heart disease) (conditional recommendation, low certainty evidence). Conclusions and Relevance: It is good practice to consider overall clinical context and alternative therapies to transfusion when making transfusion decisions about an individual patient. Red blood cell transfusion threshold guidelines from the AABB transfusion medicine association have been updated to incorporate an expanded evidence base and to introduce guidance specific to children. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (auto-HSCT) improves survival in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Traditionally, filgrastim (Neupogen; recombinant G-CSF) has been used in as a single agent or in combination with plerixafor for stem cell mobilization for auto-HSCT. In Europe, a biosimilar recombinant G-CSF (Tevagrastim) has been approved for various indications similar to those of reference filgrastim, including stem cell mobilization for auto-HSCT; however, in the United States, tbo-filgrastim (Granix) is registered under the original biological application and is not approved for stem cell mobilization. In retrospective studies, stem cell mobilization with tbo-filgrastim has shown similar efficacy and toxicity as filgrastim, but no prospective studies have been published to date. We have conducted the first prospective randomized trial comparing the safety and efficacy of tbo-filgrastim in combination with plerixafor with that of filgrastim in combination with plerixafor for stem cell mobilization in patients with MM and NHL. This is a phase 2 prospective randomized (1:1) open-label single-institution noninferiority study of tbo-filgrastim and filgrastim with plerixafor in patients with MM or NHL undergoing auto-HSCT. Here 10 µg/kg/day of tbo-filgrastim/filgrastim was administered s.c. for 5 days (days 1 to 5). On day 4 at approximately 1800 hours, 0.24 mg/kg of plerixafor was administered s.c. Apheresis was performed on day 5 with a target cumulative collection goal of at least 5.0 × 10 6 CD34 + cells/kg. The primary objective was to compare day 5 CD34 +  cells/kg collected. Secondary objectives included other mobilization endpoints, safety, engraftment outcomes, and hospital readmission rate. A total of 97 evaluable patients were enrolled (tbo-filgrastim, n = 46; filgrastim, n = 51). Tbo-filgrastim was not inferior to filgrastim in terms of day 5 CD34 +  cell collection (mean, 11.6 ± 6.7 CD34 + cells/kg versus 10.0  ± 6.8 CD34 + cells/kg. Multivariate analysis revealed a trend toward increased mobilization in the tbo-filgrastim arm, but this was not statistically significant. The tbo-filgrastim and filgrastim arms were similar in all secondary endpoints. Tbo-filgrastim is not inferior in efficacy and has similar safety compared to reference filgrastim when used for stem cell mobilization in patients with MM and NHL. Granix can be safely used instead of Neupogen for stem cell collection in patients undergoing auto-HSCT for MM or NHL. The study is registered at https://clinicaltrials.gov/ct2/show/NCT02098109 . [ABSTRACT FROM AUTHOR]

Background: Surgical transfusion has an outsized impact on hospital‐based transfusion services, leading to blood product waste and unnecessary costs. The objective of this study was to design and implement a streamlined, reliable process for perioperative blood issue ordering and delivery to reduce waste. Study Design and Methods: To address the high rates of surgical blood issue requests and red blood cell (RBC) unit waste at a large academic medical center, a failure modes and effects analysis was used to systematically examine perioperative blood management practices. Based on identified failure modes (e.g., miscommunication, knowledge gaps), a multi‐component action plan was devised involving process changes, education, electronic clinical decision support, audit, and feedback. Changes in RBC unit issue requests, returns, waste, labor, and cost were measured pre‐ and post‐intervention. Results: The number of perioperative RBC unit issue requests decreased from 358 per month (SD 24) pre‐intervention to 282 per month (SD 16) post‐intervention (p <.001), resulting in an estimated savings of 8.9 h per month in blood bank staff labor. The issue‐to‐transfusion ratio decreased from 2.7 to 2.1 (p <.001). Perioperative RBC unit waste decreased from 4.5% of units issued pre‐intervention to 0.8% of units issued post‐intervention (p <.001), saving an estimated $148,543 in RBC unit acquisition costs and $546,093 in overhead costs per year. Discussion: Our intervention, designed based on a structured failure modes analysis, achieved sustained reductions in perioperative RBC unit issue orders, returns, and waste, with associated benefits for blood conservation and transfusion program costs. [ABSTRACT FROM AUTHOR]

Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by autoantibodies that preferentially react at 4°C. Laboratory testing for cold-reactive autoantibodies is laborious and may not be ordered judiciously, particularly in patients with a negative direct antiglobulin test (DAT). We sought to determine whether a negative DAT using anti-human complement (anti-C3) rules out elevated cold agglutinin (CA) titers and the diagnosis of CAD.Study Design and Methods: We performed a retrospective study of patients with a CA test performed at three major academic medical centers: Barnes-Jewish Hospital (2003-2014), Vanderbilt University Medical Center (2007-2009), and Massachusetts General Hospital (2009-2014).Results: This study included 801 patients, of whom 51% (n = 410) had a DAT within the 7 days before CA testing. A total of 98% of patients with a negative DAT using anti-C3 had a negative CA titer (<64). Only five subjects had a negative DAT using anti-C3 and an elevated CA titer.Conclusions: Overutilization of CA testing could be reduced by establishing laboratory acceptance criteria based on a positive DAT using anti-C3. Such acceptance criteria would have reduced CA testing by 68% for those with an available DAT result. [ABSTRACT FROM AUTHOR]

Description: Coronavirus disease 2019 convalescent plasma (CCP) has emerged as a potential treatment of COVID-19. However, meta-analysis data and recommendations are limited. The Association for the Advancement of Blood and Biotherapies (AABB) developed clinical practice guidelines for the appropriate use of CCP.Methods: These guidelines are based on 2 living systematic reviews of randomized controlled trials (RCTs) evaluating CCP from 1 January 2019 to 26 January 2022. There were 33 RCTs assessing 21 916 participants. The results were summarized using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. An expert panel reviewed the data using the GRADE framework to formulate recommendations.Recommendation1 (outpatient): The AABB suggests CCP transfusion in addition to the usual standard of care for outpatients with COVID-19 who are at high risk for disease progression (weak recommendation, moderate-certainty evidence).Recommendation2 (inpatient): The AABB recommends against CCP transfusion for unselected hospitalized persons with moderate or severe disease (strong recommendation, high-certainty evidence). This recommendation does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2.Recommendation3 (inpatient): The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients with COVID-19 who do not have SARS-CoV-2 antibodies detected at admission (weak recommendation, low-certainty evidence).Recommendation4 (inpatient): The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients with COVID-19 and preexisting immunosuppression (weak recommendation, low-certainty evidence).Recommendation5 (prophylaxis): The AABB suggests against prophylactic CCP transfusion for uninfected persons with close contact exposure to a person with COVID-19 (weak recommendation, low-certainty evidence).Good Clinical Practice Statement: CCP is most effective when transfused with high neutralizing titers to infected patients early after symptom onset. [ABSTRACT FROM AUTHOR]

Transfusion-transmitted cytomegalovirus (TT-CMV) is often asymptomatic, but certain patient populations, such as very low birth weight neonates, fetuses requiring intrauterine transfusion, pregnant women, patients with primary immunodeficiencies, transplant recipients, and patients receiving chemotherapy or transplantation for malignant disease, may be at risk of life-threatening CMV infection. It is unclear whether leukoreduction of cellular blood components is sufficient to reduce TT-CMV or whether CMV serological testing adds additional benefit to leukoreduction. The AABB CMV Prevention Work Group commissioned a systematic review to address these issues and subsequently develop clinical practice guidelines. However, the data were of poor quality, and no studies of significant size have been performed for over a decade. Rather than creating guidelines of questionable utility, the Work Group (with approval of the AABB Board of Directors) voted to prepare this Committee Report. There is wide variation in practices of using leukoreduced components alone or combining CMV-serology and leukoreduction to prevent TT-CMV for at-risk patients. Other approaches may also be feasible to prevent TT-CMV, including plasma nucleic acid testing, pathogen inactivation, and patient blood management programs to reduce the frequency of inappropriate transfusions. It is unlikely that future large-scale clinical trials will be performed to determine whether leukoreduction, CMV-serology, or a combination of both is superior. Consequently, alternative strategies including pragmatic randomized controlled trials, registries, and collaborations for electronic data merging, nontraditional approaches to inform evidence, or development of a systematic approach to inform expert opinion may help to address the issue of CMV-safe blood components. [ABSTRACT FROM AUTHOR]

Background Platelet ( PLT) transfusion is indicated either prophylactically or therapeutically to reduce the risk of bleeding or to control active bleeding. Significant uncertainty exists regarding the appropriate use of PLT transfusion and the optimal threshold for transfusion in various settings. We formulated 12 key questions to assess the role of PLT transfusion. Study Design and Methods We performed a systematic review ( SR) of randomized controlled trials ( RCTs) and observational studies. A comprehensive search of Pub Med, Web of Science, and Cochrane registry of controlled trials was performed. Methodologic quality of included studies was assessed and a meta-analysis was performed if more than two studies with similar designs were identified for a specific question. Results Seventeen RCTs and 55 observational studies were included in the final SR. Results from RCTs showed a beneficial effect of prophylactic compared with therapeutic transfusion for the prevention of significant bleeding in patients with hematologic disorders undergoing chemotherapy or stem cell transplantation. We found no difference in significant bleeding events related to the PLT count threshold for transfusion or the dose of PLTs transfused. Overall methodologic quality of RCTs was moderate. Results from observational studies showed no evidence that PLT transfusion prevented significant bleeding in patients undergoing central venous catheter insertions, lumbar puncture, or other surgical procedures. The methodologic quality of observational studies was very low. Conclusion We provide a comprehensive assessment of evidence on the use of PLT transfusions in a variety of clinical settings. Our report summarizes current knowledge and identifies gaps to be addressed in future research. [ABSTRACT FROM AUTHOR]

Background: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma.Methods and Findings: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects.Conclusions: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease.Trial Registration: ClinicalTrials.gov NCT#: NCT04338360. [ABSTRACT FROM AUTHOR]

BACKGROUND: Excessive use of blood components during liver transplantation should be avoided because it has been associated with poor outcomes and it may stress blood bank resources. STUDY DESIGN AND METHODS: To determine preoperative predictors of excessive transfusion requirements in patients undergoing liver transplantation, the clinical records of 126 consecutive adult patients undergoing primary liver transplantation were retrospectively reviewed. Outcome variables included number of red blood cells (RBCs), plasma, and plateletpheresis components intraoperatively transfused. Univariate analyses of the following predictor variables were performed: recipient age, sex, ethnicity, height/weight, Model for End Stage Liver Disease score, year of transplant, previous abdominal surgery, hepatoma, wait-list time, standard recipient laboratory values obtained immediately before transplantation, cold ischemia time, donor age, sex, and height/weight. Multivariate analysis using logistic regression was used to build a model that best predicted how many blood components should be available before transplant. RESULTS: Donor age of more than 50 years old (odds ratio [OR], 2.8 95% confidence interval [CI], 1.3-6.0), and recipient serum creatinine (SCr) level of more than 1.3 mg/dL (OR, 3.8 95% CI, 1.6-8.9) were the only variables found to be predictive of RBC use in multivariate analysis. This model accurately predicted the use of more than 10 units of RBCs 79% of cases. Having both adverse factors present resulted in using more than one box in 80% of cases as compared to 44% of cases where only one or no adverse factor was present (p = 0.002). Further analyses showed a direct correlation between the number of RBCs transfused and plasma (r = 0.93) and plateletpheresis components (r = 0.74) transfused. [Corrections added after online publication 22-Jul-2009: OR updated from 3.8 to 2.8; CI from 1.6-8.9 to 1.3-6.0; OR from 2.8-3.8.] CONCLUSION: Liver donor's age and recipient's SCr are important in preoperatively predicting blood use during liver transplantation. [ABSTRACT FROM AUTHOR]

Background and Objectives: ABO blood group may affect risk of SARS‐CoV‐2 infection and/or severity of COVID‐19. We sought to determine whether IgG, IgA and neutralizing antibody (nAb) to SARS‐CoV‐2 vary by ABO blood group. Materials and Methods: Among eligible convalescent plasma donors, ABO blood group was determined via agglutination of reagent A1 and B cells, IgA and IgG were quantified using the Euroimmun anti‐SARS‐CoV‐2 ELISA, and nAb titres were quantified using a microneutralization assay. Differences in titre distribution were examined by ABO blood group using non‐parametric Kruskal–Wallis tests. Adjusted prevalence ratios (aPR) of high nAb titre (≥1:160) were estimated by blood group using multivariable modified Poisson regression models that adjusted for age, sex, hospitalization status and time since SARS‐CoV‐2 diagnosis. Results: Of the 202 potential donors, 65 (32%) were blood group A, 39 (19%) were group B, 13 (6%) were group AB, and 85 (42%) were group O. Distribution of nAb titres significantly differed by ABO blood group, whereas there were no significant differences in anti‐spike IgA or anti‐spike IgG titres by ABO blood group. There were significantly more individuals with high nAb titre (≥1:160) among those with blood group B, compared with group O (aPR = 1·9 [95%CI = 1·1–3·3], P = 0·029). Fewer individuals had a high nAb titre among those with blood group A, compared with group B (aPR = 0·6 [95%CI = 0·4‐1·0], P = 0·053). Conclusion: Eligible CCP donors with blood group B may have relatively higher neutralizing antibody titres. Additional studies evaluating ABO blood groups and antibody titres that incorporate COVID‐19 severity are needed. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource. [ABSTRACT FROM AUTHOR]

Background: Two extracorporeal photopheresis (ECP) instruments, the CELLEX and the UVARXTS are currently being used "off-label" in the US for treatment of graft versus host disease (GVHD). Our study compared the performance of the two instruments in the setting of acute and chronic GVHD.Study Design and Methods: We retrospectively analyzed the outcomes of patients with steroid refractory or steroid resistant GVHD undergoing ECP at Barnes Jewish Hospital. Multivariate logistic regression was used to evaluate the comparative efficacy of the two instruments with respect to steroid dose reduction (≥50% from baseline) and clinical improvement in GVHD. Chi-square/Fisher exact tests were used to compare the incidence of adverse events, while multivariate Cox regression was employed to assess a potential difference in mortality between the two instrument treatment cohorts.Results: After adjusting for potential confounders, there was no significant difference in the odds of steroid dose reduction (OR = 1.41, 95% confidence interval [CI]: 0.51-3.90, p = 0.50) or clinical improvement (OR 2.0, 95% CI: 0.63-6.41, p = 0.24) between the two instrument treatment cohorts. The frequency of adverse events (CELLEX 45.4%; UVAR XTS 40.5%, p = 0.55) was also comparable between the cohorts. There was no significant difference in mortality of either acute or chronic GVHD patients when treated by the CELLEX as compared to the UVAR-XTS (aHR 0.66, 95% CI: 0.35-1.25, p = 0.20).Conclusion: The efficacy and safety of the two ECP instruments, the CELLEX and the UVAR-XTS, are comparable for the treatment of acute and chronic GVHD. [ABSTRACT FROM AUTHOR]

Background: A small body of literature assessing the efficacy and safety of pathogen reduced (PR) plasma has been published.Study Design and Methods: An AABB committee systematically reviewed the literature and graded the clinical trial evidence with the assistance of a GRADE expert.Results: Most studies identified were low quality and had a small sample size; in addition, efficacy and safety were monitored in many different ways making it difficult to quantify therapeutic benefit and risk. The data analyzed in this systematic review showed that pathogen inactivation did not adversely affect the efficacy of S/D or amotosalen plasma transfusions in any patient population studied. In addition, there were no significant safety issues for these patient populations, other than the specific contraindications noted in their respective package inserts.Conclusion: Larger, well-designed trials are needed to further evaluate the efficacy and safety of all of the PR plasma products. [ABSTRACT FROM AUTHOR]

CD34 + -selected stem cell boost (SCB) without conditioning has recently been utilized for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation with promising results. Unfortunately, many patients have been unable to receive the boost infusion as their donors were unwilling or unable to undergo an additional stem cell collection. Therefore, we conducted this study utilizing either fresh or cryopreserved peripheral blood stem cell products to create CD34 + -selected boost infusions for the treatment of PGF. Additionally, to explore relationship of CD34 + dose and response, we included a cohort of donors mobilized with plerixafor in addition to the standard granulocyte colony–stimulating factor (G-CSF). Twenty-six patients with PGF were included in this study. Seventeen donor-recipient pairs were enrolled onto the prospective study; an additional 9 patients treated off protocol were reviewed retrospectively. Three different donor products were used for CD34 + selection: (1) fresh mobilized product using G-CSF only, (2) fresh mobilized products using G-CSF and plerixafor, and (3) cryopreserved cells mobilized with G-CSF. CD34 + cell selection was performed using a CliniMACS. The infusion was not preceded by administration of any chemotherapy or conditioning regimen. The primary objective was hematologic response rate and secondary objectives included CD34 + yields, incidence and severity of acute and chronic graft-versus-host disease (GVHD), overall survival (OS), and relapse-free survival (RFS). The median post-selection CD34 + counts per kilogram of recipient weight were 3.1 × 10 6 , 10.9 × 10 6 , and 1 × 10 6 for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively. The median CD34 + yields (defined as the number of CD34 + cells after selection/CD34 + cells before CD34 + selection) were 69%, 66%, and 28% for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively. After SCB, 16 of the 26 recipients (62%) had a complete response, including 5 of 8 (63%) who received cryopreserved products. Five had a partial response (19%), resulting in an overall response rate of 81%. One-year RFS and OS were 50% and 65%, respectively. There was no treatment-related toxicity reported other than GVHD: 6 (23%) developed acute GVHD (2 grade I and 4 grade II) and 8 (31%) developed chronic GVHD (2 limited and 6 extensive). Cryopreserved products are viable alternatives to create SCB for the treatment of PGF. When collecting fresh products is an option, the addition of plerixafor increases CD34 + yield over G-CSF alone; however, it is currently unclear if the CD34 + cell dose impacts the efficacy of the SCB. [ABSTRACT FROM AUTHOR]

Background: Autologous hematopoietic stem cell (HSC) transplantation has been used for almost three decades for the management of malignant hematologic diseases and some solid tumors. Dimethyl sulfoxide (DMSO) is used as a cryoprotective agent for hematopoietic progenitor cells (HPCs) collected by apheresis (HPC-A). We evaluated the factors contributing to the occurrence of adverse events (AEs) of cryopreserved HPC-A infusion.Study Design and Methods: Between January 2009 and June 2014, a total of 1269 (1191 patients) consecutive HPC-A infusions were given to adult patients undergoing autologous HSC transplantation at Barnes-Jewish Hospital. Only infusions on the first day of transplant were included in the analysis.Results: AEs were reported in 480 (37.8%) infusions. The most common AEs were facial flushing in 189 (39.4%) infusions, nausea and/or vomiting in 183 (38.1%) infusions, hypoxia requiring oxygen in 139 (29%) infusions, and chest tightness in 80 (16.7%) infusions. Multivariate analysis using logistic regression showed that female sex (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40-2.26; p < 0.0001), diagnosis other than multiple myeloma (OR, 1.44; 95% CI, 1.12-1.84; p = 0.004), larger volume of infusion per body weight (OR, 1.66; 95% CI, 1.29-2.15; p < 0.0001), and number of granulocytes infused per body weight (OR, 1.30; 95% CI, 1.01-1.67; p = 0.042) were significant predictors of occurrence of AEs during infusion.Conclusion: AEs due to HPC-A infusion occurred in more than one-third of patients. Interventions need to be instituted to reduce AEs and thus improve the safety of HPC-A infusion. Many of these toxicities can be attributed to DMSO, and this is reflected in the volume of infusion. It might be warranted to consider implementing DMSO-reducing protocols before infusion. [ABSTRACT FROM AUTHOR]

Importance: More than 100 million units of blood are collected worldwide each year, yet the indication for red blood cell (RBC) transfusion and the optimal length of RBC storage prior to transfusion are uncertain.Objective: To provide recommendations for the target hemoglobin level for RBC transfusion among hospitalized adult patients who are hemodynamically stable and the length of time RBCs should be stored prior to transfusion.Evidence Review: Reference librarians conducted a literature search for randomized clinical trials (RCTs) evaluating hemoglobin thresholds for RBC transfusion (1950-May 2016) and RBC storage duration (1948-May 2016) without language restrictions. The results were summarized using the Grading of Recommendations Assessment, Development and Evaluation method. For RBC transfusion thresholds, 31 RCTs included 12 587 participants and compared restrictive thresholds (transfusion not indicated until the hemoglobin level is 7-8 g/dL) with liberal thresholds (transfusion not indicated until the hemoglobin level is 9-10 g/dL). The summary estimates across trials demonstrated that restrictive RBC transfusion thresholds were not associated with higher rates of adverse clinical outcomes, including 30-day mortality, myocardial infarction, cerebrovascular accident, rebleeding, pneumonia, or thromboembolism. For RBC storage duration, 13 RCTs included 5515 participants randomly allocated to receive fresher blood or standard-issue blood. These RCTs demonstrated that fresher blood did not improve clinical outcomes.Findings: It is good practice to consider the hemoglobin level, the overall clinical context, patient preferences, and alternative therapies when making transfusion decisions regarding an individual patient. Recommendation 1: a restrictive RBC transfusion threshold in which the transfusion is not indicated until the hemoglobin level is 7 g/dL is recommended for hospitalized adult patients who are hemodynamically stable, including critically ill patients, rather than when the hemoglobin level is 10 g/dL (strong recommendation, moderate quality evidence). A restrictive RBC transfusion threshold of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease (strong recommendation, moderate quality evidence). The restrictive transfusion threshold of 7 g/dL is likely comparable with 8 g/dL, but RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia (not recommended due to insufficient evidence). Recommendation 2: patients, including neonates, should receive RBC units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresh (storage length: <10 days) RBC units (strong recommendation, moderate quality evidence).Conclusions and Relevance: Research in RBC transfusion medicine has significantly advanced the science in recent years and provides high-quality evidence to inform guidelines. A restrictive transfusion threshold is safe in most clinical settings and the current blood banking practices of using standard-issue blood should be continued. [ABSTRACT FROM AUTHOR]

Background: Leukoreduced (LR) or cytomegalovirus (CMV)-seronegative cellular blood components are commonly used to reduce the risk of transfusion-transmitted CMV infection in high-risk patients.Study Design and Methods: We performed a systematic review and meta-analysis to evaluate the evidence for the use of LR cellular blood components with or without concurrent CMV testing of donor units in patients undergoing chemotherapy or solid organ and hematopoietic stem cell transplantation, in pregnant women, in very-low-birthweight infants, and in patients with primary immunodeficiency. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1980 through February 2015. Studies were included if they had a comparison group. Two independent reviewers selected and appraised studies. Meta-analysis was performed when appropriate.Results: Of 457 studies screened, 11 were eligible. One study was excluded from the meta-analysis because the comparison performed differed significantly from the others. Meta-analysis of five studies that compared leukoreduction to transfusing CMV-untested blood components showed no significant difference in clinical CMV infection (relative risk [RR], 0.26; 95% confidence interval [CI], 0.04-1.57) or laboratory CMV infection (RR, 0.33; 95% CI, 0.08-1.37). Meta-analysis of three studies that compared leukoreduction to transfusing CMV-seronegative cellular components showed no significant difference in laboratory CMV infection (RR, 2.18; 95% CI, 0.96-4.98). Meta-analysis of two studies that compared adding CMV testing to leukoreduction (vs. leukoreduction alone) showed no significant difference in clinical or laboratory CMV infection. The certainty in estimates was low for all comparisons.Conclusion: At present, the scientific evidence does not favor a single strategy for reducing the risk of transfusion-related CMV infection in high-risk patients. [ABSTRACT FROM AUTHOR]

To identify preoperative predictors for the use of any blood component during and after orthotopic liver transplantation (OLT), we performed a retrospective analysis on 602 OLT patients who were randomly split into a training set (n = 482) and a validation set (n = 120). Hemoglobin and calculated MELD score were identified as independent predictors for blood use using bootstrap aggregation. A logistic regression model constructed using both variables showed comparable performance in the training and validation sets. Predictive scores can be obtained from a nomogram, and a score above −2.328 predicted transfusion of any blood component with a positive predictive value of 97% and 96% in the training and validation sets, respectively. [ABSTRACT FROM AUTHOR]

Background: The AABB (formerly, the American Association of Blood Banks) developed this guideline on appropriate use of platelet transfusion in adult patients. Methods: These guidelines are based on a systematic review of randomized, clinical trials and observational studies (1900 to September 2014) that reported clinical outcomes on patients receiving prophylactic or therapeutic platelet transfusions. An expert panel reviewed the data and developed recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Recommendation 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapy-induced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 × 109 cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective. (Grade: strong recommendation; moderate-quality evidence) Recommendation 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 × 109 cells/L. (Grade: weak recommendation; low-quality evidence) Recommendation 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 × 109 cells/L. (Grade: weak recommendation; very-low-quality evidence) Recommendation 4: The AABB suggests prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than 50 × 109 cells/L. (Grade: weak recommendation; very-low-quality evidence) Recommendation 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are nonthrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. (Grade: weak recommendation; very-low-quality evidence) Recommendation 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous). (Grade: uncertain recommendation; very-low-quality evidence) [ABSTRACT FROM AUTHOR]

Background Extracorporeal photopheresis (ECP) has been used to treat chronic rejection after lung transplantation (LTx). We investigated the effect of ECP on several immune parameters that have been associated with poor lung function, including donor-specific antibodies (DSA) to human leukocyte antigen (HLA), antibodies against the lung-associated self-antigens (SAg), Kα1-tubulin (Kα1T), collagen I and V, and circulating levels of pro-inflammatory and anti-inflammatory cytokines. Methods Sera were collected from post-LTx patients diagnosed with bronchiolitis obliterans before and 6 months after initiation of ECP. DSA and cytokine levels were measured by Luminex (Invitrogen, Carlsbad, CA). Changes in lung function over the 6 months preceding and after the initiation of ECP were measured by retrospective analysis of spirometry performed at routine clinic visits. Results ECP was associated with a significant decline in DSA levels as well as antibodies to lung-associated SAg. ECP also reduced circulating levels of pro-inflammatory cytokines and increased levels of anti-inflammatory cytokines. These immunologic changes were associated with a significant 63% reduction in the rate of decline in forced expiratory volume in 1 second over a 1-year period. Though statistically insignificant, a higher rate of clearance of antibodies to lung-associated SAg was strongly associated with better response to ECP. Conclusions ECP is associated with a reduction in the levels of circulating DSA, antibodies to lung-associated SAg (Kα1T, collagen I, and collagen V), and circulating levels of several pro-inflammatory cytokines. We propose that these changes contribute to the beneficial effect of ECP in reducing the decline in lung function. [ABSTRACT FROM AUTHOR]

Background Extracorporeal photopheresis ( ECP) is commonly used to treat patients with graft-versus-host disease ( GVHD) and lung transplant rejection ( LTR) in our institution. The quantitative relationship between the number of white blood cells treated during ECP and the cell count in peripheral blood is unclear. Study Design and Methods Patients with GVHD and LTR receiving ECP with either UVAR XTS or CELLEX (Therakos) were prospectively recruited for this study. A complete cell count with differential was performed on preprocedural peripheral blood and samples from the collected buffy coats. Correlation analysis and linear regression were performed between cell counts in peripheral blood and buffy coat. Collection efficiency was compared between UVAR XTS and CELLEX. Results In all 52 patients, lymphocyte counts in buffy coat and peripheral blood showed strong correlation (r values were 0.85 and 0.983 for UVAR XTS and CELLEX, respectively; p < 0.001) with slopes of 2 and 5.1 for UVAR XTS and CELLEX, respectively (p < 0.001). The quantitative relationship remained robust in patients stratified by diagnoses. Monocytes also showed consistent correlation and linearity, but not neutrophils or combined white blood cells, red blood cells, or platelets. CELLEX enriched approximately twice as many lymphocytes and monocytes than UVAR XTS per procedure (p < 0.001). Conclusion The preprocedural peripheral lymphocyte count can predict the number of lymphocytes within the buffy coat collected during ECP, which may justify the use of peripheral lymphocyte count as a surrogate for the cell dose treated per procedure. Peripheral monocyte counts may serve as an alternative. CELLEX is more efficient in collecting lymphocytes and monocytes than UVAR XTS under conditions tested. [ABSTRACT FROM AUTHOR]

Background AABB Standards require monitoring of hematopoietic progenitor cell ( HPC) products for microbial contamination. To date, there is no automated blood culture system cleared by the Food and Drug Administration for this application. Our objective was to validate the VersaTREK system (TREK Diagnostic Systems) for sterility testing of apheresis HPC products. Study Design and Methods Four aerobic bacteria ( Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, and Bacillus cereus), five anaerobic bacteria ( Fusobacterium necrophorum, Clostridium perfringens, Bacteroides fragilis, Prevotella loescheii, and Propionibacterium acnes), and one fungus ( Candida albicans) were spiked into apheresis HPC products at concentrations of 10, 102, 103, and 104 colony-forming units (CFUs)/ mL. Aerobic and anaerobic bottles were incubated until positive or for up to 5 days. DNA was simultaneously extracted for polymerase chain reaction amplification of 16 S ribosomal RNA ( rRNA) gene. Results All aerobic bacteria grew in both bottles at all concentrations tested within 24 hours, and the time to positivity ( TTP) was significantly shorter with aerobic bottles. C. albicans grew in the aerobic media at all concentrations within 30 hours. Anaerobes grew in the anaerobic bottle at all concentrations within 5 days. No bacteria were detected by using 16 S rRNA gene amplification at 104 CFUs/ mL. Conclusion Compared to culture, 16 S rRNA gene amplification of HPCs does not improve sensitivity or turnaround time for HPC sterility testing. The VersaTREK system is a reliable tool for detecting microbial contamination of apheresis HPC products with a limit of detection of less than or equal to 10 CFUs/ mL. Inclusion of both the aerobic and the anaerobic culture bottles achieves the shortest TTP for all species tested. [ABSTRACT FROM AUTHOR]

BACKGROUND: Therapeutic plasma exchange (TPE) is the first-line therapy for patients with thrombotic thrombocytopenic purpura (TTP). However, therapeutic response to TPE and late prognosis vary among different patients, and predictors of these outcomes may help customize treatments to individual patients. STUDY DESIGN AND METHODS: We retrospectively examined the platelet (PLT) recovery rate (PRR) in 64 consecutive patients with initial episode of TTP who received TPE in our institution between 2003 and 2010. PRRs were calculated by linear regression of the PLT counts at the start and during the first few days of TPE treatment. Its relationship with remission in response to TPE, exacerbation and relapse, and survival was analyzed by univariate and multivariate analysis. RESULTS: With multivariate analysis, which included ADAMTS13 activities, patients with a PRR by Day 3 (PRR3) of 5 × 109/L per 24 hours or above were 18 times more likely to achieve remission in response to TPE than those with a lower PRR3 (p < 0.001). In addition, short-term exacerbations and relapses beyond 1 month of remission occurred almost exclusively in patients with a PRR3 of 5 × 109/L per 24 hours or above. Survival was significantly better in these patients than in patients with PRR3 below the cutoff (p < 0.001), and the hazard ratio adjusted for ADAMTS13 and age was 23.2 (p < 0.005). CONCLUSION: PRR3 with a cutoff of 5 × 109/L per 24 hours provides a practical approach to risk stratify TTP patients receiving TPE early in their treatment and may guide the decision making both at initial encounters and during the long-term follow-up. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (AlloSCT) from an HLA-matched sibling donor is the only known curative therapy in high-risk SCD patients (Talano/Cairo, EJH , 2015). Unfortunately only about 15% of high-risk SCD patients have an HLA-matched unaffected sibling donor. T cell depletion has been employed to reduce AGVHD. We reported a very low incidence of GVHD in pediatric recipients receiving CD34 enriched HPC products with PBMNC addback from MUD donors (Geyer/Cairo et al, BJH, 2012). Rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT , 2015). Recently, we reported promising results for high-risk SCD patients at 1 yr follow-up after FHI CD34 enriched/PBMNC with addback with the probability of 1-yr OS 88.2% (Cairo, et al, JAMA Peds, 2019). To investigate donor chimerism, immune reconstitution and the incidence of GVHD in high-risk SCD patients following AlloSCT using FHI CD34 enrichment/PBMNC (2 × 105 CD3/kg) addback. CD34 cells were enriched using the CliniMACS® system, kindly provided by Miltenyi Biotec, with a target dose of 10 × 106 CD34+ cells/kg. PBMNC were added back to the final CD34 product at a dose of 2 × 10*5 CD3/kg. Whole blood and CD71-enriched erythroid lineage chimerism were determined by STR. Immune cell, subset reconstitution, NK function, CD107a and granzyme B were assessed by flow cytometry as previously described (Geyer/Cairo et al. BJH , 2012, Chu/Cairo et al, Can Imm Res , 2015). The cumulative incidence of grade II-IV and late AGVHD was 6.2 % and moderate and/or severe CGVHD incidence was 6.7%, respectively (Fig. 1A). There was 100% engraftment of neutrophils and platelets. The median day post-HISCT to neutrophil and platelet engraftment was +9 and +19, respectively. Whole blood donor chimerism (mean±SEM) at 1-yr, 2-ys, and 3-ys post-HISCT was 97±1%, 97±1%, 97±1%, respectively (Fig.1B). Donor chimerism for CD71-enriched erythroid lineage cells (mean±SEM) at 1-yr, 2-yrs, 3-yrs post-HISCT was 97±2%, 98±1%, 98±1%, respectively (Fig.1B). The time to recovery of minimal normal levels for CD3 (800 cells/ul), CD4 (400 cells/ul), CD8 (200 cells/ul), & CD19 cells (200 cells/ul), was approximately 365, 365, 270, and 60 days post-HISCT, respectively (Fig.1C). NK reconstitution was rapid and peaked at d+30 (36±9%) with higher level of activating receptors NKp46, NKG2D & KIR2DS and inhibitory receptors NKG2A, CD94 and KIR2DL2/3. NK cytotoxicity against K562 (E:T = 10:1) peaked at d+30 and d+180 vs pre-transplant (p<0.01) with enhanced CD107a (Fig. 1D). The PBMNC addback facilitated rapid donor chimerism & immune reconstitution with a low probability of Grade II-IV AGVHD. The rapid NK reconstitution may have in part contributed to the excellent 1yr OS in this study (FDA R01FD004090 (MSC)). This approach is comparable to the method of CD3 TCRa/b-CD19 depletion. [ABSTRACT FROM AUTHOR]

Background We and others have previously reported the safety of allogeneic stem cell transplantation in children with SCD without sibling HLA matched bone marrow donors who commonly have SCDT. The majority of the sibling donors donated bone marrow and received G-CSF mobilized PBSCs (Bhatia/Cairo et al, BMT 2014; Gluckman et al, Blood 2017). Furthermore, only 14-18% of siblings can serve as donors based on HLA match and presence of SCD (Mentzer, Am J Ped Hem/Onc 1994; Walters, BBMT 1996). Unrelated cord blood as a donor source for SCD patients was associated with unacceptable primary graft failure rates (Radhakrishnan/Cairo, BBMT 2013). MUD HSCT resulted in unacceptably high rates of CGVHD (Shenoy et al, Blood 2016). Parental FHI SCDT PBSCs represent an alternative donor source. However, little is known about G-CSF PBSC mobilization in older donors with SCDT. GCSF mobilization of PBSC in homozygous SCD patients in the past has been reported to be associated with major toxicity and death (Adler et al, Blood 2001). Objective To determine if FHI PBSC mobilization in older adult donors with SCDT is safe and effective. Methods Eighteen FHI donors with SCDT received 15mg/kg/d GCSF divided BID x4 days. PBSC leukapheresis on day 5, repeating qd until 10 × 106 CD34/kg and 2 × 105 CD3/kg (minimum) were cryopreserved. CD34+ enrichment utilized the CliniMACS® System (generously provided by Miltenyi), with 2 × 105 CD3/kg T-cell add-back before HSCT as we have previously described (Geyer/Cairo, BJH 2011). Donor chimerism assays for whole blood CD3, CD71, and CD56 were performed post-HSCT. Results Fifteen female/3 male FHI donors with SCDT were mobilized: mean age 41 yrs (30-55). The most common donor side effect was grade 1 bone pain (n = 11). Other side effects were grade 1 nausea/vomiting (n = 3), grade 1 headache (n = 2), grade 1 dizziness (n = 1), grade 1 fatigue (n = 2), grade 1 abdominal pain (n = 2), grade 3 bone pain (n = 1), and grade 3 thrombocytopenia (n = 1). The mean ± SEM cryopreserved CD34 count was 12.9 ± 0.8 × 106/kg recipient wt with the mean ± SEM yield 533.69 ± 48.9 × 106. Mean ± SD log T-cell (CD3) depletion was 4.84 ± 0.58 (Fig. 1). 100% of patients achieved neutrophil engraftment at a median of 9 days (range 6-13), and 92.1% of patients achieved platelet engraftment at a median of 19 days (range 8-90) (Fig 2A/2B, respectively). Mean ± SEM Blood and CD71+ (RBC) donor chimerism was 97 · 1 ± 1.4 and 96 · 4 ± 2.0%, respectively. Conclusion These data suggest that adult FHI stem cell donors with SCDT undergoing GCSF mobilization for PBSC collection is safe and well-tolerated with only minor temporary adverse events. PBSC collection and CD34 enrichment was effective and resulted in successful SCD recipient engraftment and long-term donor chimerism. Further studies are needed to evaluate the long-term outcome of high-risk SCD patients undergoing FHI AlloHSCT R01FD004090. [ABSTRACT FROM AUTHOR]